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d00466fb80aff7de22564728e29ecd3543dac915 | wikidoc | C18orf63 | C18orf63
Chromosome 18 open reading frame 63 is a protein which in humans is encoded by the C18orf63 gene. This protein is not yet well understood by the scientific community. Research has been conducted suggesting that C18orf63 could be a potential biomarker for early stage pancreatic cancer and breast cancer.
# Gene
This gene is located at band 22, sub-band 3, on the long arm of chromosome 18. It is composed of 5065 base pairs spanning from 74,315,875 to 74,359,187 bp on chromosome 18. The gene has a total of 14 exons. C18orf63 is also known by the alias DKFZP78G0119. No isoforms exist for this gene.
## Expression
C18orf63 has high expression in the testis. The gene shows low expression in the kidneys, liver, lung, and pelvis. There is no phenotype associated with this gene.
## Promoter
The promoter region for C18orf63 is 1163 bp long starting at 74,314,813 bp and ending at 74,315,975 bp. The promoter ID is GXP_4417391. The presence of multiple y-box binding transcription factors and SRY transcription factor binding sites suggest that C18orf63 is involved in male sex determination.
# Protein
The C18orf63 protein is composed up of 685 amino acids and has a molecular weight of 77230.50 Da, with a predicted isoelectric point of 9.83. No isoforms exist for this protein. This protein is rich in glutamine, isoleucine, lysine, and serine when compared to the average protein, but lacks in aspartic acid and glycine.
## Structure
In the predicted secondary structure for this protein there are a number of beta turns, beta strands and alpha helices. For C18orf63 48.6% of the protein is expected to form alpha helices and 28.6% of the structure is expected to be composed of beta strands.
## Domains and Motifs
The protein contains one domain of unknown function, DUF 4709, spanning from the 7th amino acid to the 280th amino acid. Motifs that are predicted to exist include an N-terminal motif, RxxL motif, and KEN conserving motif, which all signal for protein degradation. Another motif that is predicted to exist is a Wxxx motif, which facilitates entrance of PTS1 cargo proteins into the organellar lumen, and a RVxPx motif which allows protein transport from the trans-Golgi network to the plasma membrane of the cilia. There is also a bipartite nuclear localization signal at the end of the protein sequence. There is no trans-membrane domain present, indicating that C18orf63 is not a trans-membrane protein.
## Post-Translational Modifications
Post-translational modifications the protein is predicted to undergo include SUMOylation, PKC and CK2 phosphorylation, N-glycosylation, amiditation, and cleavage. There are six total PKC phosphorylation sites and 2 CK2 phosphorylation sites, 2 SUMOylation sites, and 2 N-glycosylation sites. There are no signal peptides present in this sequence.
## Subcellular Location
Due to the nuclear localization signal at the end of the protein sequence, C18orf63 is predicted to be nuclear. C18orf63 has also been predicted to be targeted to the mitochondria in addition to the nucleus.
# Homology
## Orhologs
Orthologs have been found in most eukaryotes, with the exception of the class Amphibia. No human paralogs exist for C18orf63. The most distant homolog detectable is Mizuhopecten yessoensis, sharing a 37% identity with the human protein sequence. The domain of unknown function was the only homologous domain present in the protein sequence, it was found to be highly conserved in all orthologs. The table below shows some examples of various orthologs for this protein.
## Rate of Evolution
C18orf63 is a mildly slow evolving protein. The protein evolves faster than Cytochorme C but slower than Betaglobin.
# Interacting proteins
Transcription factors of interest predicted to bind to the regulatory sequence include p53 tumor suppressors, SRY testis determining factors, Y-box binding transcription factors, and glucocorticoid responsive elements. The JUN protein was found to interact with C18orf63 through antibait co-immunoprecipitation. The JUN protein binds to the USP28 promoter in colorectal cancer cells and is involved in the activation of these cancer cells.
# Clinical significance
## Mutations
A variety of missense mutations occur in the human population for this protein. In the regulatory sequence missense mutations occur at two transcription factor binding sites. Transcription factors affected are glucocorticoid responsive elements and E2F-myc cell cycle regulars. There are eleven common mutations that occur that affect the protein sequence itself. None of these mutations affect predicted post-translational modifications the protein sequence undergoes.
## Disease association
C18orf63 has been associated with personality disorders, obesity, and type two diabetes through a genome-wide association study. Currently research has not shown if C18orf63 plays a direct role in any of these diseases. | C18orf63
Chromosome 18 open reading frame 63 is a protein which in humans is encoded by the C18orf63 gene.[1] This protein is not yet well understood by the scientific community. Research has been conducted suggesting that C18orf63 could be a potential biomarker for early stage pancreatic cancer and breast cancer.[2][3]
# Gene
This gene is located at band 22, sub-band 3, on the long arm of chromosome 18. It is composed of 5065 base pairs spanning from 74,315,875 to 74,359,187 bp on chromosome 18.[1] The gene has a total of 14 exons.[1] C18orf63 is also known by the alias DKFZP78G0119.[4] No isoforms exist for this gene.[1]
## Expression
C18orf63 has high expression in the testis.[1] The gene shows low expression in the kidneys, liver, lung, and pelvis.[5] There is no phenotype associated with this gene.[1][6]
## Promoter
The promoter region for C18orf63 is 1163 bp long starting at 74,314,813 bp and ending at 74,315,975 bp.[7] The promoter ID is GXP_4417391. The presence of multiple y-box binding transcription factors and SRY transcription factor binding sites suggest that C18orf63 is involved in male sex determination.[8]
# Protein
The C18orf63 protein is composed up of 685 amino acids and has a molecular weight of 77230.50 Da, with a predicted isoelectric point of 9.83.[1][9] No isoforms exist for this protein.[10] This protein is rich in glutamine, isoleucine, lysine, and serine when compared to the average protein, but lacks in aspartic acid and glycine.[11][12]
## Structure
In the predicted secondary structure for this protein there are a number of beta turns, beta strands and alpha helices. For C18orf63 48.6% of the protein is expected to form alpha helices and 28.6% of the structure is expected to be composed of beta strands.[13][14]
## Domains and Motifs
The protein contains one domain of unknown function, DUF 4709, spanning from the 7th amino acid to the 280th amino acid.[15] Motifs that are predicted to exist include an N-terminal motif, RxxL motif, and KEN conserving motif, which all signal for protein degradation.[16] Another motif that is predicted to exist is a Wxxx motif, which facilitates entrance of PTS1 cargo proteins into the organellar lumen, and a RVxPx motif which allows protein transport from the trans-Golgi network to the plasma membrane of the cilia.[17][18] There is also a bipartite nuclear localization signal at the end of the protein sequence.[19] There is no trans-membrane domain present, indicating that C18orf63 is not a trans-membrane protein.[20]
## Post-Translational Modifications
Post-translational modifications the protein is predicted to undergo include SUMOylation, PKC and CK2 phosphorylation, N-glycosylation, amiditation, and cleavage.[21][22][23][24] There are six total PKC phosphorylation sites and 2 CK2 phosphorylation sites, 2 SUMOylation sites, and 2 N-glycosylation sites. There are no signal peptides present in this sequence.[24]
## Subcellular Location
Due to the nuclear localization signal at the end of the protein sequence, C18orf63 is predicted to be nuclear. C18orf63 has also been predicted to be targeted to the mitochondria in addition to the nucleus.[25][26][27]
# Homology
## Orhologs
Orthologs have been found in most eukaryotes, with the exception of the class Amphibia.[10] No human paralogs exist for C18orf63.[10][28] The most distant homolog detectable is Mizuhopecten yessoensis, sharing a 37% identity with the human protein sequence. The domain of unknown function was the only homologous domain present in the protein sequence, it was found to be highly conserved in all orthologs. The table below shows some examples of various orthologs for this protein.
## Rate of Evolution
C18orf63 is a mildly slow evolving protein. The protein evolves faster than Cytochorme C but slower than Betaglobin.[10]
# Interacting proteins
Transcription factors of interest predicted to bind to the regulatory sequence include p53 tumor suppressors, SRY testis determining factors, Y-box binding transcription factors, and glucocorticoid responsive elements.[7] The JUN protein was found to interact with C18orf63 through antibait co-immunoprecipitation.[29] The JUN protein binds to the USP28 promoter in colorectal cancer cells and is involved in the activation of these cancer cells.[30][31]
# Clinical significance
## Mutations
A variety of missense mutations occur in the human population for this protein. In the regulatory sequence missense mutations occur at two transcription factor binding sites.[28] Transcription factors affected are glucocorticoid responsive elements and E2F-myc cell cycle regulars. There are eleven common mutations that occur that affect the protein sequence itself.[28] None of these mutations affect predicted post-translational modifications the protein sequence undergoes.
## Disease association
C18orf63 has been associated with personality disorders, obesity, and type two diabetes through a genome-wide association study.[32][33][34] Currently research has not shown if C18orf63 plays a direct role in any of these diseases. | https://www.wikidoc.org/index.php/C18orf63 | |
b0a9d79b885203f49b0725ec260d915f491113cf | wikidoc | C19orf18 | C19orf18
Chromosome 19 open reading frame 18 (c19orf18) is a protein which in humans is encoded by the c19orf18 gene. The gene is exclusive to mammals and the protein is predicted to have a transmembrane domain and a coiled coil stretch. This protein has a function that is not yet fully understood by the scientific community.
# Gene
Aliases of this gene include MGC41906 and LOC147685. The gene is located on chromosome 19 at 19q13.43. The gene spans from 58,485,905 bp to 58,469,805 bp on the minus strand and contains 6 exons and 5 introns. Transcription of this gene produces one spliced mRNA which codes for the protein c19orf18.
## Expression
C19orf18 is ubiquitously expressed at moderate levels. In humans, there is higher expression in the testis, prostate, lung, liver, pancreas, uterus, heart, and other connective tissues.
# Homology
## Paralogs
There are no known paralogs of this gene in the human genome.
## Orthologs
The gene is exclusive to mammals. The transmembrane domain is the most conserved region among close orthologs and distant homologs. The following table presents some of the orthologs found using searches in BLAST. This list does not contain all of the orthologs for c19orf18. It is meant to display the diversity of species for which orthologs are found. They are sorted by date of divergence and then protein similarity.
# Protein
The coding sequence contains 215 amino acids. The molecular weight of c19orf18 is 24.151 kdal and the isoelectric point for the unphosphorylated state is 9.06. The protein sequence is rich in leucine and is deficient in tryptophan, cysteine, and tyrosine. There is a negative charge cluster from amino acid 149 to 172.
## Structure
There is a cross-program consensus between GOR4, CFSSP, and PHYRE2 that the protein structure contains mostly coiled regions and alpha helices.
### Topology
The protein sequence is predicted to contain a signal peptide (1 aa to 24 aa), an extracellular domain (25 aa to 100 aa), a transmembrane domain (101 aa to 121 aa), and a cytoplasmic domain (122 aa to 215 aa).
## Subcellular localization
PSORTII and CELLO predicted that the human protein would localize to the plasma membrane and part of it would be in the extracellular region. Immunofluorescent staining of human cell line U-2 OS shows localization to the Golgi apparatus.
## Function
### Protein interactions
C19orf18 protein has been predicted to interact with several proteins listed in the table below. The interactions have been identified and verified through affinity capture-MS.
C19orf18 protein interacts with Nedd4 family interacting protein 1 (NDFIP1) which promotes pancreatic beta cell death reduces insulin secretion. Activin A receptor type 2A (ACVR2A) is a transmembrane receptor that is involved in ligand-binding and mediates the functions of activins. Syntaxin 6 functions in trans-Golgi network vesicle trafficking, perhaps targeting to endosomes in mammalian cells. Bone morphogenetic protein receptor type 1A(BMPR1A) is expressed almost exclusively in skeletal muscle and is a transcriptional regulator. Fibroblast growth factor receptor 2 (FGFR2) plays an essential role in the regulation of osteoblast differentiation, proliferation and apoptosis, and is required for normal skeleton development. Microfibrillar-associated protein 3 (MFAP3) has a function that is not fully understood but may be involved in nuclear signaling and may play a role in metastasis.
## Clinical Significance
### Disease association
The c19orf18 protein is down-regulated in pancreatic cancer and contains CpG sites found to be replicated for association with epithelial ovarian cancer risk. The gene also decreases in expression in teratozoospermia and increases in expression in polycystic ovary syndrome. The gene may also be involved in prostate cancer and various tumors | C19orf18
Chromosome 19 open reading frame 18 (c19orf18) is a protein which in humans is encoded by the c19orf18 gene. The gene is exclusive to mammals and the protein is predicted to have a transmembrane domain and a coiled coil stretch.[1] This protein has a function that is not yet fully understood by the scientific community.
# Gene
Aliases of this gene include MGC41906 and LOC147685.[1] The gene is located on chromosome 19 at 19q13.43.[2] The gene spans from 58,485,905 bp to 58,469,805 bp on the minus strand and contains 6 exons and 5 introns.[1] Transcription of this gene produces one spliced mRNA which codes for the protein c19orf18.
## Expression
C19orf18 is ubiquitously expressed at moderate levels.[1] In humans, there is higher expression in the testis, prostate, lung, liver, pancreas, uterus, heart, and other connective tissues.[3][4]
# Homology
## Paralogs
There are no known paralogs of this gene in the human genome.[5]
## Orthologs
The gene is exclusive to mammals.[1] The transmembrane domain is the most conserved region among close orthologs and distant homologs. The following table presents some of the orthologs found using searches in BLAST.[6] This list does not contain all of the orthologs for c19orf18. It is meant to display the diversity of species for which orthologs are found. They are sorted by date of divergence and then protein similarity.
# Protein
The coding sequence contains 215 amino acids. The molecular weight of c19orf18 is 24.151 kdal and the isoelectric point for the unphosphorylated state is 9.06.[7] The protein sequence is rich in leucine and is deficient in tryptophan, cysteine, and tyrosine. There is a negative charge cluster from amino acid 149 to 172.[8]
## Structure
There is a cross-program consensus between GOR4, CFSSP, and PHYRE2 that the protein structure contains mostly coiled regions and alpha helices.[9][10][11]
### Topology
The protein sequence is predicted to contain a signal peptide (1 aa to 24 aa), an extracellular domain (25 aa to 100 aa), a transmembrane domain (101 aa to 121 aa), and a cytoplasmic domain (122 aa to 215 aa).[12]
## Subcellular localization
PSORTII and CELLO predicted that the human protein would localize to the plasma membrane and part of it would be in the extracellular region.[13][14] Immunofluorescent staining of human cell line U-2 OS shows localization to the Golgi apparatus.[15]
## Function
### Protein interactions
C19orf18 protein has been predicted to interact with several proteins listed in the table below. The interactions have been identified and verified through affinity capture-MS.[16]
C19orf18 protein interacts with Nedd4 family interacting protein 1 (NDFIP1) which promotes pancreatic beta cell death reduces insulin secretion.[17] Activin A receptor type 2A (ACVR2A) is a transmembrane receptor that is involved in ligand-binding and mediates the functions of activins.[18] Syntaxin 6 functions in trans-Golgi network vesicle trafficking, perhaps targeting to endosomes in mammalian cells.[19] Bone morphogenetic protein receptor type 1A(BMPR1A) is expressed almost exclusively in skeletal muscle and is a transcriptional regulator.[20] Fibroblast growth factor receptor 2 (FGFR2) plays an essential role in the regulation of osteoblast differentiation, proliferation and apoptosis, and is required for normal skeleton development.[21] Microfibrillar-associated protein 3 (MFAP3) has a function that is not fully understood but may be involved in nuclear signaling and may play a role in metastasis.[22]
## Clinical Significance
### Disease association
The c19orf18 protein is down-regulated in pancreatic cancer[23] and contains CpG sites found to be replicated for association with epithelial ovarian cancer risk.[24] The gene also decreases in expression in teratozoospermia[25] and increases in expression in polycystic ovary syndrome.[26] The gene may also be involved in prostate cancer and various tumors[3] | https://www.wikidoc.org/index.php/C19orf18 | |
137c2576db8156b439b31a11c5892db165d3bc9f | wikidoc | C19orf70 | C19orf70
Chromosome 19 open reading frame 70, also known as QIL1, MICOS complex subunit MIC13 (MIC13) or Protein P117 is a protein that in humans is encoded by the C19orf70 gene.
# Structure
The C19orf70 gene is located on the p arm of chromosome 19 at position 13.3 and it spans 2,482 base pairs. The C19orf70 gene produces a 9.7 kDa protein composed of 88 amino acids.
# Function
The C19orf70 gene encodes for a subunit of the MICOS (mitochondrial contact site and cristae junction organizing system) complex of the mitochondrial innner membrane. The 700-kD complex plays diverse roles such as the maintenance of crista junctions, formation of contact junctions to the outer membrane, and the dynamic regulation of mitochondrial membrane architecture. C19orf70, a component of the mature MICOS complex, localizes to the inner mitochondrial membrane at the cristae junctions and incorporates MINOS1 and MIC10 into the MICOS complex. The protein is necessary for the creation of the cristae junction, integrity of the cristae junction, and maintenance of cristae morphology. It is also essential for normal mitochondrial function.
# Clinical Significance
Mutations in C19orf70 has been shown to result in mitochondrial deficiencies and related disorders caused by the disassembly of MICOS complex with abnormal cristae morphology and failure of mitochondrial respiration. Major clinical manifestations have included mitochondrial hepato-encephalopathy and 3-methylglutaconic aciduria accompanied by severe psychomotor retardation, intractable seizures, cerebellar atrophy, early death, Lactic acidemia, neutropenia, and elevated liver transaminases.
# Interactions
C19orf70 has been known to interact with MRPL24, APOOL,STOML2,IMMT,MTX1,CHCHD3, and other proteins. | C19orf70
Chromosome 19 open reading frame 70, also known as QIL1, MICOS complex subunit MIC13 (MIC13) or Protein P117 is a protein that in humans is encoded by the C19orf70 gene.[1][2]
# Structure
The C19orf70 gene is located on the p arm of chromosome 19 at position 13.3 and it spans 2,482 base pairs.[1] The C19orf70 gene produces a 9.7 kDa protein composed of 88 amino acids.[3][4]
# Function
The C19orf70 gene encodes for a subunit of the MICOS (mitochondrial contact site and cristae junction organizing system) complex of the mitochondrial innner membrane. The 700-kD complex plays diverse roles such as the maintenance of crista junctions, formation of contact junctions to the outer membrane, and the dynamic regulation of mitochondrial membrane architecture. C19orf70, a component of the mature MICOS complex, localizes to the inner mitochondrial membrane at the cristae junctions and incorporates MINOS1 and MIC10 into the MICOS complex. The protein is necessary for the creation of the cristae junction, integrity of the cristae junction, and maintenance of cristae morphology. It is also essential for normal mitochondrial function.[5][2]
# Clinical Significance
Mutations in C19orf70 has been shown to result in mitochondrial deficiencies and related disorders caused by the disassembly of MICOS complex with abnormal cristae morphology and failure of mitochondrial respiration. Major clinical manifestations have included mitochondrial hepato-encephalopathy and 3-methylglutaconic aciduria accompanied by severe psychomotor retardation, intractable seizures, cerebellar atrophy, early death, Lactic acidemia, neutropenia, and elevated liver transaminases.[6]
# Interactions
C19orf70 has been known to interact with MRPL24, APOOL,STOML2,IMMT,MTX1,CHCHD3, and other proteins.[7][2] | https://www.wikidoc.org/index.php/C19orf70 | |
d0e6487b7bd94726e45f2875c889327fe32f83f5 | wikidoc | C1orf106 | C1orf106
Uncharacterized protein C1orf106, sometimes referred to as hypothetical protein LOC55765, is a protein of unknown function that in humans is encoded by the C1orf106 gene. Less common gene aliases include FLJ10901 and MGC125608.
# Gene
## Location
In humans, C1orf106 is located on the long arm of chromosome 1 at locus 1q32.1. It spans from 200,891,499 to 200,915,736 (24.238 kb) on the plus strand.
## Gene neighborhood
C1orf106 is flanked by G protein-coupled receptor 25 (upstream) and maestro heat-like repeat family member 3 (MROH3P), a predicted downstream pseudogene. Ribosomal protein L34 pseudogene 6 (RPL34P6) is further upstream and kinesin family member 21B is further downstream.
## Promoter
There are seven predicted promoters for C1orf106, and experimental evidence suggests that isoform 1 and 2, the most common isoforms, are transcribed using different promoters. MatInspector, a tool available through Genomatix, was used to predict transcription factor binding sites within potential promoter regions. The transcription factors that are predicted to target the anticipated promoter for isoform 1 are expressed in a range of tissues. The most common tissues of expression are the urogenital system, nervous system and bone marrow. This coincides with expression data for the C1orf106 protein, which is highly expressed in the kidney and bone marrow. A diagram of the predicted promoter region, with highlighted transcription factor binding sites, is shown to the right. The factors that are predicted to bind to the promoter region of isoform 2 differ, and twelve of the top twenty predicted factors are expressed in blood cells and/or tissues of the cardiovascular system.
## Expression
C1orf106 is expressed in a wide range of tissues. Expression data from GEO profiles is shown below. The sites of highest expression, are listed in the table.
Expression is moderate in the placenta, prostate, testis, lung, salivary glands and dendritic cells. It is low in the brain, most immune cells, the adrenal gland, uterus, heart and adipocytes. Expression data, from various experiments, found on GEO profiles suggests that C1orf106 expression is up-regulated in several cancers including: lung, ovarian, colorectal and breast.
# mRNA
## Isoforms
Nine putative isoforms are produced from the C1orf106 gene, seven of which are predicted to encode proteins. Isoform 1 and 2, shown below, are the most common isoforms.
Isoform 1, which is the longest, is accepted as the canonical isoform. It contains ten exons, which encode a protein that is 677 amino acids long, depending on the source. Some sources report that the protein is only 663 amino acids due to the use of a start codon that is forty-two nucleotides downstream. According to NCBI, this isoform has only been predicted computationally. This may be because the Kozak sequence surrounding the downstream start codon is more similar to the consensus Kozak sequence as shown in the table below. Softberry was used to obtain the sequence of the predicted isoform. Isoform 2 is shorter due to a truncated N-terminus. Both isoforms have an alternative polyadenylation site.
## miRNA regulation
miRNA-24 was identified as a microRNA that could potentially target C1orf106 mRNA.
The binding site, which is located in the 5' untranslated region is shown.
# Protein
## General properties
Isoform 1, diagramed below, contains a DUF3338 domain, two low complexity regions and a proline rich region. The protein is arginine and proline rich, and has a lower than average amount of asparagine and hydrophobic amino acids, specifically phenylalanine and isoleucine. The isoelectric point is 9.58, and the molecular weight of the unmodified protein is 72.9 kdal. The protein is not predicted to have an N-terminal signal peptide, but there are predicted nuclear localization signals (NLS) and a leucine rich nuclear export signal.
## Modifications
C1orf106 is predicted to be highly phosphorylated. Phosphoylation sites predicted by PROSITE are shown in the table below. NETPhos predictions are illustrated in the diagram. Each line points to a predicted phosphorylation site, and connects to a letter which represents either serine (S), threonine (T) or tyrosine (Y).
## Structure
Coiled-coils are predicted to span from residue 130-160 and 200-260. The secondary composition was predicted to be about 60% random coils, 30% alpha helices and 10% beta sheets.
## Interactions
The proteins with which the C1orf106 protein interacts are not well characterized. Text mining evidence suggests C1orf106 may interact with the following proteins: DNAJC5G, SLC7A13, PIEZO2, MUC19. Experimental evidence, from a yeast two hybrid screen, suggests the C1orf106 protein interacts with 14-3-3 protein sigma, which is an adaptor protein.
## Homology
C1orf106 is well conserved in vertebrates as shown in the table below. Sequences were retrieved from BLAST and BLAT.
A graph of the sequence identity versus the time since divergence for the asteriked entries is shown below. The colors correspond to degree of relatedness (green = closely related, purple = distantly related).
## Paralogs
Proteins that are considered to be C1orf106 paralogs are not consistent between databases. A multiple sequence alignment (MSA) of potentially paralogous proteins was made to determine the likelihood of a truly paralogous relationship. The sequences were retrieved from a BLAST search in humans with the C1orf106 protein. The MSA suggests the proteins share a homologous domain, DUF3338, which is found in eukaryotes. A portion of the multiple sequence alignment is shown below. Apart from the DUF domain (boxed in green), there was little conservation. The DUF3338 domain does not have any extraordinary physical properties, however, one notable finding is that each of the proteins in the MSA is predicted to have two nuclear localization signals. The proteins in the MSA are all predicted to localize to the nucleus. A comparison of the physical properties of the proteins was also conducted using SAPS and is shown in the table.
# Clinical significance
A total of 556 single nucleotide polymorphisms (SNPs) have been identified in the gene region of C1orf106, 96 of which are associated with a clinical source. Rivas et al. identified four SNPs, shown in the table below, that may be associated with inflammatory bowel disease and Crohn's disease. According to GeneCards, other disease associations may include multiple sclerosis and ulcerative colitis.
# Model organisms
Model organisms have been used in the study of C1orf106 function. A conditional knockout mouse line called 5730559C18Riktm2a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping - in-depth bone and cartilage phenotyping | C1orf106
Uncharacterized protein C1orf106, sometimes referred to as hypothetical protein LOC55765, is a protein of unknown function that in humans is encoded by the C1orf106 gene.[1] Less common gene aliases include FLJ10901 and MGC125608.
# Gene
## Location
In humans, C1orf106 is located on the long arm of chromosome 1 at locus 1q32.1. It spans from 200,891,499 to 200,915,736 (24.238 kb) on the plus strand.[1]
## Gene neighborhood
C1orf106 is flanked by G protein-coupled receptor 25 (upstream) and maestro heat-like repeat family member 3 (MROH3P), a predicted downstream pseudogene. Ribosomal protein L34 pseudogene 6 (RPL34P6) is further upstream and kinesin family member 21B is further downstream.[1]
## Promoter
There are seven predicted promoters for C1orf106, and experimental evidence suggests that isoform 1 and 2, the most common isoforms, are transcribed using different promoters.[2] MatInspector, a tool available through Genomatix, was used to predict transcription factor binding sites within potential promoter regions. The transcription factors that are predicted to target the anticipated promoter for isoform 1 are expressed in a range of tissues. The most common tissues of expression are the urogenital system, nervous system and bone marrow. This coincides with expression data for the C1orf106 protein, which is highly expressed in the kidney and bone marrow.[3] A diagram of the predicted promoter region, with highlighted transcription factor binding sites, is shown to the right. The factors that are predicted to bind to the promoter region of isoform 2 differ, and twelve of the top twenty predicted factors are expressed in blood cells and/or tissues of the cardiovascular system.
## Expression
C1orf106 is expressed in a wide range of tissues. Expression data from GEO profiles is shown below. The sites of highest expression, are listed in the table.
Expression is moderate in the placenta, prostate, testis, lung, salivary glands and dendritic cells. It is low in the brain, most immune cells, the adrenal gland, uterus, heart and adipocytes.[3] Expression data, from various experiments, found on GEO profiles suggests that C1orf106 expression is up-regulated in several cancers including: lung, ovarian, colorectal and breast.
# mRNA
## Isoforms
Nine putative isoforms are produced from the C1orf106 gene, seven of which are predicted to encode proteins.[4] Isoform 1 and 2, shown below, are the most common isoforms.
Isoform 1, which is the longest, is accepted as the canonical isoform. It contains ten exons, which encode a protein that is 677 amino acids long, depending on the source. Some sources report that the protein is only 663 amino acids due to the use of a start codon that is forty-two nucleotides downstream. According to NCBI, this isoform has only been predicted computationally.[1] This may be because the Kozak sequence surrounding the downstream start codon is more similar to the consensus Kozak sequence as shown in the table below. Softberry was used to obtain the sequence of the predicted isoform.[5] Isoform 2 is shorter due to a truncated N-terminus. Both isoforms have an alternative polyadenylation site.[4]
## miRNA regulation
miRNA-24 was identified as a microRNA that could potentially target C1orf106 mRNA.[6]
The binding site, which is located in the 5' untranslated region is shown.
# Protein
## General properties
Isoform 1, diagramed below, contains a DUF3338 domain, two low complexity regions and a proline rich region. The protein is arginine and proline rich, and has a lower than average amount of asparagine and hydrophobic amino acids, specifically phenylalanine and isoleucine.[7] The isoelectric point is 9.58, and the molecular weight of the unmodified protein is 72.9 kdal.[8] The protein is not predicted to have an N-terminal signal peptide, but there are predicted nuclear localization signals (NLS) and a leucine rich nuclear export signal.[9][10][11]
## Modifications
C1orf106 is predicted to be highly phosphorylated.[12][13] Phosphoylation sites predicted by PROSITE are shown in the table below. NETPhos predictions are illustrated in the diagram. Each line points to a predicted phosphorylation site, and connects to a letter which represents either serine (S), threonine (T) or tyrosine (Y).
## Structure
Coiled-coils are predicted to span from residue 130-160 and 200-260.[14] The secondary composition was predicted to be about 60% random coils, 30% alpha helices and 10% beta sheets.[15]
## Interactions
The proteins with which the C1orf106 protein interacts are not well characterized. Text mining evidence suggests C1orf106 may interact with the following proteins: DNAJC5G, SLC7A13, PIEZO2, MUC19.[16] Experimental evidence, from a yeast two hybrid screen, suggests the C1orf106 protein interacts with 14-3-3 protein sigma, which is an adaptor protein.[17]
## Homology
C1orf106 is well conserved in vertebrates as shown in the table below. Sequences were retrieved from BLAST[18] and BLAT.[19]
A graph of the sequence identity versus the time since divergence for the asteriked entries is shown below. The colors correspond to degree of relatedness (green = closely related, purple = distantly related).
## Paralogs
Proteins that are considered to be C1orf106 paralogs are not consistent between databases. A multiple sequence alignment (MSA) of potentially paralogous proteins was made to determine the likelihood of a truly paralogous relationship.[20] The sequences were retrieved from a BLAST search in humans with the C1orf106 protein. The MSA suggests the proteins share a homologous domain, DUF3338, which is found in eukaryotes. A portion of the multiple sequence alignment is shown below. Apart from the DUF domain (boxed in green), there was little conservation. The DUF3338 domain does not have any extraordinary physical properties, however, one notable finding is that each of the proteins in the MSA is predicted to have two nuclear localization signals. The proteins in the MSA are all predicted to localize to the nucleus.[9] A comparison of the physical properties of the proteins was also conducted using SAPS and is shown in the table.[7]
# Clinical significance
A total of 556 single nucleotide polymorphisms (SNPs) have been identified in the gene region of C1orf106, 96 of which are associated with a clinical source.[21] Rivas et al.[22] identified four SNPs, shown in the table below, that may be associated with inflammatory bowel disease and Crohn's disease. According to GeneCards, other disease associations may include multiple sclerosis and ulcerative colitis.[23]
# Model organisms
Model organisms have been used in the study of C1orf106 function. A conditional knockout mouse line called 5730559C18Riktm2a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[24] Male and female animals underwent a standardized phenotypic screen[25] to determine the effects of deletion.[26][27][28][29] Additional screens performed: - In-depth immunological phenotyping[30] - in-depth bone and cartilage phenotyping[31] | https://www.wikidoc.org/index.php/C1orf106 | |
fa143022fec3a8deb896410c2675af03145d9ba4 | wikidoc | C1orf123 | C1orf123
C1orf123 (chromosome 1 open reading frame 23) is a gene in the human genome that encodes the protein of unknown function, C1orf123.
# Gene
C1orf123 is a gene located in the human genome on the short arm of chromosome 1 at p32.2, between 53,679,771 base pairs and 53,686,289 base pairs. It is 6,519 bases long with 8 exons and encodes the C1orf123 protein, also known as UPF0587.
Gene Neighborhood
The following genes are close to C1orf123 on chromosome 1
-LRP8:This gene encodes a member of the low density lipoprotein receptor (LDLR) family, a cell surface protein that plays a role in both signal transduction and receptor-mediated endocytosis of specific ligands for lysosomal degradation.
-CPT2: This gene encodes a nuclear protein that is transported to the mitochondrial inner membrane.
-MAGOH: Encodes protein that is a component of a splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junction on
mRNAs.
-SLC1A7: Transports L-glutamate. Its associated chloride conductance may participate in visual processing.
# Protein
The C1orf123 protein is 160 amino acids in length and weighs 18.0 kdal. It has an isoelectric point of 4.73 and belongs to the domain/family DUF866 which consists of many hypothetical eukaryotic proteins of unknown function, all of them with a length around 165 residues. Aliases of the protein include FLJ20580 and UPF0587 Protein
# Homology
C1orf123 has many orthologs in close and distant species including primates, mammals, reptiles, birds, invertebrates, moss and yeast. The protein sequences are highly conserved throughout these species, although mRNA transcripts of the gene have only been found in primates. There are no paralogs of C1orf123.
# Structure
The C1orf123 protein has no transmembrane regions so is therefore likely not a transmembrane protein. Three post-translational modification sites have been experimentally found, including a phosphotyrosine, phosphoserine, and glycyl-lysine isopeptide. A portion of the 3' UTR of C1orf123 has 100% identity with the mRNA for Homo sapiens carnitine palmityoyltransferase 2 is a nuclear gene that encodes mitochondrial protein. This gene works with carnitine palmitoyltransferase I, and the encoded protein oxidizes long-chain fatty acids in the mitochondria. C1orf123 protein secondary structure has been found to be very similar to that of MAL13P1.257 protein. C1orf123 protein is thought to have seven beta-sheet regions and one alpha helix region and according to the Phyre2 program, there is 100% confidence that the structure of 95% of the C1orf123 protein matches the hypothetical protein MAL13P1.257. The MAL13P1.257 is a hypothetical conserved plasmodium protein of unknown function
# Gene expression
Various gene expression data has shown that "C1orf123" is expressed in varying amounts within the human body. It is most highly expressed in nerve and pituitary glands and not expressed in other body sites such as ear, esophagus, larynx, and tonsil. When health states were compared for the expression of "C1orf123" it was found that expression of the gene increased in adrenal tumors and decreased to below normal levels in kidney and lung tumors. For developmental stages, "C1orf123" is most highly expressed in the fetus and not at all expressed in neonates and infants. For the most part, "C1orf123" is expressed in relatively average amounts in the human body with the exception of CD34+ and CD56+NK cells where expression is twice the amount of the average. GEO profiles give some insight into the expression of "C1orf123" under varying conditions. Expression of the gene is seen to be absent under hypoxic conditions as seen in the figure below. GEO profiles also show that expression of "C1orf123" does not change in papillary thyroid cancer or chlamydia pneumonia infection.
# Clinical significance
The loss of the short arm of chromosome 1, the part of chromosome 1 that C1orf123 is located on, cause and parathyroid gland tumorigenesis resulting in hyperparathyroidism. 60% of the tumors tested showed an alteration on either 1p or the MEN1 locus or both. The conclusion of this study is that the short arm of chromosome 1 contains at least two different tumor suppressor genes involved in parathyroid tumorigenesis. | C1orf123
C1orf123 (chromosome 1 open reading frame 23) is a gene in the human genome that encodes the protein of unknown function, C1orf123.
# Gene
C1orf123 is a gene located in the human genome on the short arm of chromosome 1 at p32.2, between 53,679,771 base pairs and 53,686,289 base pairs. It is 6,519 bases long with 8 exons and encodes the C1orf123 protein, also known as UPF0587.[1]
Gene Neighborhood
The following genes are close to C1orf123 on chromosome 1
-LRP8:This gene encodes a member of the low density lipoprotein receptor (LDLR) family, a cell surface protein that plays a role in both signal transduction and receptor-mediated endocytosis of specific ligands for lysosomal degradation.[2]
-CPT2: This gene encodes a nuclear protein that is transported to the mitochondrial inner membrane.[3]
-MAGOH: Encodes protein that is a component of a splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junction on
mRNAs.[4]
-SLC1A7: Transports L-glutamate. Its associated chloride conductance may participate in visual processing.[5]
# Protein
The C1orf123 protein is 160 amino acids in length and weighs 18.0 kdal.[1] It has an isoelectric point of 4.73 and belongs to the domain/family DUF866 which consists of many hypothetical eukaryotic proteins of unknown function, all of them with a length around 165 residues.[6] Aliases of the protein include FLJ20580 and UPF0587 Protein [7]
# Homology
C1orf123 has many orthologs in close and distant species including primates, mammals, reptiles, birds, invertebrates, moss and yeast. The protein sequences are highly conserved throughout these species, although mRNA transcripts of the gene have only been found in primates. There are no paralogs of C1orf123.[8]
# Structure
The C1orf123 protein has no transmembrane regions so is therefore likely not a transmembrane protein. Three post-translational modification sites have been experimentally found, including a phosphotyrosine, phosphoserine, and glycyl-lysine isopeptide.[9] A portion of the 3' UTR of C1orf123 has 100% identity with the mRNA for Homo sapiens carnitine palmityoyltransferase 2 is a nuclear gene that encodes mitochondrial protein. This gene works with carnitine palmitoyltransferase I, and the encoded protein oxidizes long-chain fatty acids in the mitochondria.[10] C1orf123 protein secondary structure has been found to be very similar to that of MAL13P1.257 protein. C1orf123 protein is thought to have seven beta-sheet regions and one alpha helix region and according to the Phyre2 program, there is 100% confidence that the structure of 95% of the C1orf123 protein matches the hypothetical protein MAL13P1.257.[11] The MAL13P1.257 is a hypothetical conserved plasmodium protein of unknown function [12]
# Gene expression
Various gene expression data has shown that "C1orf123" is expressed in varying amounts within the human body. It is most highly expressed in nerve and pituitary glands and not expressed in other body sites such as ear, esophagus, larynx, and tonsil.[13] When health states were compared for the expression of "C1orf123" it was found that expression of the gene increased in adrenal tumors and decreased to below normal levels in kidney and lung tumors. For developmental stages, "C1orf123" is most highly expressed in the fetus and not at all expressed in neonates and infants. For the most part, "C1orf123" is expressed in relatively average amounts in the human body with the exception of CD34+ and CD56+NK cells where expression is twice the amount of the average.[14] GEO profiles give some insight into the expression of "C1orf123" under varying conditions. Expression of the gene is seen to be absent under hypoxic conditions as seen in the figure below. GEO profiles also show that expression of "C1orf123" does not change in papillary thyroid cancer or chlamydia pneumonia infection.[15]
# Clinical significance
The loss of the short arm of chromosome 1, the part of chromosome 1 that C1orf123 is located on, cause and parathyroid gland tumorigenesis resulting in hyperparathyroidism. 60% of the tumors tested showed an alteration on either 1p or the MEN1 locus or both. The conclusion of this study is that the short arm of chromosome 1 contains at least two different tumor suppressor genes involved in parathyroid tumorigenesis.[16] | https://www.wikidoc.org/index.php/C1orf123 | |
c29b69ffd5a35251a5664986be67309deaaf9120 | wikidoc | C1orf127 | C1orf127
Uncharactarized protein C1orf127 is a protein that in humans is encoded by the C1orf127 gene, the structure and function of which is poorly understood by the scientific community. C1orf127 is targeted for extracellular secretion in humans.
# Gene
C1orf127 is located on the short arm of Chromosome 1 (1p36.22), spanning 35,566 base pairs from 10946471 to 10982037. It is oriented on the minus strand of the chromosome.
# mRNA
The primary assembly has 13 exons, and yields an 823 amino acid protein product. There are two known isoforms caused by alternative splicing.
# Protein
C1orf127’s protein product is a member of the Ensembl protein family TF607005. The primary assembly weighs 89 kDa with an isoelectric point of 5.54, making it both longer and heavier than the average protein.
## Domains and Motifs
C1orf127 is contains two protein domains: DUF4556 and PHA03247, a domain in the Atrophin-1 superfamily. The functions of both domains are unknown. The protein also appears to have a cleavable signal peptide from Met1 to Pro18.
## Subcellular Localization
The protein C1orf127 is suggested to be localized to the extracellular matrix in humans.
## Post-Translational Modifications
C1orf127 undergoes N and O-linked glycosylation, and contains a number of potential phosphorylation sites.
### Protein-Protein Interactions
C1orf127 is suggested to interact with two different proteins, CCT3, a molecular chaperone, and CCT6B, also a molecular chaperone found in the testis. Because these interacting proteins are both molecular chaperones, it is possible that C1orf127 must undergo chaperone-assisted folding or unfolding.
# Expression
C1orf127 is not constitutively expressed, but it is expressed at low to medium levels in a variety of tissues. Greatest expression is observed in the stomach and pancreas. It is also thought to be expressed in certain areas of both the developing and adult brain, such as the cerebellum, as well as skeletal muscle tissue, the testis, cardiac muscle, and throughout the digestive system.
Little else is known about this gene’s expression, however a 2012 paper published in the World Journal of Gastroenterology suggested that it’s mis-expression could be used as a diagnostic marker locus in the detection of cancer
# Evolutionary History
C1orf127 has no paralogs within the human genome, however a number of orthologs have been identified, ranging across the jawed vertebrates, including a number of other mammals, marsupials, amphibians, and fish. One of the most distant ortholog identified is found in Danio rerio. Thus, the ancestor of C1orf127 likely arose around 435 MYA. | C1orf127
Uncharactarized protein C1orf127 is a protein that in humans is encoded by the C1orf127 gene, the structure and function of which is poorly understood by the scientific community. C1orf127 is targeted for extracellular secretion in humans.
# Gene
C1orf127 is located on the short arm of Chromosome 1 (1p36.22), spanning 35,566 base pairs from 10946471 to 10982037. It is oriented on the minus strand of the chromosome.
# mRNA
The primary assembly has 13 exons, and yields an 823 amino acid protein product. There are two known isoforms caused by alternative splicing.[1]
# Protein
C1orf127’s protein product is a member of the Ensembl protein family TF607005.[2] The primary assembly weighs 89 kDa with an isoelectric point of 5.54, making it both longer and heavier than the average protein.[3]
## Domains and Motifs
C1orf127 is contains two protein domains: DUF4556 and PHA03247, a domain in the Atrophin-1 superfamily.[4] The functions of both domains are unknown. The protein also appears to have a cleavable signal peptide from Met1 to Pro18.[5]
## Subcellular Localization
The protein C1orf127 is suggested to be localized to the extracellular matrix in humans.[5]
## Post-Translational Modifications
C1orf127 undergoes N and O-linked glycosylation, and contains a number of potential phosphorylation sites.
### Protein-Protein Interactions
C1orf127 is suggested to interact with two different proteins, CCT3, a molecular chaperone, and CCT6B, also a molecular chaperone found in the testis. Because these interacting proteins are both molecular chaperones, it is possible that C1orf127 must undergo chaperone-assisted folding or unfolding.
# Expression
C1orf127 is not constitutively expressed, but it is expressed at low to medium levels in a variety of tissues. Greatest expression is observed in the stomach and pancreas.[6] It is also thought to be expressed in certain areas of both the developing and adult brain, such as the cerebellum, as well as skeletal muscle tissue, the testis, cardiac muscle, and throughout the digestive system.
Little else is known about this gene’s expression, however a 2012 paper published in the World Journal of Gastroenterology suggested that it’s mis-expression could be used as a diagnostic marker locus in the detection of cancer[7]
# Evolutionary History
C1orf127 has no paralogs within the human genome, however a number of orthologs have been identified, ranging across the jawed vertebrates, including a number of other mammals, marsupials, amphibians, and fish. One of the most distant ortholog identified is found in Danio rerio. Thus, the ancestor of C1orf127 likely arose around 435 MYA. | https://www.wikidoc.org/index.php/C1orf127 | |
31e2e9c7153b0589b933c697dac37bea0f7a2fb1 | wikidoc | C1orf131 | C1orf131
Uncharacterized protein C1orf131 is a protein that in humans is encoded by the gene C1orf131. The first ortholog of this protein was discovered in humans. Subsequently, through the use of algorithms and bioinformatics, homologs of C1orf131 have been discovered in numerous species, and as a result, the name of the majority of the proteins in this protein family is Uncharacterized protein C1orf131 homolog.
# Gene
In humans C1orf131 is located on the minus strand of chromosome 1 and on the cytogenetic band 1q42.2 along with 193 other genes. Notably, the gene upstream of C1orf131 is GNPAT, and the gene downstream of C1orf131 is TRIM67. When this gene is transcribed in humans, C1orf131 most often forms an mRNA of 1458 base pairs long which is composed of seven exons. There are at least nine others alternative splice forms in humans that produce proteins. They range in size from 129 base pairs (2 exons) to 1458 base pairs (7 exons).
# Protein
In the C1orf131 protein family, the proteins are between 93 and 450 amino acids long; however, the majority tend to be between 160-295 amino acids long. They have a molecular weight between 10.6 and 49.0 kDa with the majority between 18.6 and 32.7 kDa. They have an isoelectric point between 9.6 and 11.2. Over 30 orthologs from mammals, birds and lizards have been identified as having a poly(A) RNA binding site. All orthologs in this protein family have a domain of unknown function DUF4602. The human protein has been shown to be both phosphorylated and acetylated. These proteins are lysines rich, charged amino acids (DEHKR), and basic charged amino acids (HKR). The secondary structure of these proteins primarily consist of alpha helices and coils with a small percentage of beta strands. C1orf131 has been shown to interact with ubiquitin through affinity capture followed by mass spectrometry and APP (amyloid beta (A4) precursor protein) through reconstituted complex.
# DUF4602
DUF4602 (PF15375) is generally 120+ amino acids long. There is typically only one gene that contains this DUF domain;however, the DUF domain has been identified in two different proteins in several species. In Trichuris suis DUF4602 is found in both hypothetical protein M5114_09117 and tRNA pseudouridine synthase D, and in Echinocuccus granulosus DUF4602 has been found in hypothetical protein EGR 05135 and expressed conserved protein. DUF4602 has been found primarily in eukaryotes; however, DUF4602 has been identified in the virus DRHN1, Bacillus sp. UNC41MFS5, Enterococcus faecalis, and Enterococcus faecalis 13-SD-W-01. In the C1orf131 orthologs the DUF domains are typically located in the middle of the gene toward the C-terminus side in larger proteins (250+ residues) and in smaller orthologs (160-250 residues) the DUF domain is located near the N-terminus. Also in larger orthologs there are regions of low complexity which could indicate that these proteins are intrinsically disordered proteins.
# Evolutionary history
This gene family exists only in eukaryotes. There are no paralogs of this gene; however, there are a few pseudogenes of C1orf131. Thus far they have only been found in orangutans, mouse lemurs, and sloths. When this gene family is compared to cytochrome C, a slow evolving gene, and fibrinogen gamma chain, a fast evolving gene it is shown to evolve at a faster rate than fibrinogen. | C1orf131
Uncharacterized protein C1orf131 is a protein that in humans is encoded by the gene C1orf131. The first ortholog of this protein was discovered in humans.[1][2] Subsequently, through the use of algorithms and bioinformatics, homologs of C1orf131 have been discovered in numerous species, and as a result, the name of the majority of the proteins in this protein family is Uncharacterized protein C1orf131 homolog.
# Gene
In humans C1orf131 is located on the minus strand of chromosome 1 and on the cytogenetic band 1q42.2 along with 193 other genes.[3] Notably, the gene upstream of C1orf131 is GNPAT, and the gene downstream of C1orf131 is TRIM67. When this gene is transcribed in humans, C1orf131 most often forms an mRNA of 1458 base pairs long which is composed of seven exons. There are at least nine others alternative splice forms in humans that produce proteins. They range in size from 129 base pairs (2 exons) to 1458 base pairs (7 exons).[4]
# Protein
In the C1orf131 protein family, the proteins are between 93 and 450 amino acids long; however, the majority tend to be between 160-295 amino acids long. They have a molecular weight between 10.6 and 49.0 kDa with the majority between 18.6 and 32.7 kDa. They have an isoelectric point between 9.6 and 11.2.[5] Over 30 orthologs from mammals, birds and lizards have been identified as having a poly(A) RNA binding site.[6] All orthologs in this protein family have a domain of unknown function DUF4602.[6][7] The human protein has been shown to be both phosphorylated and acetylated.[8][9][10][11][12][13] These proteins are lysines rich, charged amino acids (DEHKR), and basic charged amino acids (HKR).[14] The secondary structure of these proteins primarily consist of alpha helices and coils with a small percentage of beta strands.[15] C1orf131 has been shown to interact with ubiquitin[16] through affinity capture followed by mass spectrometry and APP (amyloid beta (A4) precursor protein)[17] through reconstituted complex.
# DUF4602
DUF4602 (PF15375) is generally 120+ amino acids long.[18] There is typically only one gene that contains this DUF domain;however, the DUF domain has been identified in two different proteins in several species. In Trichuris suis DUF4602 is found in both hypothetical protein M5114_09117 and tRNA pseudouridine synthase D, and in Echinocuccus granulosus DUF4602 has been found in hypothetical protein EGR 05135 and expressed conserved protein. DUF4602 has been found primarily in eukaryotes; however, DUF4602 has been identified in the virus DRHN1, Bacillus sp. UNC41MFS5, Enterococcus faecalis, and Enterococcus faecalis 13-SD-W-01. In the C1orf131 orthologs the DUF domains are typically located in the middle of the gene toward the C-terminus side in larger proteins (250+ residues) and in smaller orthologs (160-250 residues) the DUF domain is located near the N-terminus. Also in larger orthologs there are regions of low complexity which could indicate that these proteins are intrinsically disordered proteins.
# Evolutionary history
This gene family exists only in eukaryotes. There are no paralogs of this gene; however, there are a few pseudogenes of C1orf131. Thus far they have only been found in orangutans, mouse lemurs, and sloths.[7] When this gene family is compared to cytochrome C, a slow evolving gene,[19] and fibrinogen gamma chain, a fast evolving gene[20] it is shown to evolve at a faster rate than fibrinogen. | https://www.wikidoc.org/index.php/C1orf131 | |
e014687813302a2d3cf57622042e2ea05c5a4207 | wikidoc | C21orf58 | C21orf58
Chromosome 21 Open Reading Frame 58 (C21orf58) is a protein that in humans is encoded by the C21orf58 gene.
# Gene
## Locus
The gene is located on the minus strand of the distal half of the long arm of Chromosome 21 at 21q22.3. Transcript 1, including UTRs, is 22,740 bp and spans the chromosomal locus 46,301,130-46,323,875.
# mRNA
## Alternative Splicing
mRNA transcript variants 1-5 encode two validated protein isoforms of C21orf58. Transcript variant 1 encodes the longer, primary isoform (1) (Accession: NP_470860). Transcript variants 2-5 encode the shorter isoform (2). Isoform 2 has a distinct N-terminus in comparison to Isoform 1 resulting from the use of an alternative start codon. A domain of unknown function, DUF4587, is conserved in all variants.
# Protein
## General Properties
The primary encoded protein consists of 322 amino acids, 8 total exons, and a molecular weight of 39.0 kDa. The predicted isoelectric point is 10.06, supporting predicted nuclear localization.
## Composition
Human protein C21orf58 Isoform 1 is rich in proline and glutamine, and poor in cysteine, phenylalanine, and tyrosine. The protein is particularly tyrosine poor containing zero tyrosine residues. Isoform 1 contains 20 more positive charged residues than negative charged residues providing additional support for the predicted isoelectric point.
## Domains & Motifs
C21orf58 Isoform 1 has three conserved domains: proline-rich domain, histidine rich domain, and DUF4587. Proline-rich domain, Pro175-Pro322, is predicted to mediate protein-protein interactions. Histidine-rich repeat domain, His292-His299, is predicted to facilitate localization. The domain of unknown function, DUF4587 (Arg234- His291), is a member of pfam15248 exclusively found in eukaryotes.
C21orf58 contains a nuclear localization signal, The135-Leu144.
## Structure
Secondary structure of C21orf58 is predicted to consist primarily of random coil domains with four regions of alpha helices throughout the span of the protein. Secondary structure predictions of C21orf58 orthologs revealed similar results; random coil and four regions of alpha helices with the addition of beta-sheets throughout.
## Post-Translational Modifications
C21orf58 is predicted to undergo multiple post-translational modifications including phosphorylation, O-GlcNAc, and SUMOylation.
## Subcelluar Localization
Immunocytochemistry revealed localization of C21orf58 to nucleoplasm and nuclear bodies. Presence of a nuclear localization sequence provides further evidence for protein import into the cell nucleus.
Subcellular localization predictions for C21orf58 based on the amino acid sequence (PSORTII) suggested nuclear localization. Predictions across orthologs agreed with nuclear localization.
# Expression
## Tissue Expression Pattern
C21orf58 is constitutively expressed at low levels across various normal tissues (GDS3113), including but not limited to brain, endocrine, bone marrow, lung, and reproductive tissues.
### DNA microarray experimental data
DNA microarray analysis from various experiments showed variable C21orf58 expression in unique physiological conditions.
- An elevated level of C21orf58 expression was observed in astrocytes treated with harmane, a chemical compound associated with essential tremor (ET), compared to control (GDS2919).
- C21orf58 expression up-regulated and then down-regulated in T lymphocytes over time following exposure to Azaspiracid-1 (AZ-10), a marine phycotoxin (GDS3429).
- C21orf58 expression was found to be up-regulated in teratozoopermic individuals compared to expression in normospermic individuals (GDS2697). Teratozoospermia is a condition where sperm have abnormal morphology affecting male fertility.
C21orf58 was found to be expressed through all stages of development at similar levels throughout.
### In situ Hybridization
C21orf58 ortholog in mouse 2610028H24Rik was found to be ubiquitously expressed at high levels throughout the mouse brain.
# Regulation of Expression
## Transcriptional
The primary promoter for the longest variant of C21orf58 aligns with the start of the 5'UTR and is 1143bp in length. The predicted promoter sequence overlaps with the 5'UTR and coding sequence of Pericentrin (PCNT) on the plus strand of Chromosome 21. Predicted transcription factors are associated with regulation of the cell cycle, neurogenesis, early development, and sex determination.
# Interacting Proteins
Yeast-two hybrid screening confirmed protein-protein interactions with PNMA1, MTUS2, GRB2. Affinity Capture-MS indicated interactions with MTA2, ASH2L, and FAM199X. Two hybrid prey pooling followed by two hybrid array approach revealed interactions with Ccdc136, Ccdc125, KRT37, KRT27, KRT35, SPTA1, MKRN3, USHBP1, and KLHL20.
Predicted interactions involved proteins associated with the cytoskeleton, cell migration, histone modification, and signal transduction.
# Homology
## Paralogs
No human paralogs for C21orf58 were identified.
## Orthologs
C21orf58 orthologs were identified in bony fish but not in cartilaginous fish. The first 35 bases of DUF4587, Arg234- Pro265, were conserved across ortholog sequences. The most distantly related ortholog identified was the zebrafish.
## Molecular Evolution
The rate of C21orf58 evolution was determined through an application of the Molecular Clock Hypothesis. Through comparison with alpha fibrinogen and cytochorme C, it was determined that C21orf58 has evolved at an intermediate rate. | C21orf58
Chromosome 21 Open Reading Frame 58 (C21orf58) is a protein that in humans is encoded by the C21orf58 gene.[1]
# Gene
## Locus
The gene is located on the minus strand of the distal half of the long arm of Chromosome 21 at 21q22.3.[2] Transcript 1, including UTRs, is 22,740 bp and spans the chromosomal locus 46,301,130-46,323,875.[2]
# mRNA
## Alternative Splicing
mRNA transcript variants 1-5 encode two validated protein isoforms of C21orf58.[3][2] Transcript variant 1 encodes the longer, primary isoform (1) (Accession: NP_470860).[1] Transcript variants 2-5 encode the shorter isoform (2).[2] Isoform 2 has a distinct N-terminus in comparison to Isoform 1 resulting from the use of an alternative start codon.[2] A domain of unknown function, DUF4587, is conserved in all variants.[2]
# Protein
## General Properties
The primary encoded protein consists of 322 amino acids, 8 total exons, and a molecular weight of 39.0 kDa.[1][4][5] The predicted isoelectric point is 10.06, supporting predicted nuclear localization.[5][4]
## Composition
Human protein C21orf58 Isoform 1 is rich in proline and glutamine, and poor in cysteine, phenylalanine, and tyrosine.[5] The protein is particularly tyrosine poor containing zero tyrosine residues.[5] Isoform 1 contains 20 more positive charged residues than negative charged residues providing additional support for the predicted isoelectric point.[5]
## Domains & Motifs
C21orf58 Isoform 1 has three conserved domains: proline-rich domain, histidine rich domain, and DUF4587. Proline-rich domain, Pro175-Pro322, is predicted to mediate protein-protein interactions.[6] Histidine-rich repeat domain, His292-His299, is predicted to facilitate localization.[7][8] The domain of unknown function, DUF4587 (Arg234- His291), is a member of pfam15248 exclusively found in eukaryotes.[9]
C21orf58 contains a nuclear localization signal, The135-Leu144.[10]
## Structure
Secondary structure of C21orf58 is predicted to consist primarily of random coil domains with four regions of alpha helices throughout the span of the protein.[12][13][14] Secondary structure predictions of C21orf58 orthologs revealed similar results; random coil and four regions of alpha helices with the addition of beta-sheets throughout.[12][13][14]
## Post-Translational Modifications
C21orf58 is predicted to undergo multiple post-translational modifications including phosphorylation, O-GlcNAc, and SUMOylation.[15][16][17][18]
## Subcelluar Localization
Immunocytochemistry revealed localization of C21orf58 to nucleoplasm and nuclear bodies.[19] Presence of a nuclear localization sequence provides further evidence for protein import into the cell nucleus.[12]
Subcellular localization predictions for C21orf58 based on the amino acid sequence (PSORTII) suggested nuclear localization.[20] Predictions across orthologs agreed with nuclear localization.[20]
# Expression
## Tissue Expression Pattern
C21orf58 is constitutively expressed at low levels across various normal tissues (GDS3113), including but not limited to brain, endocrine, bone marrow, lung, and reproductive tissues.[21]
### DNA microarray experimental data
DNA microarray analysis from various experiments showed variable C21orf58 expression in unique physiological conditions.
- An elevated level of C21orf58 expression was observed in astrocytes treated with harmane, a chemical compound associated with essential tremor (ET), compared to control (GDS2919).[23]
- C21orf58 expression up-regulated and then down-regulated in T lymphocytes over time following exposure to Azaspiracid-1 (AZ-10), a marine phycotoxin (GDS3429).[24]
- C21orf58 expression was found to be up-regulated in teratozoopermic individuals compared to expression in normospermic individuals (GDS2697).[25] Teratozoospermia is a condition where sperm have abnormal morphology affecting male fertility.[26]
C21orf58 was found to be expressed through all stages of development at similar levels throughout.[27]
### In situ Hybridization
C21orf58 ortholog in mouse 2610028H24Rik was found to be ubiquitously expressed at high levels throughout the mouse brain.[28]
# Regulation of Expression
## Transcriptional
The primary promoter for the longest variant of C21orf58 aligns with the start of the 5'UTR and is 1143bp in length.[29] The predicted promoter sequence overlaps with the 5'UTR and coding sequence of Pericentrin (PCNT) on the plus strand of Chromosome 21. Predicted transcription factors are associated with regulation of the cell cycle, neurogenesis, early development, and sex determination.
# Interacting Proteins
Yeast-two hybrid screening confirmed protein-protein interactions with PNMA1, MTUS2, GRB2.[30] Affinity Capture-MS indicated interactions with MTA2, ASH2L, and FAM199X.[30] Two hybrid prey pooling followed by two hybrid array approach revealed interactions with Ccdc136, Ccdc125, KRT37, KRT27, KRT35, SPTA1, MKRN3, USHBP1, and KLHL20.[31]
Predicted interactions involved proteins associated with the cytoskeleton, cell migration, histone modification, and signal transduction.
# Homology
## Paralogs
No human paralogs for C21orf58 were identified.[47]
## Orthologs
C21orf58 orthologs were identified in bony fish but not in cartilaginous fish.[48] The first 35 bases of DUF4587, Arg234- Pro265, were conserved across ortholog sequences.[49] The most distantly related ortholog identified was the zebrafish.[48]
## Molecular Evolution
The rate of C21orf58 evolution was determined through an application of the Molecular Clock Hypothesis. Through comparison with alpha fibrinogen and cytochorme C, it was determined that C21orf58 has evolved at an intermediate rate. | https://www.wikidoc.org/index.php/C21orf58 | |
623af4c02c3fe1ec4df57174704620f88c7c520a | wikidoc | C21orf62 | C21orf62
C21orf62 is a protein that, in humans, is encoded by the C21orf62 gene. C21orf62 is found on human chromosome 21, and it is thought to be expressed in tissues of the brain and reproductive organs. Additionally, C21orf62 is highly expressed in ovarian surface epithelial cells during normal regulation, but is not expressed in cancerous ovarian surface epithelial cells.
# Gene
Common aliases of C21orf62 are C21orf120, PRED81, and B37. C21orf62 is located on chromosome 21 in humans, and is specifically at the q22.11 position. The C21orf62 gene is 4132 base pairs in length and contains five exons.
# mRNA
The mRNA sequence of C21orf62 in humans has one known isoform. This isoform is called uncharacterized protein C21orf62 isoform X1. This isoform is 458 base pairs, or 104 amino acids, in length, and it is significantly shorter than the most observed sequence of C21orf62 in humans. In addition to having an isoform, C21orf62 also has splice variants. All splice variants encode the same gene, but the differences in splice variant sequences occur in the 5' untranslated region of the mRNA sequence.
# Protein
## General protein characteristics
The C21orf62 protein in humans has a sequence that is 219 amino acids in length. The primary sequence of C21orf62 in humans has a molecular weight of 24.9 kDa and an isoelectric point of 8. When it's cleavable signal peptide, which spans amino acids 1-19, is removed, it has a molecular weight of 22.8 kDa and an isoelectric point of 7.8.
## Protein composition
C21orf62 in humans has higher cysteine and lower valine concentrations than expected compared to other human proteins. This trend, as showed in Table 1, is the same for other mammals. It does not, however, occur in taxa other than mammalia.
## Protein structure
The protein structure of C21orf62 in humans consists of a combination of alpha helices and beta sheets. Figure 1 shows a predicted structure of the protein.
## Post-translational modifications
C21orf62 has a myristoylation site from amino acid 26-31. It has a sumoylation site from amino acid 132-135. Additionally, it has a nuclear export signal from amino acid 98-104.
# Expression
## Tissue expression
C21orf62 is expressed in human tissues of the brain and reproductive organs.
## Expression level
C21orf62 in humans is moderately expressed in the brain, kidneys, pancreas, prostate, testes, and ovaries.
## Regulation of expression
C21orf62 is expressed during blastocyst, fetus, and adult states of human development. It is overexpressed during some tumor states, including pancreatic, gastrointestinal, germ cell, and glioma tumors.
# Function
The specific function of C21orf62 in humans is not yet well understood.
# Interacting proteins
C21orf62 is thought to potentially interact with nine other proteins. These interactions are shown in Table 2, and they were found through text mining.
# Clinical significance
C21orf62 over or under expression is linked to some types of cancerous cells and tumors.
# Homology
## Paralogs
There are no known paralogs of C21orf62 in humans at this time.
## Orthologs
There are currently 193 organisms that are known to be orthologs of C21orf62. The orthologs of C21orf62 are deuterostome animals in the clade Chordata. Table 3 shows a range of C21orf62 orthologs, their NCBI accession numbers, sequence lengths, and sequence identity to the C21orf62 human protein. At this time, C21orf62 is not known to have any protostome or invertebrate orthologs.
## Evolution rate
C21orf62 has an evolution rate that is faster than cytochrome C and fibrinogen. Figure 2 shows the rate of evolution of the C21orf62 gene over the past 473 million years. | C21orf62
C21orf62 is a protein that, in humans, is encoded by the C21orf62 gene.[2] C21orf62 is found on human chromosome 21, and it is thought to be expressed in tissues of the brain and reproductive organs.[3] Additionally, C21orf62 is highly expressed in ovarian surface epithelial cells during normal regulation, but is not expressed in cancerous ovarian surface epithelial cells.[3]
# Gene
Common aliases of C21orf62 are C21orf120, PRED81, and B37.[2] C21orf62 is located on chromosome 21 in humans, and is specifically at the q22.11 position.[4] The C21orf62 gene is 4132 base pairs in length and contains five exons.[2]
# mRNA[2]
The mRNA sequence of C21orf62 in humans has one known isoform. This isoform is called uncharacterized protein C21orf62 isoform X1. This isoform is 458 base pairs, or 104 amino acids, in length, and it is significantly shorter than the most observed sequence of C21orf62 in humans. In addition to having an isoform, C21orf62 also has splice variants. All splice variants encode the same gene, but the differences in splice variant sequences occur in the 5' untranslated region of the mRNA sequence.
# Protein
## General protein characteristics
The C21orf62 protein in humans has a sequence that is 219 amino acids in length.[5] The primary sequence of C21orf62 in humans has a molecular weight of 24.9 kDa and an isoelectric point of 8.[6][7] When it's cleavable signal peptide, which spans amino acids 1-19, is removed, it has a molecular weight of 22.8 kDa and an isoelectric point of 7.8.[6][7][8][9]
## Protein composition
C21orf62 in humans has higher cysteine and lower valine concentrations than expected compared to other human proteins. This trend, as showed in Table 1, is the same for other mammals. It does not, however, occur in taxa other than mammalia.[10]
## Protein structure
The protein structure of C21orf62 in humans consists of a combination of alpha helices and beta sheets.[11][12] Figure 1 shows a predicted structure of the protein.[1]
## Post-translational modifications
C21orf62 has a myristoylation site from amino acid 26-31.[13] It has a sumoylation site from amino acid 132-135.[13][14] Additionally, it has a nuclear export signal from amino acid 98-104.[15]
# Expression
## Tissue expression
C21orf62 is expressed in human tissues of the brain and reproductive organs.[2]
## Expression level
C21orf62 in humans is moderately expressed in the brain, kidneys, pancreas, prostate, testes, and ovaries.[2][16][17]
## Regulation of expression
C21orf62 is expressed during blastocyst, fetus, and adult states of human development.[16] It is overexpressed during some tumor states, including pancreatic, gastrointestinal, germ cell, and glioma tumors.[16]
# Function
The specific function of C21orf62 in humans is not yet well understood.[2]
# Interacting proteins
C21orf62 is thought to potentially interact with nine other proteins.[18] These interactions are shown in Table 2, and they were found through text mining.
# Clinical significance
C21orf62 over or under expression is linked to some types of cancerous cells and tumors.[3][16]
# Homology
## Paralogs
There are no known paralogs of C21orf62 in humans at this time.[2]
## Orthologs
There are currently 193 organisms that are known to be orthologs of C21orf62.[2] The orthologs of C21orf62 are deuterostome animals in the clade Chordata.[2] Table 3 shows a range of C21orf62 orthologs, their NCBI accession numbers, sequence lengths, and sequence identity to the C21orf62 human protein. At this time, C21orf62 is not known to have any protostome or invertebrate orthologs.[2]
## Evolution rate
C21orf62 has an evolution rate that is faster than cytochrome C and fibrinogen. Figure 2 shows the rate of evolution of the C21orf62 gene over the past 473 million years.
# External links
- Human C21orf62 genome location and C21orf62 gene details page in the UCSC Genome Browser. | https://www.wikidoc.org/index.php/C21orf62 | |
43f1c348be87ed619737eabcd43e9fb326ea55df | wikidoc | C6orf165 | C6orf165
Chromosome 6 open reading frame 165 (C6orf165) is a gene that in humans encodes a protein “DUF3508”. This protein has a function that is not currently very well understood. Other known aliases are “dJ382I10.1, UPF0704 Protein C6orf165.” In humans, the gene coding sequence is 56,501 base pairs long, with an mRNA of 2,215 base pairs, and a protein sequence of 622 amino acids. The C6orf165 gene is conserved in chimpanzee, rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, mosquito, frog, and more
C6orf165 is rarely expressed in humans, with relatively high expression in brain, lungs(trachea) and testis. The molecular weight of UPF0704 is 71,193 Da and the PI is 6.38
# Gene Locus
The C6orf165 gene is located at Chromosome 6 from 88119558-88173965(6q15). It contains 12 exons.
The genomic DNA is 54,407 base pairs long, while the longest mRNA that it produces is 2,215 bp long.
# Homology and Evolution
## Orthologs
This protein is well conserved through a series of distantly related organisms including mammals, birds, amphibians, tunicates, bony fish, lancelets, insects, and sea urchins. The list of organisms in which orthologs have been found is shown below.
## Paralogs
C6orf165 has no paralog.
## Phylogeny
The rooted phylogeny tree is shown below
# Protein
The protein that is produced by the C6orf165 gene is termed DUF3508 and is 622 amino acids long. The protein has a predicated molecular weight of 71.20 kDa and isoelectric point of 6.38.
## Domains
The C6orf165 gene protein product contains a well conserved domain DUF3508 This presumed domain is functionally uncharacterized. This domain is found in eukaryotes. This domain is about 280 amino acids in length.
## Motifs
This domain has two conserved sequence motifs: GFC and GLL.
## Post-translational modifications
The only predicted post-translational modification this protein undergo is phosphorylation after trying all tools under post translational modification category on expasy.org. Three phosphorylation site is predicted with score over 0.8.
Phosphorylation on Ser 176,Thr 232 and Ser 310 are notified on the conceptual translation.
## Secondary structure
The consensus of the prediction software PELE predicts that protein UPF0704 is dominated by alpha helices with interspersed regions of random coil.
## Location
PSORT II analysis trained on yeast data predicts that the subcellular location of this protein is most likely in the cytoplasm (56%). Less likely possibilities are in the mitochondria (21%) or in the nucleus (17%) or in vacuoles (4%).
# Gene expression
## Gene expression data
From the EST file of Unigene, the gene expression in human is not strong, the gene EST/EST in pool is really low, even low than 0.01%. These little expression is in brain, connective tissue, kidney, lungs,parathyroid,pharynx,placenta, testis and trachea. In mouse, the gene expression of C6orf165 is even lower, the gene is only expressed in two body parts, ovary and testis. In chicken, the weak expressions are in two body part, brain and testis. In zebra fish, gene expression is still low, the very weak expressions are in eye, kidney and reproductive system. In sea squirt, the expressions are in gonad, heart and neural complex.
In summary, c6orf165 is expressed conservatively in testis across the species and partially conservatively in brain or neural complex.
## Promoter
The promoter region for human c6orf165 is identified by ElDorado (at Genomatix).
In addition to this, the start codon is at the second exon of the mRNA and this indicate the first exon is spliced during the modification.
## Transcript variants
In humans, the c6orf165 gene produces 4 different transcripts, 2 of which form a protein product (one undergoes nonsense mediated decay ang the other is retained intron). The main transcript in humans is transcript ID ENST00000369562, or C6ORF165-001; it has 13 exons and 12 coding exons; the translation length is 622 residues
The second protein coding transcript in human is transcript ID ENST00000480123 or C6ORF165-002;it contains 7 exons and only 6 exons are protein coding; the translation length is 252 residues
# Interactions
Two-hybrid experiments revealed interacting proteins such as Myogenic repressor I-mf. This repressor is highly expressed in sclerotome. It inhibits the transactivation activity of the MyoD family and represses myogenesis.
rotein complex co-immunoprecipitation (Co-IP) experiments revealed interacting protein NRF1 nuclear respiratory factor 1 This gene encodes a protein that homodimerizes and functions as a transcription factor which activates the expression of some key metabolic genes regulating cellular growth and nuclear genes required for respiration, heme biosynthesis, and mitochondrial DNA transcription and replication.
Two-hybrid experiments revealed interacting protein RNF138 (ring finger protein 138), an E3 ubiquitin protein ligase.
Affinity Capture-Western reveal an interaction protein called TP73 tumor protein p73, which is a protein related to the p53 tumor protein.
# Clinical significance
C6orf165 has no currently known disease associations or mutations. | C6orf165
Chromosome 6 open reading frame 165 (C6orf165) is a gene that in humans encodes a protein “DUF3508”. This protein has a function that is not currently very well understood.[1][2] Other known aliases are “dJ382I10.1, UPF0704 Protein C6orf165.”[3] In humans, the gene coding sequence is 56,501 base pairs long, with an mRNA of 2,215 base pairs, and a protein sequence of 622 amino acids. The C6orf165 gene is conserved in chimpanzee, rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, mosquito, frog, and more[4]
C6orf165 is rarely expressed in humans, with relatively high expression in brain, lungs(trachea) and testis.[5] The molecular weight of UPF0704 is 71,193 Da [6] and the PI is 6.38[6]
# Gene Locus
The C6orf165 gene is located at Chromosome 6 from 88119558-88173965(6q15).[7] It contains 12 exons.[8]
The genomic DNA is 54,407 base pairs long, while the longest mRNA that it produces is 2,215 bp long.[8]
# Homology and Evolution
## Orthologs
This protein is well conserved through a series of distantly related organisms including mammals, birds, amphibians, tunicates, bony fish, lancelets, insects, and sea urchins. The list of organisms in which orthologs have been found is shown below.
## Paralogs
C6orf165 has no paralog.
## Phylogeny
The rooted phylogeny tree is shown below[9]
# Protein
The protein that is produced by the C6orf165 gene is termed DUF3508 and is 622 amino acids long.[10] The protein has a predicated molecular weight of 71.20 kDa and isoelectric point of 6.38.[11]
## Domains
The C6orf165 gene protein product contains a well conserved domain DUF3508[7] This presumed domain is functionally uncharacterized. This domain is found in eukaryotes. This domain is about 280 amino acids in length.[12]
## Motifs
This domain has two conserved sequence motifs: GFC and GLL.[13]
## Post-translational modifications
The only predicted post-translational modification this protein undergo is phosphorylation after trying all tools under post translational modification category on expasy.org.[14] Three phosphorylation site is predicted with score over 0.8.
Phosphorylation on Ser 176,Thr 232 and Ser 310 are notified on the conceptual translation.
## Secondary structure
The consensus of the prediction software PELE[15] predicts that protein UPF0704 is dominated by alpha helices with interspersed regions of random coil.
## Location
PSORT II analysis[16] trained on yeast data predicts that the subcellular location of this protein is most likely in the cytoplasm (56%). Less likely possibilities are in the mitochondria (21%) or in the nucleus (17%) or in vacuoles (4%).
# Gene expression
## Gene expression data
From the EST file of Unigene, the gene expression in human is not strong, the gene EST/EST in pool is really low, even low than 0.01%. These little expression is in brain, connective tissue, kidney, lungs,parathyroid,pharynx,placenta, testis and trachea. In mouse, the gene expression of C6orf165 is even lower, the gene is only expressed in two body parts, ovary and testis. In chicken, the weak expressions are in two body part, brain and testis. In zebra fish, gene expression is still low, the very weak expressions are in eye, kidney and reproductive system. In sea squirt, the expressions are in gonad, heart and neural complex.
In summary, c6orf165 is expressed conservatively in testis across the species and partially conservatively in brain or neural complex.[17]
## Promoter
The promoter region for human c6orf165 is identified by ElDorado (at Genomatix).[18]
In addition to this, the start codon is at the second exon of the mRNA and this indicate the first exon is spliced during the modification.
## Transcript variants
In humans, the c6orf165 gene produces 4 different transcripts, 2 of which form a protein product (one undergoes nonsense mediated decay ang the other is retained intron). The main transcript in humans is transcript ID ENST00000369562, or C6ORF165-001; it has 13 exons and 12 coding exons; the translation length is 622 residues[19]
The second protein coding transcript in human is transcript ID ENST00000480123 or C6ORF165-002;it contains 7 exons and only 6 exons are protein coding; the translation length is 252 residues[20]
# Interactions
Two-hybrid experiments revealed interacting proteins such as Myogenic repressor I-mf.[21] This repressor is highly expressed in sclerotome. It inhibits the transactivation activity of the MyoD family and represses myogenesis.[22]
rotein complex co-immunoprecipitation (Co-IP) experiments revealed interacting protein NRF1 nuclear respiratory factor 1[23] This gene encodes a protein that homodimerizes and functions as a transcription factor which activates the expression of some key metabolic genes regulating cellular growth and nuclear genes required for respiration, heme biosynthesis, and mitochondrial DNA transcription and replication.
Two-hybrid experiments revealed interacting protein RNF138 (ring finger protein 138),[21] an E3 ubiquitin protein ligase.
Affinity Capture-Western reveal an interaction protein called TP73 tumor protein p73,[24] which is a protein related to the p53 tumor protein.
# Clinical significance
C6orf165 has no currently known disease associations or mutations. | https://www.wikidoc.org/index.php/C6orf165 | |
4c44fe253633bbca53f4d1b44e254865e578d6cf | wikidoc | C6orf201 | C6orf201
Chromosome 6 open reading frame 201, C6orf201, is a protein that in humans is encoded by the C6orf201 gene.
In humans this gene encodes for a nuclear protein that is primarily expressed in the testis.
# Gene
In humans, the gene is 51,558 base pairs long. The transcript that produces the longest protein of 140 amino acids is translated from unprocessed mRNA that has six exons and is 1664 nucleotides in length.
C6orf201-gene
## Aliases
Chromosome 6 open reading frame 201 (C6orf201) is also referred to as: dJ1013A10.5, MGC87625, RP5-1013A10.5, and LOC404220.
## Locus
C6orf201 is located on chromosome 6 at 6p25.2 position and is encoded on the plus strand. C6orf201 is located near the FAM217A gene and the ECI2 gene.
# Conservation
C6orf201 is highly conserved in primates, is moderately conserved in other mammals, and there is also conservation in a few reptiles. There is enough conservation in mycoplasma gallinarum to suggest that there may have been a horizontal gene transfer event sometime during the evolutionary history of C6orf201. There are no paralogs or gene duplication events for C6orf201.
## Orthologs
Homolog List
## Homologous domains
C6orf201 belongs to DUF4523 (Pfam15023), a functionally uncharacterized family of proteins that is found in mammals.
# Protein
## Names
Less common names of the C6orf201 protein are: protein MGC87625, hypothetical protein LOC404220, OTTHUMP00000213693, and OTTHUMP00000213725.
## General properties/features
In humans the longest protein variant is 140 amino acids long, has a molecular weight of 16.2 kDa, and an isoelectric point of 10.88. C6orf201 is predicted to be a nuclear protein.
## Modification and Structure
C6orf201 has multiple predicted PKC and CKII phosphorylation sites in humans. The protein also has a nuclear localization signal. C6orf201 has a conserved alpha helix and a conserved beta strand in the protein.
## Protein interactions
C6orf201 interacts with SRPK1,TMEM106B, and APP.
# Expression
C6orf201 is primarily expressed in the testis of humans and is also expressed in the testis of adult mice and rats. GEO microarray data also supports expression of C6orf201 in the testis of humans and mouse.
# Clinical relevance
## Research Results
A toxicology study revealed that C6orf201 was one of the top 20 deregulated genes in monkeys that had been exposed to welding fumes for an extended period of time. Another study investigated gene expression after the use of a methylation inhibitor, C6orf201 being one of many genes investigated. | C6orf201
Chromosome 6 open reading frame 201, C6orf201, is a protein that in humans is encoded by the C6orf201 gene.[1]
In humans this gene encodes for a nuclear protein that is primarily expressed in the testis.[2][3]
# Gene
In humans, the gene is 51,558 base pairs long. The transcript that produces the longest protein of 140 amino acids is translated from unprocessed mRNA that has six exons and is 1664 nucleotides in length.[4][5]
C6orf201-gene
## Aliases
Chromosome 6 open reading frame 201 (C6orf201) is also referred to as: dJ1013A10.5, MGC87625, RP5-1013A10.5, and LOC404220.[6]
## Locus
C6orf201 is located on chromosome 6 at 6p25.2 position and is encoded on the plus strand.[7] C6orf201 is located near the FAM217A gene and the ECI2 gene.[8]
# Conservation
C6orf201 is highly conserved in primates, is moderately conserved in other mammals, and there is also conservation in a few reptiles.[9] There is enough conservation in mycoplasma gallinarum to suggest that there may have been a horizontal gene transfer event sometime during the evolutionary history of C6orf201. There are no paralogs or gene duplication events for C6orf201.
## Orthologs
Homolog List
## Homologous domains
C6orf201 belongs to DUF4523 (Pfam15023), a functionally uncharacterized family of proteins that is found in mammals.[10]
# Protein
## Names
Less common names of the C6orf201 protein are: protein MGC87625, hypothetical protein LOC404220, OTTHUMP00000213693, and OTTHUMP00000213725.[6]
## General properties/features
In humans the longest protein variant is 140 amino acids long,[11] has a molecular weight of 16.2 kDa,[12] and an isoelectric point of 10.88.[12] C6orf201 is predicted to be a nuclear protein.[3]
## Modification and Structure
C6orf201 has multiple predicted PKC and CKII phosphorylation sites in humans.[13] The protein also has a nuclear localization signal.[3] C6orf201 has a conserved alpha helix and a conserved beta strand in the protein.[12]
## Protein interactions
C6orf201 interacts with SRPK1,[14]TMEM106B,[15] and APP.[16]
# Expression
C6orf201 is primarily expressed in the testis of humans and is also expressed in the testis of adult mice and rats.[2] GEO microarray data also supports expression of C6orf201 in the testis of humans and mouse.[17][18]
# Clinical relevance
## Research Results
A toxicology study revealed that C6orf201 was one of the top 20 deregulated genes in monkeys that had been exposed to welding fumes for an extended period of time.[19] Another study investigated gene expression after the use of a methylation inhibitor, C6orf201 being one of many genes investigated.[20] | https://www.wikidoc.org/index.php/C6orf201 | |
28ba94eb4170f7e32a3cf7ca803331c35e02a71d | wikidoc | C9orf135 | C9orf135
C9orf135 is a gene that encodes a 229 amino acid protein. It is located on Chromosome 9 of the Homo sapiens genome at 9q12.21. The protein has a transmembrane domain from amino acids 124-140 and a glycosylation site at amino acid 75. C9orf135 is part of the GRCh37 gene on Chromosome 9 and is contained within the domain of unknown function superfamily 4572. Also, c9orf135 is known by the name of LOC138255 which is a description of the gene location on Chromosome 9.1.
There is some evidence associating the c9orf135 gene with premature ovarian failure. In affected women, an autosomal recessive microduplication occurs which may be linked to premature ovarian failure. A Single Nucleotide Polymorphism (SNP) the c9orf135 gene has been linked to Parkinson’s disease; a statistically significant mutation has been seen on a Manhattan plot. Further research is required to establish whether c9orf135 relates to Parkinson’s disease.
# mRNA
The mRNA of c9orf135 is 906 nucleotides in length. The 5' and 3' Untranslated regions (UTR) contain hairpin loops. The 3' UTR comprises 123 nucleotides and the 5' UTR comprises 18 nucleotides. The mRNA encodes a protein with a secondary structure composed of both beta-sheets and alpha-helices.
- Secondary structure of c9orf135
Secondary structure of c9orf135
- 5' UTR loop structure of c9orf135 of mRNA
5' UTR loop structure of c9orf135 of mRNA
- 3' UTR loop structure of c9orf135 mRNA
3' UTR loop structure of c9orf135 mRNA
# Protein
## Properties of c9orf135
It is likely that c9orf135 is a nuclear protein because it has properties that match attributes of nuclear proteins rather than secretory pathways. Furthermore, there is a nuclear localization signal (PEKVKKL) from amino acid 67 to 73 on c9orf135. C9orf135 is soluble with an average hydrophobicity of -0.772. The negative hydrophobicity value is due to its slightly acidic properties.
## Post-translational modifications
Serine phosphorylation sites were seen at amino acid positions 7, 50, 86, 98, and 194. Threonine phosphorylation occurs at 34, 129, 155, and 201. Tyrosine phosphorylation sites occur at 78, 160, 177, and 209. Also, a N-terminal acetylation site is present at amino acid 3. A Signal cleavage site is present between amino acids 11 and 12.
## Protein Interaction
PB2 interacts with c9orf135 which was found from a two-hybrid yeast assay. The information provided about PB2 (Polymerase Basic Protein 2) is that it is a viral protein that is involved with the influenza A virus. It is primarily involved in Cap stealing in which it binds the pre-mRNA cap an ultimately cleaves 10-13 nucleotides off. PB2 is also important for starting the replication of viral genomes. PB2 is also known to inhibit type 1 interferon by inhibiting the mitochondrial antiviral signalling protein MAVS.
## Mutations
Eleven different common DNA genome variants of the human c9orf135 gene have been identified. All of the mutations within those genome variants have been compiled into the following table. Mutations that were present at levels of 0.01 frequency or higher have been incorporated into the table; synonymous mutations were excluded.
# Gene Expression
c9orf135 is expressed in connective tissue and testicular tissue at high levels. It is likely that the expression of c9orf135 is expressed at low levels throughout human cells. It was also found that c9orf135 is found at significantly higher levels in the adult human umbilical cord versus the foetal human umbilical cord. Furthermore, in women with ovarian adenocarcinoma the expression of c9orf135 is much higher in the epithelial cells within the ovaries. Women with polycystic ovarian syndrome have a lower expression of c9orf135 than those people who do not have the condition.
- Fetal and Adult Umbilical cord expression
Fetal and Adult Umbilical cord expression
- Ovarian normal surface epithelia and ovarian cancer epithelial cells
Ovarian normal surface epithelia and ovarian cancer epithelial cells
- Polycystic ovarian syndrome versus obese women regarding c9orf135.
Polycystic ovarian syndrome versus obese women regarding c9orf135.
## Amino Acid Quantity
A comparison between the c9orf135 from Mus musculus (House Mouse) and Pteropus alecto (Black Flying Fox) is described here. There were no significant amino acids that differed in c9orf135 from the rest of the mouse body. However, in the Black Flying Fox, it was valine poor and tryptophan rich. As seen from the human results, the Black Flying fox only shared the tryptophan surplus results. The House Mouse and Black Flying Fox were both used because they shared 64% and 79% similarity in the c9orf135 genome respectively. Analysis demonstrates that alanine and tyrosine could predict points of interest because they both contained results differing from the rest of the human gene averages.
# Homology
c9orf135 is conserved through eukaryotes, ranging from mammals, reptiles and Annelida.
## Orthologs
The orthologs of c9orf135 were sequenced in BLAST and 20 orthologs were picked. The orthologs were all multicellular organisms and were limited to aquatic animals, reptiles, amphibians, and warm-blooded animals. Also, protists, bacteria, archea, and fungi did not have orthologs. However, no paralogs were found when c9orf135 was sequenced in BLAST. Please refer to the spreadsheet for the complete list of orthologs to c9orf135. Time tree was a program that was used to find the evolutionary branching shown in MYA There were no paralogs found for c9orf135.
## Divergence of c9orf135
A divergence comparison of c9orf135 with fast diverging cytochrome C, and slow diverging fibrinogen is shown in the chart. Overall, c9orf135 has diverged significantly quicker than fibrinogen and slightly slower than cytochrome C. | C9orf135
C9orf135 is a gene that encodes a 229 amino acid protein. It is located on Chromosome 9 of the Homo sapiens genome at 9q12.21.[1] The protein has a transmembrane domain from amino acids 124-140 and a glycosylation site at amino acid 75. C9orf135 is part of the GRCh37 gene on Chromosome 9 and is contained within the domain of unknown function superfamily 4572.[2] Also, c9orf135 is known by the name of LOC138255 which is a description of the gene location on Chromosome 9.1.[3]
There is some evidence associating the c9orf135 gene with premature ovarian failure.[4] In affected women, an autosomal recessive microduplication occurs which may be linked to premature ovarian failure. A Single Nucleotide Polymorphism (SNP) the c9orf135 gene has been linked to Parkinson’s disease; a statistically significant mutation has been seen on a Manhattan plot.[5] Further research is required to establish whether c9orf135 relates to Parkinson’s disease.[5]
# mRNA
The mRNA of c9orf135 is 906 nucleotides in length.[6] The 5' and 3' Untranslated regions (UTR) contain hairpin loops[7]. The 3' UTR comprises 123 nucleotides and the 5' UTR comprises 18 nucleotides. The mRNA encodes a protein with a secondary structure composed of both beta-sheets and alpha-helices.[8]
- Secondary structure of c9orf135
Secondary structure of c9orf135
- 5' UTR loop structure of c9orf135 of mRNA
5' UTR loop structure of c9orf135 of mRNA
- 3' UTR loop structure of c9orf135 mRNA
3' UTR loop structure of c9orf135 mRNA
# Protein
## Properties of c9orf135
It is likely that c9orf135 is a nuclear protein because it has properties that match attributes of nuclear proteins rather than secretory pathways.[9][10] Furthermore, there is a nuclear localization signal (PEKVKKL) from amino acid 67 to 73 on c9orf135.[11] C9orf135 is soluble with an average hydrophobicity of -0.772. The negative hydrophobicity value is due to its slightly acidic properties.[12]
## Post-translational modifications
Serine phosphorylation sites were seen at amino acid positions 7, 50, 86, 98, and 194. Threonine phosphorylation occurs at 34, 129, 155, and 201. Tyrosine phosphorylation sites occur at 78, 160, 177, and 209. Also, a N-terminal acetylation site is present at amino acid 3. A Signal cleavage site is present between amino acids 11 and 12.[13]
## Protein Interaction
PB2 interacts with c9orf135 which was found from a two-hybrid yeast assay. The information provided about PB2 (Polymerase Basic Protein 2) is that it is a viral protein that is involved with the influenza A virus. It is primarily involved in Cap stealing in which it binds the pre-mRNA cap an ultimately cleaves 10-13 nucleotides off. PB2 is also important for starting the replication of viral genomes. PB2 is also known to inhibit type 1 interferon by inhibiting the mitochondrial antiviral signalling protein MAVS.[14]
## Mutations
Eleven different common DNA genome variants of the human c9orf135 gene have been identified. All of the mutations within those genome variants have been compiled into the following table.[15] Mutations that were present at levels of 0.01 frequency or higher have been incorporated into the table; synonymous mutations were excluded.
# Gene Expression
c9orf135 is expressed in connective tissue and testicular tissue at high levels.[16] It is likely that the expression of c9orf135 is expressed at low levels throughout human cells. It was also found that c9orf135 is found at significantly higher levels in the adult human umbilical cord versus the foetal human umbilical cord.[17] Furthermore, in women with ovarian adenocarcinoma the expression of c9orf135 is much higher in the epithelial cells within the ovaries.[18] Women with polycystic ovarian syndrome have a lower expression of c9orf135 than those people who do not have the condition.[19]
- Fetal and Adult Umbilical cord expression
Fetal and Adult Umbilical cord expression
- Ovarian normal surface epithelia and ovarian cancer epithelial cells
Ovarian normal surface epithelia and ovarian cancer epithelial cells
- Polycystic ovarian syndrome versus obese women regarding c9orf135.
Polycystic ovarian syndrome versus obese women regarding c9orf135.
## Amino Acid Quantity
A comparison between the c9orf135 from Mus musculus (House Mouse) and Pteropus alecto (Black Flying Fox) is described here. There were no significant amino acids that differed in c9orf135 from the rest of the mouse body. However, in the Black Flying Fox, it was valine poor and tryptophan rich. As seen from the human results, the Black Flying fox only shared the tryptophan surplus results. The House Mouse and Black Flying Fox were both used because they shared 64% and 79% similarity in the c9orf135 genome respectively. Analysis demonstrates that alanine and tyrosine could predict points of interest because they both contained results differing from the rest of the human gene averages.[12]
# Homology
c9orf135 is conserved through eukaryotes, ranging from mammals, reptiles and Annelida.
## Orthologs
The orthologs of c9orf135 were sequenced in BLAST and 20 orthologs were picked. The orthologs were all multicellular organisms and were limited to aquatic animals, reptiles, amphibians, and warm-blooded animals. Also, protists, bacteria, archea, and fungi did not have orthologs. However, no paralogs were found when c9orf135 was sequenced in BLAST. Please refer to the spreadsheet for the complete list of orthologs to c9orf135. Time tree was a program that was used to find the evolutionary branching shown in MYA[20] There were no paralogs found for c9orf135.
## Divergence of c9orf135
A divergence comparison of c9orf135 with fast diverging cytochrome C, and slow diverging fibrinogen is shown in the chart. Overall, c9orf135 has diverged significantly quicker than fibrinogen and slightly slower than cytochrome C. | https://www.wikidoc.org/index.php/C9orf135 | |
6852d0f39a0a5dcab0c0666c713b347fbff7fb8a | wikidoc | C9orf152 | C9orf152
Chromosome 9 open reading frame 152 is a protein that in humans is encoded by the C9orf152 gene. The exact function of the protein is not completely understood.
# Gene
The human gene C9orf152 is located on the long (q) arm of Chromosome 9. Its cytogenetic location is 9q31.1. It has one known alias: bA470J20.2.
The DNA sequence encoding C9orf152 contains a single intron. The final mRNA consists of 2698 base pairs. Nucleotides 66-68 encode an upstream in frame stop codon.
# Evolution
C9orf152 has orthologs in mammals, birds, reptiles and amphibians. No orthologs have been detected in bony fish or in any invertebrates. The following table lists a subset of conserved orthologs.
Differences among shown orthologs suggest a slow rate of evolution.
# Protein
Chromosome 9 open reading frame 152 contains 239 amino acids. The molecular weight is 26.3 kilodaltons. The protein has a high chance of existing nuclear region of cells. There are likely no transmembrane regions. One isoform exists, containing 194 amino acids.
Within the coding sequence, there are two sumoylation sites and a single serine phosphorylation site.
There are three regions predicted to form alpha helices on the final protein.
# Expression
C9orf152 is expressed in the bladder, intestine, mammary gland, and trachea and in smaller amounts in the lungs, liver, prostate, uterus, and brain. Within the brain, expression of C9orf152 is limited to the olfactory bulb. Gene expression was found to increase in the presence of stress, including disease and heat stress.
A wide variety of transcription factors interact with the promoter of C9orf152, most notably two olfactory related factors (specifically, a neuron-specific olfactory factor and an olfactory associated zinc finger protein) and a negative glucocorticoid response element. | C9orf152
Chromosome 9 open reading frame 152 is a protein that in humans is encoded by the C9orf152 gene.[1][2] The exact function of the protein is not completely understood.
# Gene
The human gene C9orf152 is located on the long (q) arm of Chromosome 9.[3] Its cytogenetic location is 9q31.1. It has one known alias: bA470J20.2.[4]
The DNA sequence encoding C9orf152 contains a single intron.[3] The final mRNA consists of 2698 base pairs. Nucleotides 66-68 encode an upstream in frame stop codon.[1]
# Evolution
C9orf152 has orthologs in mammals, birds, reptiles and amphibians. No orthologs have been detected in bony fish or in any invertebrates.[3][5] The following table lists a subset of conserved orthologs.
Differences among shown orthologs suggest a slow rate of evolution.[6]
# Protein
Chromosome 9 open reading frame 152 contains 239 amino acids. The molecular weight is 26.3 kilodaltons. The protein has a high chance of existing nuclear region of cells.[7] There are likely no transmembrane regions.[8] One isoform exists, containing 194 amino acids.[5][9]
Within the coding sequence, there are two sumoylation sites[10][11][12] and a single serine phosphorylation site.[13]
There are three regions predicted to form alpha helices on the final protein.[14][15]
# Expression
C9orf152 is expressed in the bladder, intestine, mammary gland, and trachea and in smaller amounts in the lungs, liver, prostate, uterus, and brain.[16] Within the brain, expression of C9orf152 is limited to the olfactory bulb.[17] Gene expression was found to increase in the presence of stress, including disease and heat stress.[18]
A wide variety of transcription factors interact with the promoter of C9orf152, most notably two olfactory related factors (specifically, a neuron-specific olfactory factor and an olfactory associated zinc finger protein) and a negative glucocorticoid response element.[19] | https://www.wikidoc.org/index.php/C9orf152 | |
3678acece68c6baf741c7f3f0a24d06de971ae30 | wikidoc | CACNA2D1 | CACNA2D1
Voltage-dependent calcium channel subunit alpha-2/delta-1 is a protein that in humans is encoded by the CACNA2D1 gene.
This gene encodes a member of the alpha-2/delta subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Research on a highly similar protein in rabbit suggests the protein described in this record is cleaved into alpha-2 and delta subunits. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized.
# Gabapentinoids
alpha2/delta proteins are believed to be the molecular target of the gabapentinoids gabapentin and pregabalin, which are used to treat epilepsy and neuropathic pain. | CACNA2D1
Voltage-dependent calcium channel subunit alpha-2/delta-1 is a protein that in humans is encoded by the CACNA2D1 gene.[1][2]
This gene encodes a member of the alpha-2/delta subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Research on a highly similar protein in rabbit suggests the protein described in this record is cleaved into alpha-2 and delta subunits. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized.[2]
# Gabapentinoids
alpha2/delta proteins are believed to be the molecular target of the gabapentinoids gabapentin and pregabalin, which are used to treat epilepsy and neuropathic pain.[3][4][5] | https://www.wikidoc.org/index.php/CACNA2D1 | |
4b3257c72687aea436f11a1ed71b4f65a027ab85 | wikidoc | CACNA2D3 | CACNA2D3
Calcium channel, voltage-dependent, alpha 2/delta subunit 3 is a protein that in humans is encoded by the CACNA2D3 gene on chromosome 3 (locus 3p21.1).
# Function
This gene encodes a member of the alpha-2/delta subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Various versions of each of these subunits exist, either expressed from similar genes or the result of alternative splicing. Research on a highly similar protein in rabbit suggests the protein described in this record is cleaved into alpha-2 and delta subunits. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized.
# Clinical significance
Number of studies reported an association between methylation of the CACNA2D3 gene and cancer.
## Breast cancer
Methylation-dependent transcriptional silencing of CACNA2D3 gene may contribute to the metastatic phenotype of breast cancer. Analysis of methylation in the CACNA2D3 CpG island may have potential as a biomarker for risk of development of metastatic disease.
## Gastric cancer
The loss of CACNA2D3 gene expression through aberrant promoter hypermethylation may contribute to gastric carcinogenesis, and CACNA2D3 gene methylation is a useful prognostic marker for patients with advanced gastric cancer. Physical exercise was correlated with a lower methylation frequency of CACNA2D3. | CACNA2D3
Calcium channel, voltage-dependent, alpha 2/delta subunit 3 is a protein that in humans is encoded by the CACNA2D3 gene on chromosome 3 (locus 3p21.1).
[1]
# Function
This gene encodes a member of the alpha-2/delta subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Various versions of each of these subunits exist, either expressed from similar genes or the result of alternative splicing. Research on a highly similar protein in rabbit suggests the protein described in this record is cleaved into alpha-2 and delta subunits. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized.
# Clinical significance
Number of studies reported an association between methylation of the CACNA2D3 gene and cancer.
## Breast cancer
Methylation-dependent transcriptional silencing of CACNA2D3 gene may contribute to the metastatic phenotype of breast cancer. Analysis of methylation in the CACNA2D3 CpG island may have potential as a biomarker for risk of development of metastatic disease.[2]
## Gastric cancer
The loss of CACNA2D3 gene expression through aberrant promoter hypermethylation may contribute to gastric carcinogenesis, and CACNA2D3 gene methylation is a useful prognostic marker for patients with advanced gastric cancer.[3] Physical exercise was correlated with a lower methylation frequency of CACNA2D3.[4] | https://www.wikidoc.org/index.php/CACNA2D3 | |
df7f2a5271e53ea816ba589ce68306342ff80110 | wikidoc | CCDC144A | CCDC144A
Coiled-coil domain-containing protein 144A is a protein that in humans is encoded by the CCDC144A gene. An alias of this gene is called KIAA0565. There are four members of the CCDC family: CCDC 144A, 144B, 144C and putative CCDC 144 N-terminal like proteins.
# Gene
This gene has a nucleotide sequence that is 5140 bp long, and it encodes 641 amino acids. It is found on the short arm, plus (forward) strand of chromosome 17 at p11.2. The mRNA for the CCDC144A gene has 3 alternative splicing isoforms named A2RUR9-1, A2RUR9-2, AND A2RUR9-3, but there is no experimental confirmation available yet.
# Protein
This protein for this gene is also known as coiled coil domain containing 144A (CCDC144A) protein. It consists of 641 amino acids. This protein weighs 75.8 kDa and has an isoelecric point of 6.357. This protein localizes near the nucleus, and is a soluble protein with a hydrophobicity of -1.021842. This protein is also non-secretory and has 10 potential serine and 3 potential threonine phosphorylation sites. There are no tyrosine sulfation sites, but there are a few potential sumoylation sites on this protein. Also, this protein is predicted to be non-myristoylated and does not contain a signal peptide.
## Structure
This protein has a domain of unknown function (DUF) 3496, which has been conserved in eukaryotes. The DUF3496 domain is found from amino acids 547-622.
CCDC144A, an alias of this gene, indicates that there should be a coiled coil domain within the protein. Coiled coils are structural motifs in proteins in which 2 more alpha helices are coiled together, and they usually contain a heptad repeat, hxxhcxc, or hydrophobic (h) and charge (c) amino acid residues. The 5' and 3' untranslated regions of the nucleotide sequence of this gene are rich in stem-loop structures. In place of a coiled coil, a leucine zipper was found. Residues from 478-499, "LHNTRDALGRESLILERVQRDL", are the residues that form the leucine zipper pattern. The structure of this protein consists of mostly alpha helices, with some random coils.
# Evolution
Orthologs of KIAA0565 protein have been identified mostly in mammals, but some birds, reptiles, amphibians, and fish as well.
## Potential Orthologs
# Clinical significance
This gene has been linked to Smith-Magenis Syndrome (SMS), which is also known as chromosome 17p11.2 deletion syndrome, chromosome 17p deletion syndrome, deletion 17p syndrome, partial monosomy 17p, and deletion abnormality.
## Interacting proteins
There may potentially be two proteins that interact with KIAA0565, and they are ubiquitin specific peptidase 32 (USP32) and ubiquitin specific peptidase 25 (USP25).
## Expression
This protein has been shown to have relatively low expression in all tissues. | CCDC144A
Coiled-coil domain-containing protein 144A is a protein that in humans is encoded by the CCDC144A gene.[1] An alias of this gene is called KIAA0565. There are four members of the CCDC family: CCDC 144A, 144B, 144C and putative CCDC 144 N-terminal like proteins.[2]
# Gene
This gene has a nucleotide sequence that is 5140 bp long, and it encodes 641 amino acids.[3] It is found on the short arm, plus (forward) strand of chromosome 17 at p11.2.[4][5] The mRNA for the CCDC144A gene has 3 alternative splicing isoforms named A2RUR9-1, A2RUR9-2, AND A2RUR9-3, but there is no experimental confirmation available yet.[6]
# Protein
This protein for this gene is also known as coiled coil domain containing 144A (CCDC144A) protein. It consists of 641 amino acids.[7] This protein weighs 75.8 kDa and has an isoelecric point of 6.357.[8] This protein localizes near the nucleus,[9] and is a soluble protein with a hydrophobicity of -1.021842.[10] This protein is also non-secretory[11] and has 10 potential serine and 3 potential threonine phosphorylation sites.[12] There are no tyrosine sulfation sites,[13] but there are a few potential sumoylation sites on this protein.[14][15] Also, this protein is predicted to be non-myristoylated[16] and does not contain a signal peptide.[11][17]
## Structure
This protein has a domain of unknown function (DUF) 3496, which has been conserved in eukaryotes.[18] The DUF3496 domain is found from amino acids 547-622.[7]
CCDC144A, an alias of this gene, indicates that there should be a coiled coil domain within the protein. Coiled coils are structural motifs in proteins in which 2 more alpha helices are coiled together, and they usually contain a heptad repeat, hxxhcxc, or hydrophobic (h) and charge (c) amino acid residues.[5] The 5' and 3' untranslated regions of the nucleotide sequence of this gene are rich in stem-loop structures.[19] In place of a coiled coil, a leucine zipper was found.[9] Residues from 478-499, "LHNTRDALGRESLILERVQRDL", are the residues that form the leucine zipper pattern.[9] The structure of this protein consists of mostly alpha helices, with some random coils.[20]
# Evolution
Orthologs of KIAA0565 protein have been identified mostly in mammals, but some birds, reptiles, amphibians, and fish as well.[21]
## Potential Orthologs
[21]
# Clinical significance
This gene has been linked to Smith-Magenis Syndrome (SMS), which is also known as chromosome 17p11.2 deletion syndrome,[22] chromosome 17p deletion syndrome,[23] deletion 17p syndrome,[23] partial monosomy 17p,[23] and deletion abnormality.[24][25]
## Interacting proteins
There may potentially be two proteins that interact with KIAA0565, and they are ubiquitin specific peptidase 32 (USP32) and ubiquitin specific peptidase 25 (USP25).[26]
## Expression
This protein has been shown to have relatively low expression in all tissues.[27] | https://www.wikidoc.org/index.php/CCDC144A | |
2e83ff254c7783b45cbcb4cc53ece7937d198ee2 | wikidoc | Cyclin H | Cyclin H
Cyclin-H is a protein that in humans is encoded by the CCNH gene.
# Function
The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with CDK7 kinase and ring finger protein MAT1. The kinase complex is able to phosphorylate CDK2 and CDC2 kinases, thus functions as a CDK-activating kinase (CAK). This cyclin and its kinase partner are components of TFIIH, as well as RNA polymerase II protein complexes. They participate in two different transcriptional regulation processes, suggesting an important link between basal transcription control and the cell cycle machinery.
# Interactions
Cyclin H has been shown to interact with P53, Cyclin-dependent kinase 7 and MNAT1. | Cyclin H
Cyclin-H is a protein that in humans is encoded by the CCNH gene.[1][2]
# Function
The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with CDK7 kinase and ring finger protein MAT1. The kinase complex is able to phosphorylate CDK2 and CDC2 kinases, thus functions as a CDK-activating kinase (CAK). This cyclin and its kinase partner are components of TFIIH, as well as RNA polymerase II protein complexes. They participate in two different transcriptional regulation processes, suggesting an important link between basal transcription control and the cell cycle machinery.[2]
# Interactions
Cyclin H has been shown to interact with P53,[3] Cyclin-dependent kinase 7[4][5][6] and MNAT1.[7][8] | https://www.wikidoc.org/index.php/CCNH | |
985bf737b5c64994dccd755d10cff931ee46902f | wikidoc | Cyclin K | Cyclin K
Cyclin-K is a protein that in humans is encoded by the CCNK gene.
# Function
The protein encoded by this gene is a member of the transcription cyclin family. These cyclins may regulate transcription through their association with and activation of cyclin-dependent kinases (CDKs) through conformational changes. Activation of CDKs through their cyclin partner, creates kinase complexes that will activate target proteins through phosphorylation. Targeted proteins can then ultimately regulate decisions of a cell’s progression within the cell cycle to occur. This gene product may be seen to play a dual role in both regulating CDK and RNA polymerase II (RNAP2) activities. Cyclin K only uses RNA recruitment to activate transcription.
# Interactions
Cyclin K has been shown to interact with multiple CDKs including CDK9 and latest CDK12 and CDK13. Roles include helping to phosphorylate C-terminal domains of subunits of RNAP2. Cyclin K is most noted for its associated induction of processive elongation. Also, identified with G1 and S phase cyclin activity, however functions are not deeply understood.
Cyclin K also interacts with HIV nef protein. In the presence of overexpressed Nef protein, Cyclin k and CDK9 binding is induced, inhibiting the positive elongation factor of other CDK9 binding complexes, resulting in an inhibition of specific HIV-1 gene expression. CDK 13 may also be characterized to interact with HIV mRNA splicing, alongside Nef, and the underexpression of Gag and Env related proteins.
Cyclin K is indispensable for Leukemia growth. SETD1A, is also known to bind Cyclin K through its FLOS domain. The interaction is shown to be important to DNA damage response genes and for Leukemia proliferation. | Cyclin K
Cyclin-K is a protein that in humans is encoded by the CCNK gene.[1][2][3]
# Function
The protein encoded by this gene is a member of the transcription cyclin family. These cyclins may regulate transcription through their association with and activation of cyclin-dependent kinases (CDKs) through conformational changes.[4][5] Activation of CDKs through their cyclin partner, creates kinase complexes that will activate target proteins through phosphorylation. Targeted proteins can then ultimately regulate decisions of a cell’s progression within the cell cycle to occur. This gene product may be seen to play a dual role in both regulating CDK and RNA polymerase II (RNAP2) activities.[3] Cyclin K only uses RNA recruitment to activate transcription.[6]
# Interactions
Cyclin K has been shown to interact with multiple CDKs including CDK9 and latest CDK12 and CDK13.[2][5] Roles include helping to phosphorylate C-terminal domains of subunits of RNAP2.[7] Cyclin K is most noted for its associated induction of processive elongation.[4] Also, identified with G1 and S phase cyclin activity, however functions are not deeply understood.[1][8]
Cyclin K also interacts with HIV nef protein.[9] In the presence of overexpressed Nef protein, Cyclin k and CDK9 binding is induced, inhibiting the positive elongation factor of other CDK9 binding complexes, resulting in an inhibition of specific HIV-1 gene expression.[5][9] CDK 13 may also be characterized to interact with HIV mRNA splicing, alongside Nef, and the underexpression of Gag and Env related proteins. [8][6]
Cyclin K is indispensable for Leukemia growth. SETD1A, is also known to bind Cyclin K through its FLOS domain.[10] The interaction is shown to be important to DNA damage response genes and for Leukemia proliferation.[6][10] | https://www.wikidoc.org/index.php/CCNK | |
c45b190267b7f0313a196d1bcd3013a361cea569 | wikidoc | Endoglin | Endoglin
Endoglin (ENG) is a type I membrane glycoprotein located on cell surfaces and is part of the TGF beta receptor complex. It is also commonly referred to as CD105, END, FLJ41744, HHT1, ORW and ORW1. It has a crucial role in angiogenesis, therefore, making it an important protein for tumor growth, survival and metastasis of cancer cells to other locations in the body.
# Gene and expression
The human endoglin gene is located on human chromosome 9 with location of the cytogenic band at 9q34.11. Endoglin glycoprotein is encoded by 39,757 bp and translates into 658 amino acids.
The expression of the endoglin gene is usually low in resting endothelial cells. This, however, changes once neoangiogenesis begins and endothelial cells become active in places like tumor vessels, inflamed tissues, skin with psoriasis, vascular injury and during embryogenesis. The expression of the vascular system begins at about 4 weeks and continues after that. Other cells in which endoglin is expressed consist of monocytes, especially those transitioning into macrophages, low expression in normal smooth muscle cells, high expression vascular smooth muscle cells and in kidney and liver tissues undergoing fibrosis.
# Structure
The glycoprotein consists of a homodimer of 180 kDA with disulfide links. It is the cysteines 350 and 582 that are involved with the disulfide linkage in these homodimers. It has a large extracellular domain of about 561 amino acids, a hydrophobic transmembrane domain and a short cytoplasmic tail domain composed of 45 amino acids. The 260 amino acid region closest to the extracellular membrane is referred to as the ZP domain (or, more correctly, ZP module). The outermost extracellular region is termed as the orphan domain and it is the part that binds ligands such as BMP-9.
There are two isoforms of endoglin created by alternative splicing: the long isoform (L-endoglin) and the short isoform (S-endoglin). However, the L-isoform is expressed to a greater extent than the S-isoform. A soluble form of endoglin can be produced by the proteolytic cleaving action of metalloproteinase MMP-14 in the extracellular domain near the membrane.
It has been found on endothelial cells in all tissues, activated macrophages, activated monocytes, lymphoblasts fibroblasts, and smooth muscle cells. Endoglin was first identified using monoclonal antibody (mAb) 44G4 but more mAbs against endoglin have been discovered, giving more ways to identify it in tissues.
It is suggested that endoglin has 5 potential N-linked glycosylation sites in the N-terminal domain and an O-glycan domain near the membrane domain that is rich in Serine and Threonine. The cytoplasmic tail contains a PDZ-binding motif that allows it to bind to PDZ containing proteins and interact with them. It contains an Arginine-Glycine-Aspartic Acid (RGD) tripeptide sequence that enables cellular adhesion, through the binding of integrins or other RGD binding receptors that are present in the extracellular matrix (ECM). This RGD sequence on endoglin is the first RGD sequence identified on endothelial tissue.
X-ray crystallographic structures of human endoglin (PDB: 5I04, 5HZV) and its complex with ligand BMP-9 (PDB: 5HZW) revealed that the orphan region of the protein consists of two domains (OR1 and OR2) with a new fold resulting from gene duplication and circular permutation. The ZP module, whose ZP-N and ZP-C moieties are closely packed against each other, mediates the homodimerization of endoglin by forming an intermolecular disulfide bond that involves cysteine 516. Together with the aforementioned intermolecular disulfide involving cysteine 582, this generates a molecular clamp that secures the ligand via interaction of two copies of OR1 with the knuckle regions of homodimeric BMP-9. In addition to rationalizing a large number of HHT1 mutations, the crystal structure of endoglin shows that the epitope of anti-ENG monoclonal antibody TRC105 overlaps with the binding site for BMP-9.
# Interactions
Endoglin has been shown to interact with high affinity to TGF beta receptor 3 and TGF beta receptor 1, and with lower affinity to TGF beta receptor 2. It has high sequence similarity to another TGF beta binding protein, beta-glycan, which was one of the first cues that indicated that endoglin is a TGF beta binding proteins. However, it has been shown that TGF beta binds with high affinity to only a small amount of the available endoglin, which suggests that there is another factor regulating this binding.
Endoglin itself doesn't bind the TGF beta ligands, but is present with the TGF beta receptors when the ligand is bound, indicating an important role for endoglin. The full length endoglin will bind to the TGF beta receptor complex whether TGF beta is bound or not, but the truncated forms of endoglin have more specific binding. The amino acid (aa) region 437-558 in the extracellular domain of endoglin will bind to TGF beta receptor II. TGF beta receptor I binds to the 437-588 aa region and to the aa region between 437 and the N-terminus. Unlike TGF beta receptor I which can only bind the cytoplasmic tail when its kinase domain is inactive, TGF beta receptor II can bind endoglin with an inactive and active kinase domain. The kinase is active when it is phosphorylated. Furthermore, TGF beta receptor I will dissociate from endoglin soon after it phosphorylates its cytoplasmic tail, leaving TGF beta receptor I inactive. Endoglin is constituitively phosphorylated at the serine and threonine residues in the cytoplasmic domain. The high interaction between endoglin's cytoplasmic and extracellular tail with the TGF beta receptor complexes indicates an important role for endoglin in the modulation of the TGF beta responses, such as cellular localization and cellular migration.
Endoglin can also mediate F-actin dynamics, focal adhesions, microtubular structures, endocytic vesicular transport through its interaction with zyxin, ZRP-1, beta-arrestin and Tctex2beta, LK1, ALK5, TGF beta receptor II, and GIPC. In one study with mouse fibroblasts, the overexpression of endoglin resulted in a reduction of some ECM components, decreased cellular migration, a change in cellular morphology and intercellular cluster formation.
# Function
Endoglin has been found to be an auxiliary receptor for the TGF-beta receptor complex. It thus is involved in modulating a response to the binding of TGF-beta1, TGF-beta3, activin-A, BMP-2, and BMP-7. Beside TGF-beta signaling endoglin may have other functions. It has been postulated that endoglin is involved in the cytoskeletal organization affecting cell morphology and migration.
Endoglin has a role in the development of the cardiovascular system and in vascular remodeling. Its expression is regulated during heart development . Experimental mice without the endoglin gene die due to cardiovascular abnormalities.
# Clinical significance
In humans endoglin may be involved in the autosomal dominant disorder known as hereditary hemorrhagic telangiectasia (HHT) type 1. HHT is actually the first human disease linked to the TGF beta receptor complex. This condition leads to frequent nose bleeds, telangiectases on skin and mucosa and may cause arteriovenous malformations in different organs including brain, lung, and liver.
## Mutations causing HHT
Some mutations that lead to this disorder are:
- a Cytosine (C) to Guanine (G) substitution which converts a tyrosine to stop codon
- a 39 base pair deletion
- a 2 base pair deletion which creates an early stop codon
Endoglin levels have been found to be elevated in pregnant women who subsequently develop preeclampsia.
## Role in cancer
The important role that endoglin plays in angiogenesis and the modulation of TGF beta receptor signaling, which mediates cellular localization, cellular migration, cellular morphology, cell proliferation, cluster formation, etc., makes endoglin an important player in tumor growth and metastasis. Being able to target and efficiently reduce or halt neoangiogenesis in tumors would prevent metastasis of primary cancer cells into other areas of the body. Also, it has been suggested that endoglin can be used for tumor imaging and prognosis.
The role of endoglin in cancer can be contradicting at times since it is needed for neoangiogenesis in tumors, which is needed for tumor growth and survival, yet the reduction in expression of endoglin has in many cancers correlated with a negative outcome of that cancer. In breast cancer, for example, the reduction of the full form of endoglin, and the increase of the soluble form of endoglin correlate with metastasis of cancer cells. The TGF beta receptor-endoglin complex relay contradicting signals from TGF beta as well. TGF beta can act as a tumor suppressor in the premalignant stage of the benign neoplasm by inhibiting its growth and inducing apoptosis. However, once the cancer cells have gone through the Hallmarks of Cancer and lost inhibitory growth responses, TGF beta mediates cell invasion, angiogenesis (with the help of endoglin), immune system evasion, and their ECM composition, allowing them to become malignant.
### Prostate cancer and endoglin expression
It has been shown that endoglin expression and TGF-beta secretion are attenuated in bone marrow stromal cells when they are cocultured with prostate cancer cells. Also, the downstream TGF-beta/bone morphogenic protein (BMP) signaling pathway, which includes Smad1 and Smad2/3, were attenuated along with Smad-dependent gene transcription. Another result in this study was that both Smad1/5/8-dependent inhibitor of DNA binding 1 expression and Smad2/3-dependent plasminogen activator inhibitor I had a reduction in expression and cell proliferation. Ultimately, the cocultured prostate cancer cells altered the TGF-beta signaling in the bone stromal cells, which suggests this modulation is a mechanism of prostate cancer metastases facilitating their growth and survival in the reactive bone stroma. This study emphasizes the importance of endoglin in TGF-beta signaling pathways in other cell types other than endothelial cells.
### As a drug target
TRC105 is an experimental antibody targeted at endoglin as an anti-angiogenesis treatment for soft-tissue sarcoma. | Endoglin
Endoglin (ENG) is a type I membrane glycoprotein located on cell surfaces and is part of the TGF beta receptor complex. It is also commonly referred to as CD105, END, FLJ41744, HHT1, ORW and ORW1.[1] It has a crucial role in angiogenesis, therefore, making it an important protein for tumor growth, survival and metastasis of cancer cells to other locations in the body.
# Gene and expression
The human endoglin gene is located on human chromosome 9 with location of the cytogenic band at 9q34.11.[2][3] Endoglin glycoprotein is encoded by 39,757 bp and translates into 658 amino acids.[1]
The expression of the endoglin gene is usually low in resting endothelial cells. This, however, changes once neoangiogenesis begins and endothelial cells become active in places like tumor vessels, inflamed tissues, skin with psoriasis, vascular injury and during embryogenesis.[1] The expression of the vascular system begins at about 4 weeks and continues after that.[1] Other cells in which endoglin is expressed consist of monocytes, especially those transitioning into macrophages, low expression in normal smooth muscle cells, high expression vascular smooth muscle cells and in kidney and liver tissues undergoing fibrosis.[1][4]
# Structure
The glycoprotein consists of a homodimer of 180 kDA with disulfide links.[5] It is the cysteines 350 and 582 that are involved with the disulfide linkage in these homodimers.[1] It has a large extracellular domain of about 561 amino acids, a hydrophobic transmembrane domain and a short cytoplasmic tail domain composed of 45 amino acids.[5] The 260 amino acid region closest to the extracellular membrane is referred to as the ZP domain (or, more correctly, ZP module).[1] The outermost extracellular region is termed as the orphan domain and it is the part that binds ligands such as BMP-9.[1]
There are two isoforms of endoglin created by alternative splicing: the long isoform (L-endoglin) and the short isoform (S-endoglin).[6] However, the L-isoform is expressed to a greater extent than the S-isoform. A soluble form of endoglin can be produced by the proteolytic cleaving action of metalloproteinase MMP-14 in the extracellular domain near the membrane.[1]
It has been found on endothelial cells in all tissues,[5] activated macrophages, activated monocytes, lymphoblasts fibroblasts, and smooth muscle cells. Endoglin was first identified using monoclonal antibody (mAb) 44G4 but more mAbs against endoglin have been discovered, giving more ways to identify it in tissues.[7]
It is suggested that endoglin has 5 potential N-linked glycosylation sites in the N-terminal domain and an O-glycan domain near the membrane domain that is rich in Serine and Threonine.[5] The cytoplasmic tail contains a PDZ-binding motif that allows it to bind to PDZ containing proteins and interact with them.[8] It contains an Arginine-Glycine-Aspartic Acid (RGD) tripeptide sequence that enables cellular adhesion, through the binding of integrins or other RGD binding receptors that are present in the extracellular matrix (ECM).[5] This RGD sequence on endoglin is the first RGD sequence identified on endothelial tissue.[5]
X-ray crystallographic structures of human endoglin (PDB: 5I04, 5HZV) and its complex with ligand BMP-9 (PDB: 5HZW) revealed that the orphan region of the protein consists of two domains (OR1 and OR2) with a new fold resulting from gene duplication and circular permutation. The ZP module, whose ZP-N and ZP-C moieties are closely packed against each other, mediates the homodimerization of endoglin by forming an intermolecular disulfide bond that involves cysteine 516. Together with the aforementioned intermolecular disulfide involving cysteine 582, this generates a molecular clamp that secures the ligand via interaction of two copies of OR1 with the knuckle regions of homodimeric BMP-9. In addition to rationalizing a large number of HHT1 mutations, the crystal structure of endoglin shows that the epitope of anti-ENG monoclonal antibody TRC105 overlaps with the binding site for BMP-9.[9]
# Interactions
Endoglin has been shown to interact with high affinity to TGF beta receptor 3[2][10] and TGF beta receptor 1,[8][11] and with lower affinity to TGF beta receptor 2.[2] It has high sequence similarity to another TGF beta binding protein, beta-glycan, which was one of the first cues that indicated that endoglin is a TGF beta binding proteins.[12] However, it has been shown that TGF beta binds with high affinity to only a small amount of the available endoglin, which suggests that there is another factor regulating this binding.[12]
Endoglin itself doesn't bind the TGF beta ligands, but is present with the TGF beta receptors when the ligand is bound, indicating an important role for endoglin.[8] The full length endoglin will bind to the TGF beta receptor complex whether TGF beta is bound or not, but the truncated forms of endoglin have more specific binding.[8] The amino acid (aa) region 437-558 in the extracellular domain of endoglin will bind to TGF beta receptor II. TGF beta receptor I binds to the 437-588 aa region and to the aa region between 437 and the N-terminus.[8] Unlike TGF beta receptor I which can only bind the cytoplasmic tail when its kinase domain is inactive, TGF beta receptor II can bind endoglin with an inactive and active kinase domain.[8] The kinase is active when it is phosphorylated. Furthermore, TGF beta receptor I will dissociate from endoglin soon after it phosphorylates its cytoplasmic tail, leaving TGF beta receptor I inactive.[8] Endoglin is constituitively phosphorylated at the serine and threonine residues in the cytoplasmic domain. The high interaction between endoglin's cytoplasmic and extracellular tail with the TGF beta receptor complexes indicates an important role for endoglin in the modulation of the TGF beta responses, such as cellular localization and cellular migration.[8]
Endoglin can also mediate F-actin dynamics, focal adhesions, microtubular structures, endocytic vesicular transport through its interaction with zyxin, ZRP-1, beta-arrestin and Tctex2beta, LK1, ALK5, TGF beta receptor II, and GIPC.[1] In one study with mouse fibroblasts, the overexpression of endoglin resulted in a reduction of some ECM components, decreased cellular migration, a change in cellular morphology and intercellular cluster formation.[13]
# Function
Endoglin has been found to be an auxiliary receptor for the TGF-beta receptor complex.[8] It thus is involved in modulating a response to the binding of TGF-beta1, TGF-beta3, activin-A, BMP-2, and BMP-7. Beside TGF-beta signaling endoglin may have other functions. It has been postulated that endoglin is involved in the cytoskeletal organization affecting cell morphology and migration.[14]
Endoglin has a role in the development of the cardiovascular system and in vascular remodeling. Its expression is regulated during heart development . Experimental mice without the endoglin gene die due to cardiovascular abnormalities.[14]
# Clinical significance
In humans endoglin may be involved in the autosomal dominant disorder known as hereditary hemorrhagic telangiectasia (HHT) type 1.[5] HHT is actually the first human disease linked to the TGF beta receptor complex.[15] This condition leads to frequent nose bleeds, telangiectases on skin and mucosa and may cause arteriovenous malformations in different organs including brain, lung, and liver.
## Mutations causing HHT
Some mutations that lead to this disorder are:[15]
- a Cytosine (C) to Guanine (G) substitution which converts a tyrosine to stop codon
- a 39 base pair deletion
- a 2 base pair deletion which creates an early stop codon
Endoglin levels have been found to be elevated in pregnant women who subsequently develop preeclampsia.[16]
## Role in cancer
The important role that endoglin plays in angiogenesis[17] and the modulation of TGF beta receptor signaling, which mediates cellular localization, cellular migration, cellular morphology, cell proliferation, cluster formation, etc., makes endoglin an important player in tumor growth and metastasis.[18][19] Being able to target and efficiently reduce or halt neoangiogenesis in tumors would prevent metastasis of primary cancer cells into other areas of the body.[18] Also, it has been suggested that endoglin can be used for tumor imaging and prognosis.[18]
The role of endoglin in cancer can be contradicting at times since it is needed for neoangiogenesis in tumors, which is needed for tumor growth and survival, yet the reduction in expression of endoglin has in many cancers correlated with a negative outcome of that cancer.[1] In breast cancer, for example, the reduction of the full form of endoglin, and the increase of the soluble form of endoglin correlate with metastasis of cancer cells.[20] The TGF beta receptor-endoglin complex relay contradicting signals from TGF beta as well. TGF beta can act as a tumor suppressor in the premalignant stage of the benign neoplasm by inhibiting its growth and inducing apoptosis.[1] However, once the cancer cells have gone through the Hallmarks of Cancer and lost inhibitory growth responses, TGF beta mediates cell invasion, angiogenesis (with the help of endoglin), immune system evasion, and their ECM composition, allowing them to become malignant.[1]
### Prostate cancer and endoglin expression
It has been shown that endoglin expression and TGF-beta secretion are attenuated in bone marrow stromal cells when they are cocultured with prostate cancer cells.[21] Also, the downstream TGF-beta/bone morphogenic protein (BMP) signaling pathway, which includes Smad1 and Smad2/3, were attenuated along with Smad-dependent gene transcription.[21] Another result in this study was that both Smad1/5/8-dependent inhibitor of DNA binding 1 expression and Smad2/3-dependent plasminogen activator inhibitor I had a reduction in expression and cell proliferation.[21] Ultimately, the cocultured prostate cancer cells altered the TGF-beta signaling in the bone stromal cells, which suggests this modulation is a mechanism of prostate cancer metastases facilitating their growth and survival in the reactive bone stroma.[21] This study emphasizes the importance of endoglin in TGF-beta signaling pathways in other cell types other than endothelial cells.
### As a drug target
TRC105 is an experimental antibody targeted at endoglin as an anti-angiogenesis treatment for soft-tissue sarcoma.[22] | https://www.wikidoc.org/index.php/CD105 | |
cd4709e8177c215a7bd083e3485256c73f7aef8c | wikidoc | CDK5RAP2 | CDK5RAP2
CDK5 regulatory subunit-associated protein 2 is a protein that in humans is encoded by the CDK5RAP2 gene. Multiple transcript variants exist for this gene, but the full-length nature of only two has been determined. CDK5RAP2 is homologous to the Drosophila protein centrosomin (cnn).
# Function
Neuronal CDC2-like kinase, which is involved in the regulation of neuronal differentiation, is composed of a catalytic subunit, CDK5, and an activating subunit, p25NCK5A. The protein encoded by this gene binds to p25NCK5A and therefore may be involved in neuronal differentiation. The encoded protein may also be a substrate of neuronal CDC2-like kinase.
# Clinical significance
A magnetic resonance imaging study has demonstrated a link between common variation in the CDK5RAP2 gene and brain structure. More specifically, associations were found between several single nucleotide polymorphisms (SNPs) and brain cortical surface area and total brain volume. These associations were found exclusively in male subjects and all SNPs were located upstream in non-exonic regions. The functional significance of these loci is not yet known. However, given their location close to regulatory elements, it is possible that they are involved in gene regulation, which suggests that common variance in brain structure could be associated with differences in gene regulation rather than protein structure, consistent with findings in other complex human traits.
CDK5RAP2 is needed as a scaffolding protein in the Corona of the centrosome of the Dictyostelium.
# Interactions
CDK5RAP2 has been shown to interact with CDK5R1. | CDK5RAP2
CDK5 regulatory subunit-associated protein 2 is a protein that in humans is encoded by the CDK5RAP2 gene. Multiple transcript variants exist for this gene, but the full-length nature of only two has been determined.[1][2] CDK5RAP2 is homologous to the Drosophila protein centrosomin (cnn).[3]
# Function
Neuronal CDC2-like kinase, which is involved in the regulation of neuronal differentiation, is composed of a catalytic subunit, CDK5, and an activating subunit, p25NCK5A. The protein encoded by this gene binds to p25NCK5A and therefore may be involved in neuronal differentiation. The encoded protein may also be a substrate of neuronal CDC2-like kinase.[2]
# Clinical significance
A magnetic resonance imaging study has demonstrated a link between common variation in the CDK5RAP2 gene and brain structure.[4] More specifically, associations were found between several single nucleotide polymorphisms (SNPs) and brain cortical surface area and total brain volume. These associations were found exclusively in male subjects and all SNPs were located upstream in non-exonic regions. The functional significance of these loci is not yet known. However, given their location close to regulatory elements, it is possible that they are involved in gene regulation, which suggests that common variance in brain structure could be associated with differences in gene regulation rather than protein structure, consistent with findings in other complex human traits.
CDK5RAP2 is needed as a scaffolding protein in the Corona of the centrosome of the Dictyostelium.[5]
# Interactions
CDK5RAP2 has been shown to interact with CDK5R1.[6] | https://www.wikidoc.org/index.php/CDK5RAP2 | |
451320d25572deb946c6a56459a2d5a4eaaa36cd | wikidoc | CHRFAM7A | CHRFAM7A
CHRNA7-FAM7A fusion protein is a protein that in humans is encoded by the CHRFAM7A gene.
The nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. The family member CHRNA7, which is located on chromosome 15 in a region associated with several neuropsychiatric disorders, is partially duplicated and forms a hybrid with a novel gene from the family with sequence similarity 7 (FAM7A). Alternative splicing has been observed, and two variants exist, for this hybrid gene. The N-terminally truncated products predicted by the largest open reading frames for each variant would lack the majority of the neurotransmitter-gated ion-channel ligand binding domain but retain the transmembrane region that forms the ion channel. Although current evidence supports transcription of this hybrid gene, translation of the nicotinic acetylcholine receptor-like protein-encoding open reading frames has not been confirmed.
CHRFAM7A has not been found in nonhuman primates, and its occurrence in individuals of African descent is significantly lower than in Caucasian populations. | CHRFAM7A
CHRNA7-FAM7A fusion protein is a protein that in humans is encoded by the CHRFAM7A gene.[1][2]
The nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. The family member CHRNA7, which is located on chromosome 15 in a region associated with several neuropsychiatric disorders, is partially duplicated and forms a hybrid with a novel gene from the family with sequence similarity 7 (FAM7A). Alternative splicing has been observed, and two variants exist, for this hybrid gene. The N-terminally truncated products predicted by the largest open reading frames for each variant would lack the majority of the neurotransmitter-gated ion-channel ligand binding domain but retain the transmembrane region that forms the ion channel. Although current evidence supports transcription of this hybrid gene, translation of the nicotinic acetylcholine receptor-like protein-encoding open reading frames has not been confirmed.[2]
CHRFAM7A has not been found in nonhuman primates, and its occurrence in individuals of African descent is significantly lower than in Caucasian populations.[3] | https://www.wikidoc.org/index.php/CHRFAM7A | |
7fabc3e23f98abe40fcfad78300d61b3b123267a | wikidoc | COL4A3BP | COL4A3BP
Collagen type IV alpha-3-binding protein, also known as ceramide transfer protein (CERT) or StAR-related lipid transfer protein 11 (STARD11) is a protein that in humans is encoded by the COL4A3BP gene. The protein contains a pleckstrin homology domain at its amino terminus and a START domain towards the end of the molecule. It is a member of the StarD2 subfamily of START domain proteins.
# Function and structure
Ceramide transferase protein (or CERT) is responsible for the transfer of ceramide from the endoplasmic reticulum (ER) to the Golgi apparatus. Ceramide plays a very important role in the metabolism and biosynthesis of sphingolipid. More specifically, it is synthesized at the ER, then is transferred by CERT to Golgi where it is converted to sphingomyelin (SM).
There are two pathways through which this transfer takes place: a major pathway, which is ATP and cytosol-dependent and a minor pathway, which is ATP- and cytosol-independent.
CERT is a 68kDa protein that consists of three different parts, each of which with a special role:
- Pleckstrin homology domain (PH): It is the aminoterminal domain and it consists of about 100 aminoacid residues. The main function of this part of CERT is to recognize and bind various phosphatidyloinositol phosphates (PIPs) with different level of specificity. The isomers of PIPs are distributed to various organelles: PI-4,5-diphosphate goes to the plasma membrane, PI-3-monophosphate to endosomes and PI-4-monophosphate to Golgi. PH domain of wild-type CERT has been found to recognize specifically PI4P and therefore CERT targets the Golgi apparatus or the trans-Golgi network.
- START domain: It consists of about 210 amino acid residues and has an important role in the transfer of ceramide, which is that it can recognize specifically only the natural D-erythro isomer of ceramide and extract it from the membrane.
- FFAT motif (two phenylalanines in an acidic tract, that has a conserved sequence "EFFDAxE"): It is a short domain situated between PH and START domain and is the one responsible for the interaction of CERT with ER. More specifically, it binds to the ER resident type II membrane protein, vesicle-associated membrane protein (VAMP) associated protein (VAP), an interaction that is necessary for the transfer of ceramide from the ER to Golgi.
All of these domains are important for the transfer of ceramide, since first of all CERT will extract newly synthesized ceramide from the membrane with the help of its START domain. Then, ceramide will be transferred through the cytosol towards Golgi because of the interaction between the PH domain and PI4P. Finally, interaction with ER is facilitated through the binding of the FFAT motif with Vesicle-associated membrane protein.
# Regulation
The transport of ceramide by CERT requires ATP. CERT – when expressed in mammalian cells - has been found to receive a lot of possible phosphorylations at the serine repeat (SR) motif, which is close to the PH domain.
It has been shown that the phosphorylation of this SR motif leads to inactivation of the PI4P-binding and ceramide transferring activities of CERT, since it induces an autoinhibitory reaction between the PH and START domains of CERT, transforming it from the active form to the inactive form.
Protein kinase D (PKD) has been found to phosphorylate the SR motif of CERT. Also, CERT is further phosphorylated by the casein kinase 1 family leading to hyperphosphorylation of the SR motif. On the other hand, the integral membrane protein protein phosphatase 2Cε (PP2Cε), which is located on the endoplasmic reticulum induces dephosphorylation of CERT. Dephosphorylated CERT is in the active form in order to be functional and transfer ceramide from ER to Golgi.
# Inhibitor HPA-12
The chemically synthesized compound N-(30hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecamide (HPA-12) has been found to be an inhibitor of CERT-mediated ceramide trafficking.
More specifically, this drug inhibits the ATP-dependent transport of ceramide from ER to Golgi (and therefore the conversion of ceramide to sphingomyelin), but it does not inhibit protein trafficking. This suggests that Ceramide is still transformed to Glycosylceramide at Golgi. Moreover, it has been shown that it does not inhibit the Sphingomyelin synthase in vitro or in vivo.
Moreover, only the (1R, 3R) isomer of HPA-12 has been found to be an active inhibitor and the length of the chain as well as the two hydroxyl-groups are very important for the inhibitory activity.
# Clinical significance
This gene encodes a kinase also known as Goodpasture antigen-binding protein that specifically phosphorylates the N-terminal region of the non-collagenous domain of the alpha 3 chain of type IV collagen, known as the Goodpasture antigen. Goodpasture's syndrome is the result of an autoimmune response directed at this antigen. One isoform of this protein is also involved in ceramide intracellular transport. Two transcripts exist for this gene.
# Model organisms
Model organisms have been used in the study of COL4A3BP function. A conditional knockout mouse line called Col4a3bptm1a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping - in-depth bone and cartilage phenotyping | COL4A3BP
Collagen type IV alpha-3-binding protein, also known as ceramide transfer protein (CERT) or StAR-related lipid transfer protein 11 (STARD11) is a protein that in humans is encoded by the COL4A3BP gene.[1][2] The protein contains a pleckstrin homology domain at its amino terminus and a START domain towards the end of the molecule. It is a member of the StarD2 subfamily of START domain proteins.
# Function and structure
Ceramide transferase protein (or CERT) is responsible for the transfer of ceramide from the endoplasmic reticulum (ER) to the Golgi apparatus. Ceramide plays a very important role in the metabolism and biosynthesis of sphingolipid. More specifically, it is synthesized at the ER, then is transferred by CERT to Golgi where it is converted to sphingomyelin (SM).[3]
There are two pathways through which this transfer takes place: a major pathway, which is ATP and cytosol-dependent and a minor pathway, which is ATP- and cytosol-independent.[2]
CERT is a 68kDa protein[4] that consists of three different parts, each of which with a special role:
- Pleckstrin homology domain (PH): It is the aminoterminal domain and it consists of about 100 aminoacid residues.[1][5] The main function of this part of CERT is to recognize and bind various phosphatidyloinositol phosphates (PIPs) with different level of specificity.[6] The isomers of PIPs are distributed to various organelles: PI-4,5-diphosphate goes to the plasma membrane, PI-3-monophosphate to endosomes and PI-4-monophosphate to Golgi.[7] PH domain of wild-type CERT has been found to recognize specifically PI4P and therefore CERT targets the Golgi apparatus or the trans-Golgi network.[4][8][9]
- START domain: It consists of about 210 amino acid residues and has an important role in the transfer of ceramide, which is that it can recognize specifically only the natural D-erythro isomer of ceramide and extract it from the membrane.[4]
- FFAT motif (two phenylalanines in an acidic tract, that has a conserved sequence "EFFDAxE"): It is a short domain situated between PH and START domain and is the one responsible for the interaction of CERT with ER. More specifically, it binds to the ER resident type II membrane protein, vesicle-associated membrane protein (VAMP) associated protein (VAP), an interaction that is necessary for the transfer of ceramide from the ER to Golgi.[10]
All of these domains are important for the transfer of ceramide, since first of all CERT will extract newly synthesized ceramide from the membrane with the help of its START domain. Then, ceramide will be transferred through the cytosol towards Golgi because of the interaction between the PH domain and PI4P. Finally, interaction with ER is facilitated through the binding of the FFAT motif with Vesicle-associated membrane protein.
# Regulation
The transport of ceramide by CERT requires ATP.[11] CERT – when expressed in mammalian cells - has been found to receive a lot of possible phosphorylations at the serine repeat (SR) motif, which is close to the PH domain.[12]
It has been shown that the phosphorylation of this SR motif leads to inactivation of the PI4P-binding and ceramide transferring activities of CERT, since it induces an autoinhibitory reaction between the PH and START domains of CERT, transforming it from the active form to the inactive form.[12]
Protein kinase D (PKD) has been found to phosphorylate the SR motif of CERT.[13] Also, CERT is further phosphorylated by the casein kinase 1 family leading to hyperphosphorylation of the SR motif.[14] On the other hand, the integral membrane protein protein phosphatase 2Cε (PP2Cε), which is located on the endoplasmic reticulum induces dephosphorylation of CERT.[15] Dephosphorylated CERT is in the active form in order to be functional and transfer ceramide from ER to Golgi.[16]
# Inhibitor HPA-12
The chemically synthesized compound N-(30hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecamide (HPA-12) has been found to be an inhibitor of CERT-mediated ceramide trafficking.[17]
More specifically, this drug inhibits the ATP-dependent transport of ceramide from ER to Golgi (and therefore the conversion of ceramide to sphingomyelin), but it does not inhibit protein trafficking. This suggests that Ceramide is still transformed to Glycosylceramide at Golgi. Moreover, it has been shown that it does not inhibit the Sphingomyelin synthase in vitro or in vivo.[17]
Moreover, only the (1R, 3R) isomer of HPA-12 has been found to be an active inhibitor[17] and the length of the chain as well as the two hydroxyl-groups are very important for the inhibitory activity.[18]
# Clinical significance
This gene encodes a kinase also known as Goodpasture antigen-binding protein that specifically phosphorylates the N-terminal region of the non-collagenous domain of the alpha 3 chain of type IV collagen, known as the Goodpasture antigen. Goodpasture's syndrome is the result of an autoimmune response directed at this antigen. One isoform of this protein is also involved in ceramide intracellular transport. Two transcripts exist for this gene.[2]
# Model organisms
Model organisms have been used in the study of COL4A3BP function. A conditional knockout mouse line called Col4a3bptm1a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute.[19] Male and female animals underwent a standardized phenotypic screen[20] to determine the effects of deletion.[21][22][23][24] Additional screens performed: - In-depth immunological phenotyping[25] - in-depth bone and cartilage phenotyping[26] | https://www.wikidoc.org/index.php/COL4A3BP | |
993ec490af7b8c6e49e86864e3a60cc06e0b9507 | wikidoc | Troponin | Troponin
# Overview
Troponin is a complex of three proteins that is integral to muscle contraction in skeletal and cardiac muscle, but not smooth muscle. Troponin is attached to the protein tropomyosin and lies within the groove between actin filaments in muscle tissue. In a relaxed muscle, tropomyosin blocks the attachment site for the myosin crossbridge, thus preventing contraction. When the muscle cell is stimulated to contract by an action potential, calcium channels open in the sarcoplasmic reticulum and release calcium into the sarcoplasm. Some of this calcium attaches to troponin, causing a conformational change that moves tropomyosin out of the way so that the cross bridges can attach to actin and produce muscle contraction. Troponin is found in both skeletal muscle and cardiac muscle, but the specific versions of troponin differ between types of muscle. The main difference is that the TnC subunit of troponin in skeletal muscle has four calcium ion binding sites, whereas in cardiac muscle there are only three.
Discussions of troponin often pertain to its functional characteristics and/or to its usefulness as a diagnostic marker for various heart disorders. When cardiac injury occurs (such as in case of an acute MI), these intracellular proteins are then released into the bloodstream. Along with the patient's history and the electrocardiogram, the release of these enzymes forms the basis of the diagnosis of ST elevation myocardial infarction.
Until the 1980s, the enzymes SGOT and LDH were used to assess cardiac injury. In the early 1980s it was found that disproportional elevation of the MB subtype of the enzyme creatine kinase (CK) was very specific for myocardial injury. More recently, troponin sub-units I or T, have been used as an even more specific marker of myonecrosis. The 2007 Joint ESC/ACCF/AHA/WHF Task Force for the definition of myocardial infarction emphasized the importance of both elevated cardiac biomarkers and clinical evidence for MI.
# Physiologic Role of Troponins in the Absence of Disease
Both cardiac and skeletal muscles are controlled by changes in the intracellular calcium concentration. When calcium rises, the muscles contract, and when calcium falls the muscles relax.
Troponin is a component of thin filaments (along with actin and tropomyosin), and is the protein to which calcium binds to accomplish this regulation. Troponin has three subunits, TnC, TnI, and TnT. When calcium is bound to specific sites on TnC, tropomyosin rolls out of the way of the actin filament active sites, so that myosin (a molecular motor organized in muscle thick filaments) can attach to the thin filament and produce force and/or movement. In the absence of calcium, tropomyosin interferes with this action of myosin, and therefore muscles remain relaxed.
Troponin I has also been shown to inhibit angiogenesis in vivo and in vitro.
Individual subunits serve different functions:
- Troponin C binds to calcium ions to produce a conformational change in TnI
- Troponin T binds to tropomyosin, interlocking them to form a troponin-tropomyosin complex
- Troponin I binds to actin in thin myofilaments to hold the troponin-tropomyosin complex in place
# Diagnostic Use
See also Acute coronary syndromes
Two subtypes of troponin (cardiac troponin I and T) are very sensitive and specific indicators of damage to the heart muscle (myocardium). The agreement between hscTNT and hscTNI measurements is excellent (Cohen's kappa =0.9).
One of the more common uses of troponin is to determine if a patient with chest pain has sustained death of the myocytes (heart muscle cells) as a result of thrombotic (blood clot related) occlusion of a coronary artery which would warrant urgent medical or interventional therapy. The level of troponin is measured in the bloodstream and it is used to differentiate between unstable angina (no elevation of troponin, the myocardium is not irreversibly damaged) versus either non ST elevation MI or ST elevation MI (heart attack) in patients with chest pain. Troponin is a simple yet potent tool for risk stratification. If a patient is troponin positive, and has signs and symptoms of ischemic heart disease (substernal chest pain or pressure, electrocardiographic EKG changes), then an early invasive strategy is warranted. This should be preceded by aggressive antiplatelet and antithrombin therapy (see acute coronary syndromes).
## Use of Troponin to "Rule Out" or "Rule In" a Heart Attack
While it is commonly said that a negative troponin "rules out" a non ST elevation MI or ST elevation MI, it should be noted that among those patients who are ultimately found to be troponin positive, approximately 20% will be troponin negative at the time of the initial testing. These patients are sometimes referred to as an "MI in evolution" and form the basis for checking serial or multiple troponins in a monitored setting. A negative troponin on a single test does not exclude the possibility that the patient has ongoing myonecrosis.
On the other hand, a positive troponin does not "rule in" (i.e. does not allow one to conclude) that there is a thrombotic occlusion of the epicardial artery. As shown below, there are a wide variety of other causes for an elevated troponin.
## Role of Pre-Test Probability in the Positive Predictive Value of Troponin
If troponin values are checked in a population with a low pre-test probability of disease, then the positive predictive value of the test will drop dramatically. Patients who have a low pre-test probability of an acute coronary syndrome (negative family history, few or absent cardiac risk factors, absent EKG changes, absent ischemic chest pain) do not derive benefit from an early invasive strategy. Identification of an alternate source of the troponin other than an acute coronary syndrome should be sought and the underlying disease treated. Not all troponin positive patients should undergo cardiac catheterization. Indeed, patients with a low pre-test probability of heart disease should not be treated with aggressive antiplatelet therapy, antithrombin therapy, diagnostic catheterization and revascularization.
## Absence of Troponin Elevation in the General Population
Among 3,557 individuals in the general population, only 0.7% of patients had a troponin ≥0.01 microg/L, which is > than the 99th percentile of the reference range. The underlying disease state in those individuals with elevated troponins included chronic kidney disease, heart failure, left ventricular hypertrophy and diabetes.
## Prognostic Value of an Elevated Troponin in the Absence of Thrombotic Acute Coronary Syndromes
Even in the absence of an acute coronary syndrome, and in the presence of "normal coronary arteries" on diagnostic cardiac catheterization, an elevated troponin is associated with adverse outcomes. There is no data to suggest that aggressive antiplatelet and / or antithrombin strategies improve clinical outcomes in these patients who are often critically ill from non-cardiac conditions. Aspirin is safe to administer to these patients.
# General Mechanisms by Which Troponin May be Elevated in Disease
## 1. Injury or Death of Heart Muscle Cells due to Reduced Oxygen Supply
In these scenarios there is reduced blood flow to the heart muscle:
## 2. Injury or Death of the Heart Muscle Cells due to Increased Demands for Oxygen
Classic example of this would the patient with tachycardia and strenuous exercise such as a marathon or the patient with new onset atrial fibrillation and a rapid ventricular response. This form of myonecrosis is classified as a Type II MI in the new universal definition of MI proposed by the 2007 Joint European Society of Cardiology/American College of Cardiology/American Heart Association/World Health Federation (ESC/ACCF/AHA/WHF). Demand can be increased due to tachycardia, increased oxygen consumption and changes in loading conditions. Sepsis is associated with troponin elevations in part due to this mechanism, and in part due to the increased permeability of myocytes during sepsis.
## 3. Injury or Death of the Myocytes due to Increased Stretch of the Cells
Patients with congestive heart failure, pulmonary hypertension and acute valvular disorders such as aortic insufficiency often have dilated hearts. Both subendocardial ischemia and excess stretch due to the dilation may damage the myocytes. Increase demand due to tachycardia and subendocardial ischemia may play a role as well.
## 4. Direct Injury of the Heart Muscle Cells
## 5. Drug toxicity or toxins
Drug toxicity such as high-dose chemotherapy and compounds such as adriamycin, 5-flurouracil, herceptin, snake venom
## 6. Leakage of Troponin from the Heart Muscle Cells
A classic example is sepsis.
## 7. Reduced Clearance of Troponin from the Bloodstream
A classic example of this would include renal failure.
# "False Positive" Troponin Elevations That Are Not Due to Thrombotic Coronary Occlusion
Again, it should be re-emphasized that while a troponin elevation reflects myocardial injury, thrombotic occlusion of an epicardial coronary artery is just one of many causes of myocardial injury. Non-thrombotic causes of an elevated troponin are often referred to as "false positive" causes of a troponin elevation. Troponin release in the context of coronary thrombosis and vessel occlusion is due to irreversible damage (myocyte necrosis or cell death) with the release of the intracardiac enzymes into the bloodstream as the myocyte's cell membranes break down. However, in the absence of thrombotic occlusion of a coronary artery, troponin can also be released from myocytes in the absence of necrosis or cell death. This release can occur as a result of changes in the permeability of the cell membrane. Sepsis for instance can cause the breakdown of troponin to lower-molecular-weight fragments that can then leak into the bloodstream through a myocyte membrane that is also rendered more porous by sepsis. The fact that patients who survive sepsis do not have an irreversible decline in LV function supports this mechanism as well. Among patients who have an elevated troponin and a normal angiogram, a very small study of 21 patients identified the following as the underlying causes :
- 47% No clear precipitant
- 28% Tachycardia
- 10% Strenuous exercise
- 10% Pericarditis
- 5% Congestive heart failure
## Non-Thrombotic Cardiac Causes of Troponin Elevation
- Ablation procedures to treat arrhythmias
- Amyloidosis and other cardiac infiltrative disorders
- Aortic dissection
- Atrial septal defect closure
- Cardiac contusion (blunt chest wall trauma)
- Cardiac surgery and heart transplant
- Cardioversion
- Defibrillation and defibrillator implantation
- Congestive heart failure
- Coronary artery vasospasm
- Dilated cardiomyopathy
- Endomyocardial biopsy
- Heart block
- Heart failure (acute or chronic)
- Hypertrophic cardiomyopathy
- Hypertension
- Hypotension
- Kawasaki disease. Troponin elevations have been variably associated with Kawasaki's disease and it has been speculated that the troponin elevation may reflect the underlying myositis.
- Myocarditis
- Percutaneous coronary intervention
- Pericarditis
- Pulmonary hypertension
- Radiofrequency ablation
- Stress cardiomyopathy (Apical ballooning syndrome, Takotsubo Cardiomyopathy)
- Supraventricular tachycardia including atrial fibrillation
- Transplant vasculopathy
## Non-cardiac Causes of Troponin Elevation
- Burns, especially if it affects >25 percent of body surface area
- Critical illness, e.g. sepsis
- Drug toxicity such as high-dose chemotherapy and compounds such as adriamycin, 5-flurouracil, herceptin, snake venom
- Diabetes
- Strenuous exercise (e.g. marathon)
- Hypovolemia
- Hypothyroidism
- Infiltrative disorders like amyloidosis, hemochromatosis, sarcoidosis, and scleroderma
- Pulmonary embolism
- Intracranial hemorrhage
- Pulmonary hypertension
- Renal failure
- Respiratory failure
- Rhabdomyolysis with cardiac injury
- Severe asthma
- Subarachnoid hemorrhage
- Scorpion venom
- Stroke
- Sympathomimetic ingestion
# Technical Aspects
Cardiac troponin T (cTnT) and I (cTnI) are measured by immunoassay methods. A single manufacturer distributes cTnT but a host of diagnostic companies make cTnI methods available on many different immunoassay platforms.
Drug-induced cardiotoxicity is common to all classes of therapeutic drugs. It is essential that cardiotoxicity is detected with a high degree of sensitivity and specificity. The newly developed troponins are especially useful in this context
# Troponin Elevation During Pregnancy
- Troponin is validated for the diagnosis of AMI in pregnancy.
- After normal delivery, troponin concentration may slightly increase. The increase may be above or below the upper limit of normal.
- More prominent troponin concentration elevation is observed among women with pre-eclampsia or gestational hypertension.
- To view changes in CK and CK-MB concentrations during labor and delivery, click here. | Troponin
Editor-in-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
# Overview
Troponin is a complex of three proteins that is integral to muscle contraction in skeletal and cardiac muscle, but not smooth muscle. Troponin is attached to the protein tropomyosin and lies within the groove between actin filaments in muscle tissue. In a relaxed muscle, tropomyosin blocks the attachment site for the myosin crossbridge, thus preventing contraction. When the muscle cell is stimulated to contract by an action potential, calcium channels open in the sarcoplasmic reticulum and release calcium into the sarcoplasm. Some of this calcium attaches to troponin, causing a conformational change that moves tropomyosin out of the way so that the cross bridges can attach to actin and produce muscle contraction. Troponin is found in both skeletal muscle and cardiac muscle, but the specific versions of troponin differ between types of muscle. The main difference is that the TnC subunit of troponin in skeletal muscle has four calcium ion binding sites, whereas in cardiac muscle there are only three.
Discussions of troponin often pertain to its functional characteristics and/or to its usefulness as a diagnostic marker for various heart disorders. When cardiac injury occurs (such as in case of an acute MI), these intracellular proteins are then released into the bloodstream. Along with the patient's history and the electrocardiogram, the release of these enzymes forms the basis of the diagnosis of ST elevation myocardial infarction.
Until the 1980s, the enzymes SGOT and LDH were used to assess cardiac injury. In the early 1980s it was found that disproportional elevation of the MB subtype of the enzyme creatine kinase (CK) was very specific for myocardial injury. More recently, troponin sub-units I or T, have been used as an even more specific marker of myonecrosis.[1][2][3] The 2007 Joint ESC/ACCF/AHA/WHF Task Force[4] for the definition of myocardial infarction emphasized the importance of both elevated cardiac biomarkers and clinical evidence for MI.
# Physiologic Role of Troponins in the Absence of Disease
Both cardiac and skeletal muscles are controlled by changes in the intracellular calcium concentration. When calcium rises, the muscles contract, and when calcium falls the muscles relax.
Troponin is a component of thin filaments (along with actin and tropomyosin), and is the protein to which calcium binds to accomplish this regulation. Troponin has three subunits, TnC, TnI, and TnT. When calcium is bound to specific sites on TnC, tropomyosin rolls out of the way of the actin filament active sites, so that myosin (a molecular motor organized in muscle thick filaments) can attach to the thin filament and produce force and/or movement. In the absence of calcium, tropomyosin interferes with this action of myosin, and therefore muscles remain relaxed.
Troponin I has also been shown to inhibit angiogenesis in vivo and in vitro.
Individual subunits serve different functions:
- Troponin C binds to calcium ions to produce a conformational change in TnI
- Troponin T binds to tropomyosin, interlocking them to form a troponin-tropomyosin complex
- Troponin I binds to actin in thin myofilaments to hold the troponin-tropomyosin complex in place
# Diagnostic Use
See also Acute coronary syndromes
Two subtypes of troponin (cardiac troponin I and T) are very sensitive and specific indicators of damage to the heart muscle (myocardium). The agreement between hscTNT and hscTNI measurements is excellent (Cohen's kappa =0.9)[5].
One of the more common uses of troponin is to determine if a patient with chest pain has sustained death of the myocytes (heart muscle cells) as a result of thrombotic (blood clot related) occlusion of a coronary artery which would warrant urgent medical or interventional therapy. The level of troponin is measured in the bloodstream and it is used to differentiate between unstable angina (no elevation of troponin, the myocardium is not irreversibly damaged) versus either non ST elevation MI or ST elevation MI (heart attack) in patients with chest pain. Troponin is a simple yet potent tool for risk stratification. If a patient is troponin positive, and has signs and symptoms of ischemic heart disease (substernal chest pain or pressure, electrocardiographic EKG changes), then an early invasive strategy is warranted. This should be preceded by aggressive antiplatelet and antithrombin therapy (see acute coronary syndromes).
## Use of Troponin to "Rule Out" or "Rule In" a Heart Attack
While it is commonly said that a negative troponin "rules out" a non ST elevation MI or ST elevation MI, it should be noted that among those patients who are ultimately found to be troponin positive, approximately 20% will be troponin negative at the time of the initial testing. These patients are sometimes referred to as an "MI in evolution" and form the basis for checking serial or multiple troponins in a monitored setting. A negative troponin on a single test does not exclude the possibility that the patient has ongoing myonecrosis.
On the other hand, a positive troponin does not "rule in" (i.e. does not allow one to conclude) that there is a thrombotic occlusion of the epicardial artery. As shown below, there are a wide variety of other causes for an elevated troponin.
## Role of Pre-Test Probability in the Positive Predictive Value of Troponin
If troponin values are checked in a population with a low pre-test probability of disease, then the positive predictive value of the test will drop dramatically. Patients who have a low pre-test probability of an acute coronary syndrome (negative family history, few or absent cardiac risk factors, absent EKG changes, absent ischemic chest pain) do not derive benefit from an early invasive strategy. Identification of an alternate source of the troponin other than an acute coronary syndrome should be sought and the underlying disease treated. Not all troponin positive patients should undergo cardiac catheterization. Indeed, patients with a low pre-test probability of heart disease should not be treated with aggressive antiplatelet therapy, antithrombin therapy, diagnostic catheterization and revascularization.
## Absence of Troponin Elevation in the General Population
Among 3,557 individuals in the general population, only 0.7% of patients had a troponin ≥0.01 microg/L, which is > than the 99th percentile of the reference range. The underlying disease state in those individuals with elevated troponins included chronic kidney disease, heart failure, left ventricular hypertrophy and diabetes.[6]
## Prognostic Value of an Elevated Troponin in the Absence of Thrombotic Acute Coronary Syndromes
Even in the absence of an acute coronary syndrome, and in the presence of "normal coronary arteries" on diagnostic cardiac catheterization, an elevated troponin is associated with adverse outcomes.[7] There is no data to suggest that aggressive antiplatelet and / or antithrombin strategies improve clinical outcomes in these patients who are often critically ill from non-cardiac conditions. Aspirin is safe to administer to these patients.
# General Mechanisms by Which Troponin May be Elevated in Disease
## 1. Injury or Death of Heart Muscle Cells due to Reduced Oxygen Supply
In these scenarios there is reduced blood flow to the heart muscle:
## 2. Injury or Death of the Heart Muscle Cells due to Increased Demands for Oxygen
Classic example of this would the patient with tachycardia and strenuous exercise such as a marathon or the patient with new onset atrial fibrillation and a rapid ventricular response.[9] This form of myonecrosis is classified as a Type II MI in the new universal definition of MI proposed by the 2007 Joint European Society of Cardiology/American College of Cardiology/American Heart Association/World Health Federation (ESC/ACCF/AHA/WHF). [10] Demand can be increased due to tachycardia, increased oxygen consumption and changes in loading conditions. Sepsis is associated with troponin elevations in part due to this mechanism, and in part due to the increased permeability of myocytes during sepsis.[11] [12][13]
## 3. Injury or Death of the Myocytes due to Increased Stretch of the Cells
Patients with congestive heart failure, pulmonary hypertension and acute valvular disorders such as aortic insufficiency often have dilated hearts. Both subendocardial ischemia and excess stretch due to the dilation may damage the myocytes. Increase demand due to tachycardia and subendocardial ischemia may play a role as well.
## 4. Direct Injury of the Heart Muscle Cells
## 5. Drug toxicity or toxins
Drug toxicity such as high-dose chemotherapy and compounds such as adriamycin, 5-flurouracil, herceptin, snake venom
## 6. Leakage of Troponin from the Heart Muscle Cells
A classic example is sepsis. [14] [15][16]
## 7. Reduced Clearance of Troponin from the Bloodstream
A classic example of this would include renal failure.
# "False Positive" Troponin Elevations That Are Not Due to Thrombotic Coronary Occlusion
Again, it should be re-emphasized that while a troponin elevation reflects myocardial injury, thrombotic occlusion of an epicardial coronary artery is just one of many causes of myocardial injury. Non-thrombotic causes of an elevated troponin are often referred to as "false positive" causes of a troponin elevation. [17] [18] [19] Troponin release in the context of coronary thrombosis and vessel occlusion is due to irreversible damage (myocyte necrosis or cell death) with the release of the intracardiac enzymes into the bloodstream as the myocyte's cell membranes break down. However, in the absence of thrombotic occlusion of a coronary artery, troponin can also be released from myocytes in the absence of necrosis or cell death. This release can occur as a result of changes in the permeability of the cell membrane. Sepsis for instance can cause the breakdown of troponin to lower-molecular-weight fragments that can then leak into the bloodstream through a myocyte membrane that is also rendered more porous by sepsis. [20] The fact that patients who survive sepsis do not have an irreversible decline in LV function supports this mechanism as well. [21] Among patients who have an elevated troponin and a normal angiogram, a very small study of 21 patients identified the following as the underlying causes [22]:
- 47% No clear precipitant
- 28% Tachycardia
- 10% Strenuous exercise
- 10% Pericarditis
- 5% Congestive heart failure
## Non-Thrombotic Cardiac Causes of Troponin Elevation
- Ablation procedures to treat arrhythmias
- Amyloidosis and other cardiac infiltrative disorders
- Aortic dissection
- Atrial septal defect closure
- Cardiac contusion (blunt chest wall trauma)
- Cardiac surgery and heart transplant
- Cardioversion
- Defibrillation and defibrillator implantation
- Congestive heart failure
- Coronary artery vasospasm
- Dilated cardiomyopathy
- Endomyocardial biopsy
- Heart block
- Heart failure (acute or chronic)
- Hypertrophic cardiomyopathy
- Hypertension
- Hypotension
- Kawasaki disease. Troponin elevations have been variably associated with Kawasaki's disease and it has been speculated that the troponin elevation may reflect the underlying myositis.[23]
- Myocarditis
- Percutaneous coronary intervention
- Pericarditis
- Pulmonary hypertension
- Radiofrequency ablation
- Stress cardiomyopathy (Apical ballooning syndrome, Takotsubo Cardiomyopathy)
- Supraventricular tachycardia including atrial fibrillation
- Transplant vasculopathy
## Non-cardiac Causes of Troponin Elevation
- Burns, especially if it affects >25 percent of body surface area
- Critical illness, e.g. sepsis
- Drug toxicity such as high-dose chemotherapy and compounds such as adriamycin, 5-flurouracil, herceptin, snake venom
- Diabetes
- Strenuous exercise (e.g. marathon)
- Hypovolemia
- Hypothyroidism
- Infiltrative disorders like amyloidosis, hemochromatosis, sarcoidosis, and scleroderma
- Pulmonary embolism
- Intracranial hemorrhage
- Pulmonary hypertension
- Renal failure
- Respiratory failure
- Rhabdomyolysis with cardiac injury
- Severe asthma
- Subarachnoid hemorrhage
- Scorpion venom
- Stroke
- Sympathomimetic ingestion
# Technical Aspects
Cardiac troponin T (cTnT) and I (cTnI) are measured by immunoassay methods. A single manufacturer distributes cTnT but a host of diagnostic companies make cTnI methods available on many different immunoassay platforms.[24]
Drug-induced cardiotoxicity is common to all classes of therapeutic drugs. It is essential that cardiotoxicity is detected with a high degree of sensitivity and specificity. The newly developed troponins are especially useful in this context[25]
# Troponin Elevation During Pregnancy
- Troponin is validated for the diagnosis of AMI in pregnancy.[26][27][28][29]
- After normal delivery, troponin concentration may slightly increase. The increase may be above or below the upper limit of normal.[26]
- More prominent troponin concentration elevation is observed among women with pre-eclampsia or gestational hypertension.[28][29]
- To view changes in CK and CK-MB concentrations during labor and delivery, click here. | https://www.wikidoc.org/index.php/CTnI | |
09d269c50f3478bf88065c2214572f94c16172f2 | wikidoc | Cachexia | Cachexia
# Overview
Cachexia (Template:PronEng) is loss of weight, muscle atrophy, fatigue, weakness and significant loss of appetite in someone who is not actively trying to lose weight. It can be a sign of various underlying disorders; when a patient presents with cachexia, a doctor will generally consider the possibility of cancer, certain infectious diseases (e.g. tuberculosis, AIDS) and some autoimmune disorders, or addiction to drugs such as amphetamines or cocaine.
Cachexia physically weakens patients to a state of immobility stemming from loss of appetite, asthenia, and anemia, and response to standard treatment is usually poor.
# Disease settings
Cachexia is often seen in end-stage cancer, and in that context is called "cancer cachexia". It was also prevalent in AIDS patients before the advent of triple-therapy for that condition; now it is seen less frequently in those countries where such treatment is available. In those patients who have Congestive Heart Failure, there is also a cachectic syndrome. Also, a cachexia co-morbidity is seen in patients that have any of the range of illnesses classified as "COPD" (chronic obstructive pulmonary disease), particularly emphysema. Some severe cases of schizophrenia can present this condition where it is named vesanic cachexia.
In each of these settings there is full-body wasting, which hits the skeletal muscle especially hard, resulting in muscle atrophy.
- Cachexia
# Mechanism
The exact mechanism in which these diseases cause cachexia is poorly understood, but there is probably a role for inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) -which is also nicknamed cachexin for this reason-, Interferon gamma (IFNɣ), and Interleukin 6 (IL-6), as well as the tumor secreted proteolysis inducing factor (PIF).
Related malnutrition syndromes are kwashiorkor and marasmus, although these do not always have an underlying causative illness; they are most often symptomatic of severe malnutrition.
Those suffering from the eating disorder anorexia nervosa appear to have high plasma levels of ghrelin. Ghrelin levels are also high in patients who have cancer-induced cachexia (Garcia et al 2005).
# Causes
## Common Causes
- AIDS
- Cancer cachexia
- Cardiac cachexia
## Causes by Organ System
## Causes in Alphabetical Order
- Acute myelosclerosis
- Addison's disease
- AIDS
- Amphetamine
- Andrade's disease
- Anorexia nervosa
- Atypical pneumonia
- Breast cancer
- Brucellosis
- Cancer cachexia
- Cardiac cachexia
- Celiac disease
- Chemotherapy
- Chronic diarrhea
- Chronic lymphocytic leukaemia
- Chronic renal failure
- Cidofovir
- Colorectal cancer
- Congestive heart failure
- COPD
- Crohn's disease
- Cystic fibrosis
- Depression
- Endocarditis
- Familial amyloid polyneuropathy
- Hepatitis B
- Kaposi sarcoma
- Leishmaniasis
- Leukemia
- Liver cancer
- Lung abscess
- Malignancy
- Mastocytosis
- Mercury
- Metabolic acidosis
- Metastatic neoplasm
- Multiple sclerosis
- Mycobacterium tuberculosis
- Myeloma
- Pancreatic cancer
- Paraneoplastic syndrome
- Pergolide
- Polyarteritis nodosa
- Radiotherapy
- Sarcoidosis
- Sepsis
- Starvation
- Stomach cancer
- Systemic lupus erythematosus
- Trypanosomiasis
- Tuberculosis
- Visceral leishmaniasis | Cachexia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
# Overview
Cachexia (Template:PronEng) is loss of weight, muscle atrophy, fatigue, weakness and significant loss of appetite in someone who is not actively trying to lose weight. It can be a sign of various underlying disorders; when a patient presents with cachexia, a doctor will generally consider the possibility of cancer, certain infectious diseases (e.g. tuberculosis, AIDS) and some autoimmune disorders, or addiction to drugs such as amphetamines or cocaine.
Cachexia physically weakens patients to a state of immobility stemming from loss of appetite, asthenia, and anemia, and response to standard treatment is usually poor.
# Disease settings
Cachexia is often seen in end-stage cancer, and in that context is called "cancer cachexia". It was also prevalent in AIDS patients before the advent of triple-therapy for that condition; now it is seen less frequently in those countries where such treatment is available. In those patients who have Congestive Heart Failure, there is also a cachectic syndrome. Also, a cachexia co-morbidity is seen in patients that have any of the range of illnesses classified as "COPD" (chronic obstructive pulmonary disease), particularly emphysema. Some severe cases of schizophrenia can present this condition where it is named vesanic cachexia.[1]
In each of these settings there is full-body wasting, which hits the skeletal muscle especially hard, resulting in muscle atrophy.
- Cachexia
# Mechanism
The exact mechanism in which these diseases cause cachexia is poorly understood, but there is probably a role for inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) -which is also nicknamed cachexin for this reason-, Interferon gamma (IFNɣ), and Interleukin 6 (IL-6), as well as the tumor secreted proteolysis inducing factor (PIF).
Related malnutrition syndromes are kwashiorkor and marasmus, although these do not always have an underlying causative illness; they are most often symptomatic of severe malnutrition.
Those suffering from the eating disorder anorexia nervosa appear to have high plasma levels of ghrelin. Ghrelin levels are also high in patients who have cancer-induced cachexia (Garcia et al 2005).
# Causes
## Common Causes
- AIDS
- Cancer cachexia
- Cardiac cachexia
## Causes by Organ System
## Causes in Alphabetical Order
- Acute myelosclerosis
- Addison's disease
- AIDS
- Amphetamine
- Andrade's disease
- Anorexia nervosa
- Atypical pneumonia
- Breast cancer
- Brucellosis
- Cancer cachexia
- Cardiac cachexia
- Celiac disease
- Chemotherapy
- Chronic diarrhea
- Chronic lymphocytic leukaemia
- Chronic renal failure
- Cidofovir
- Colorectal cancer
- Congestive heart failure
- COPD
- Crohn's disease
- Cystic fibrosis
- Depression
- Endocarditis
- Familial amyloid polyneuropathy
- Hepatitis B
- Kaposi sarcoma
- Leishmaniasis
- Leukemia
- Liver cancer
- Lung abscess
- Malignancy
- Mastocytosis
- Mercury
- Metabolic acidosis
- Metastatic neoplasm
- Multiple sclerosis
- Mycobacterium tuberculosis
- Myeloma
- Pancreatic cancer
- Paraneoplastic syndrome
- Pergolide
- Polyarteritis nodosa
- Radiotherapy
- Sarcoidosis
- Sepsis
- Starvation
- Stomach cancer
- Systemic lupus erythematosus
- Trypanosomiasis
- Tuberculosis
- Visceral leishmaniasis | https://www.wikidoc.org/index.php/Cachexia | |
e54eac13824c85d5c4910dfdfec8670197e54bcf | wikidoc | Cadherin | Cadherin
# Overview
Cadherins are a class of type-1 transmembrane proteins. They play important roles in cell adhesion, ensuring that cells within tissues are bound together. They are dependent on calcium (Ca2+) ions to function, hence their name.
The cadherin superfamily includes cadherins, protocadherins, desmogleins, and desmocollins, and more. In structure, they share cadherin repeats, which are the extracellular Ca2+-binding domains. There are multiple classes of cadherin molecule, each designated with a one-letter prefix (generally noting the type of tissue with which it is associated). Cadherins within one class will bind only to themselves. For example, an N-cadherin will bind only to another N-cadherin molecule. Because of this specificity, groups of cells that express the same type of cadherin molecule tend to cluster together during development, whereas cells expressing different types of cadherin molecules tend to separate.
# Types
Different members of the cadherin family are found in different locations.
E-cadherins are found in epithelial tissue; N-cadherins are found in neurons; and P-cadherins are found in the placenta. T-cadherins have no cytoplasmic domains and must be tethered to the plasma membrane.
# E-cadherin
E-cadherin (epithelial) is probably the best understood cadherin. It consists of 5 cadherin repeats (EC1 ~ EC5) in the extracellular domain, one transmembrane domain, and an intracellular domain that binds p120-catenin and beta-catenin. The intracellular domain contains a highly-phosphorylated region vital to beta-catenin binding and therefore to E-cadherin function. Beta-catenin can also bind to alpha-catenin. Alpha-catenin participates in regulation of actin-containing cytoskeletal filaments. In epithelial cells, E-cadherin-containing cell-to-cell junctions are often adjacent to actin-containing filaments of the cytoskeleton.
E-cadherin is first expressed in the 2-cell stage of mammalian development, and becomes phosphorylated by the 8-cell stage, where it causes compaction. In adult tissues, E-cadherin is expressed in epithelial tissues, where it is constantly regenerated with a 5-hour half-life on the cell surface.
Loss of E-cadherin function or expression has been implicated in cancer progression and metastasis. E-cadherin downregulation decreases the strength of cellular adhesion within a tissue, resulting in an increase in cellular motility. This in turn may allow cancer cells to cross the basement membrane and invade surrounding tissues. | Cadherin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Cadherins are a class of type-1 transmembrane proteins. They play important roles in cell adhesion, ensuring that cells within tissues are bound together. They are dependent on calcium (Ca2+) ions to function, hence their name.
The cadherin superfamily includes cadherins, protocadherins, desmogleins, and desmocollins, and more. In structure, they share cadherin repeats, which are the extracellular Ca2+-binding domains. There are multiple classes of cadherin molecule, each designated with a one-letter prefix (generally noting the type of tissue with which it is associated). Cadherins within one class will bind only to themselves. For example, an N-cadherin will bind only to another N-cadherin molecule. Because of this specificity, groups of cells that express the same type of cadherin molecule tend to cluster together during development, whereas cells expressing different types of cadherin molecules tend to separate.
# Types
Different members of the cadherin family are found in different locations.
E-cadherins are found in epithelial tissue; N-cadherins are found in neurons; and P-cadherins are found in the placenta. T-cadherins have no cytoplasmic domains and must be tethered to the plasma membrane.
# E-cadherin
E-cadherin (epithelial) is probably the best understood cadherin. It consists of 5 cadherin repeats (EC1 ~ EC5) in the extracellular domain, one transmembrane domain, and an intracellular domain that binds p120-catenin and beta-catenin. The intracellular domain contains a highly-phosphorylated region vital to beta-catenin binding and therefore to E-cadherin function. Beta-catenin can also bind to alpha-catenin. Alpha-catenin participates in regulation of actin-containing cytoskeletal filaments. In epithelial cells, E-cadherin-containing cell-to-cell junctions are often adjacent to actin-containing filaments of the cytoskeleton.
E-cadherin is first expressed in the 2-cell stage of mammalian development, and becomes phosphorylated by the 8-cell stage, where it causes compaction. In adult tissues, E-cadherin is expressed in epithelial tissues, where it is constantly regenerated with a 5-hour half-life on the cell surface.
Loss of E-cadherin function or expression has been implicated in cancer progression and metastasis. E-cadherin downregulation decreases the strength of cellular adhesion within a tissue, resulting in an increase in cellular motility. This in turn may allow cancer cells to cross the basement membrane and invade surrounding tissues. | https://www.wikidoc.org/index.php/Cadherin | |
09e293cb2c7bf2fad4b09fa8bc17c9daf2bf0803 | wikidoc | Caecitis | Caecitis
# Overview
Caecitis, also called typhlitis or typhlenteritis, is an inflammation of the caecum (part of the small intestine) that may be associated with infection.
# Cause
The condition is usually caused by gram negative enteric commensal bacteria of the gut (gut flora). The most common agent associated with the condition is Pseudomonas aeruginosa.
Caecitis affects immunocompromised patients, such as those undergoing chemotherapy, patients with AIDS, kidney transplant patients, or the elderly.
# Signs and symptoms
Signs and symptoms of caecitis include a distended abdomen, fever, chills, nausea, vomiting, abdominal pain and tenderness, and diarrhea.
# Prognosis
Inflammation can spread to other parts of the gut in patients with caecitis.
The condition can also cause the cecum to become distended and can cut off its blood supply. This and other factors can result in necrosis and perforation of the bowel, which can cause peritonitis and sepsis. The mortality rate for caecitis can be as high as 40 to 50%, mostly because it is frequently associated with bowel perforation. Caecitis is diagnosed with a radiograph CT scan showing thickening of the caecum and "fat stranding". | Caecitis
# Overview
Caecitis, also called typhlitis or typhlenteritis, is an inflammation of the caecum (part of the small intestine) that may be associated with infection.[1]
# Cause
The condition is usually caused by gram negative enteric commensal bacteria of the gut (gut flora). The most common agent associated with the condition is Pseudomonas aeruginosa.
Caecitis affects immunocompromised patients, such as those undergoing chemotherapy, patients with AIDS, kidney transplant patients, or the elderly[2].
# Signs and symptoms
Signs and symptoms of caecitis include a distended abdomen, fever, chills, nausea, vomiting, abdominal pain and tenderness, and diarrhea.[2]
# Prognosis
Inflammation can spread to other parts of the gut in patients with caecitis.
The condition can also cause the cecum to become distended and can cut off its blood supply. This and other factors can result in necrosis and perforation of the bowel, which can cause peritonitis and sepsis.[3] The mortality rate for caecitis can be as high as 40 to 50%, mostly because it is frequently associated with bowel perforation.[2] Caecitis is diagnosed with a radiograph CT scan showing thickening of the caecum and "fat stranding". | https://www.wikidoc.org/index.php/Caecitis | |
d7d62eb76dff3854045c18833147cfceb06a7483 | wikidoc | Cafergot | Cafergot
Cafergot is the proprietary name of a medication consisting of ergotamine tartrate or ergoline and caffeine. This combination is used for the treatment of vascular headaches, such as migraine headache.
# Use
Correct timing of use is important. Cafergot is an abortive headache treatment, which prevents the development of the headache, rather than a treatment for an established headache. The medication should be administered at the first sign of headache.
# Mechanism of action
The causes of migraine are not fully understood, but dilation of blood vessels in the brain may play a part in causing the headache pain. Ergotamine tartrate and caffeine both are vasoconstrictors, substances which act to constrict blood vessels.
# Adverse effects
Because the vasoconstrictive effects of ergotamine and caffeine are not selective for the brain, adverse effects due to systemic vasoconstiction can occur. Cold feet or hands, angina pectoris or dizziness are some examples.
Ergotamine, if used frequently over a prolonged period of time, can cause dependence in the patient. If dependence occurs then cessation of ergotamine use can precipitate the same headaches which the drug was being used to treat. For this reason frequency of use must be restricted. | Cafergot
Cafergot is the proprietary name of a medication consisting of ergotamine tartrate or ergoline and caffeine. This combination is used for the treatment of vascular headaches, such as migraine headache.
# Use
Correct timing of use is important. Cafergot is an abortive headache treatment, which prevents the development of the headache, rather than a treatment for an established headache. The medication should be administered at the first sign of headache.
# Mechanism of action
The causes of migraine are not fully understood, but dilation of blood vessels in the brain may play a part in causing the headache pain. Ergotamine tartrate and caffeine both are vasoconstrictors, substances which act to constrict blood vessels.
# Adverse effects
Because the vasoconstrictive effects of ergotamine and caffeine are not selective for the brain, adverse effects due to systemic vasoconstiction can occur. Cold feet or hands, angina pectoris or dizziness are some examples.
Ergotamine, if used frequently over a prolonged period of time, can cause dependence in the patient. If dependence occurs then cessation of ergotamine use can precipitate the same headaches which the drug was being used to treat. For this reason frequency of use must be restricted.
Template:Pharma-stub
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Cafergot | |
efac3de9d9d7971c5bb9501b6b7911981b5e36e7 | wikidoc | Cage bed | Cage bed
A cage bed is a bed with either metal bars or netting designed to restrain a person within the boundaries of the bed.
Psychiatric practitioners in the Czech Republic have stubbornly defended the use of the beds, calling them the best way to restrain patients who could harm themselves or others. "We can either use cage beds, or increase people's medication, strap them down, or put them in solitary confinement," says Jan Slezak, director of Social Care Home in Raby, eastern Bohemia. "We see cage beds as the best solution."
A political campaign to ban the use of cage beds in the Czech Republic was popularized by author J. K. Rowling. | Cage bed
A cage bed is a bed with either metal bars or netting designed to restrain a person within the boundaries of the bed.
Psychiatric practitioners in the Czech Republic have stubbornly defended the use of the beds, calling them the best way to restrain patients who could harm themselves or others. "We can either use cage beds, or increase people's medication, strap them down, or put them in solitary confinement," says Jan Slezak, director of Social Care Home in Raby, eastern Bohemia. "We see cage beds as the best solution."[1]
A political campaign to ban the use of cage beds in the Czech Republic was popularized by author J. K. Rowling. [2]
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Cage_bed | |
8f2e631d3e490fa37daf5ce7ca80c437f752d938 | wikidoc | Calmurid | Calmurid
Calmurid is the name of a cream that is manufactured by Galderma. Calmurid Cream contains the active ingredients lactic acid and urea, whereas Calmurid HC contains an additional ingredient, the mild corticosteroid hydrocortisone.
Due to lactic acid's keratolytic properties (to break down hard skin cells) and urea's hydrating properties, Calmurid is used primarily in the treatment of dry, scaly skin. Ichthyosis and general dermatitis in the absence of inflammation are some of its indications.
When the extra steroid component is added (as in Calmurid HC), it is used to treat dry, scaly skin that is accompanied by inflammation of the skin. This may include various forms of eczema. The presence of a corticosteroid, however, means that the cream should be used only sparingly and only for the shortest time period due to possible side effects that may occur due to systemic absorption of the steroid. | Calmurid
Calmurid is the name of a cream that is manufactured by Galderma. Calmurid Cream contains the active ingredients lactic acid and urea, whereas Calmurid HC contains an additional ingredient, the mild corticosteroid hydrocortisone.
Due to lactic acid's keratolytic properties (to break down hard skin cells) and urea's hydrating properties, Calmurid is used primarily in the treatment of dry, scaly skin. Ichthyosis and general dermatitis in the absence of inflammation are some of its indications.
When the extra steroid component is added (as in Calmurid HC), it is used to treat dry, scaly skin that is accompanied by inflammation of the skin. This may include various forms of eczema. The presence of a corticosteroid, however, means that the cream should be used only sparingly and only for the shortest time period due to possible side effects that may occur due to systemic absorption of the steroid.
Template:Pharma-stub | https://www.wikidoc.org/index.php/Calmurid | |
aaa4fcbdc770a77de04c99c726c2daac28e7b689 | wikidoc | Calnexin | Calnexin
Calnexin (CNX) is a 67kDa integral protein (that appears variously as a 90kDa, 80kDa, or 75kDa band on western blotting depending on the source of the antibody) of the endoplasmic reticulum (ER). It consists of a large (50 kDa) N-terminal calcium-binding lumenal domain, a single transmembrane helix and a short (90 residues), acidic cytoplasmic tail.
# Function
Calnexin is a chaperone, characterized by assisting protein folding and quality control, ensuring that only properly folded and assembled proteins proceed further along the secretory pathway. It specifically acts to retain unfolded or unassembled N-linked glycoproteins in the ER. Calnexin binds only those N-glycoproteins that have GlcNAc2Man9Glc1 oligosaccharides. These monoglucosylated oligosaccharides result from the trimming of two glucose residues by the sequential action of two glucosidases, I and II. Glucosidase II can also remove the third and last glucose residue. If the glycoprotein is not properly folded, an enzyme called UGGT (for UDP-glucose:glycoprotein glucosyltransferase) will add the glucose residue back onto the oligosaccharide thus regenerating the glycoprotein's ability to bind to calnexin. The improperly-folded glycoprotein chain thus loiters in the ER, risking the encounter with MNS1 (alpha-mannosidase), which eventually sentences the underperforming glycoprotein to degradation by removing one of the nine mannose residues. If the protein is correctly translated, the chance of it being correctly folded before it encounters MNS1 is high.
Calnexin also functions as a chaperone for the folding of MHC class I α-chain in the membrane of the ER. As newly synthesized MHC class I α-chains enter the endoplasmic reticulum, calnexin binds on to them retaining them in a partly folded state. After the β2-microglobulin binds to the MHC class I peptide-loading complex (PLC), calreticulin and ERp57 take over the job of chaperoning the MHC class I protein while the tapasin links the complex to the Transporter associated with antigen processing (TAP) complex. This association prepares the MHC class I for binding an antigen for presentation on the cell surface.
# Cofactors
ATP and calcium ions are cofactors involved in substrate binding for calnexin. | Calnexin
Calnexin (CNX) is a 67kDa integral protein (that appears variously as a 90kDa, 80kDa, or 75kDa band on western blotting depending on the source of the antibody) of the endoplasmic reticulum (ER). It consists of a large (50 kDa) N-terminal calcium-binding lumenal domain, a single transmembrane helix and a short (90 residues), acidic cytoplasmic tail.
# Function
Calnexin is a chaperone, characterized by assisting protein folding and quality control, ensuring that only properly folded and assembled proteins proceed further along the secretory pathway. It specifically acts to retain unfolded or unassembled N-linked glycoproteins in the ER. Calnexin binds only those N-glycoproteins that have GlcNAc2Man9Glc1 oligosaccharides. These monoglucosylated oligosaccharides result from the trimming of two glucose residues by the sequential action of two glucosidases, I and II. Glucosidase II can also remove the third and last glucose residue. If the glycoprotein is not properly folded, an enzyme called UGGT (for UDP-glucose:glycoprotein glucosyltransferase) will add the glucose residue back onto the oligosaccharide thus regenerating the glycoprotein's ability to bind to calnexin. The improperly-folded glycoprotein chain thus loiters in the ER, risking the encounter with MNS1 (alpha-mannosidase), which eventually sentences the underperforming glycoprotein to degradation by removing one of the nine mannose residues. If the protein is correctly translated, the chance of it being correctly folded before it encounters MNS1 is high.
Calnexin also functions as a chaperone for the folding of MHC class I α-chain in the membrane of the ER. As newly synthesized MHC class I α-chains enter the endoplasmic reticulum, calnexin binds on to them retaining them in a partly folded state.[1] After the β2-microglobulin binds to the MHC class I peptide-loading complex (PLC), calreticulin and ERp57 take over the job of chaperoning the MHC class I protein while the tapasin links the complex to the Transporter associated with antigen processing (TAP) complex. This association prepares the MHC class I for binding an antigen for presentation on the cell surface.
# Cofactors
ATP and calcium ions are cofactors involved in substrate binding for calnexin. | https://www.wikidoc.org/index.php/Calnexin | |
e87960b3eb6f70d5b352c22383db3484cd10208c | wikidoc | Calutron | Calutron
A Calutron was a mass spectrometer used for separating the isotopes of uranium developed by Ernest O. Lawrence during the Manhattan Project and was similar to the Cyclotron invented by Lawrence. Its name is a concatenation of Cal. U.-tron, in tribute to the University of California, Lawrence's institution and the contractor of the Los Alamos laboratory. They were implemented for industrial scale uranium enrichment at the Oak Ridge, Tennessee Y-12 plant established during the war and provided much of the uranium used for the "Little Boy" nuclear weapon, which was dropped onto Hiroshima in 1945.
In a mass spectrometer, a vaporised quantity of a sample is bombarded with high energy electrons which causes them to become positively charged ions. They are then accelerated and subsequently deflected by magnetic fields. They then collide with a plate, producing a measurable electric current. The mass of the ions can be calculated according to the strength of the field and the charge of the ions.
To maximize the separation and the use of the required large electromagnet, multiple Calutrons were arranged around the magnet in a massive oval, which resembled (and were called) race tracks. Two types of Calutrons were created, known as Alpha and Beta, as the technology was improved. Magnetic separation was later abandoned in favor of the more complicated, but more effective, gaseous diffusion method. Due to the copper shortage during WWII, the electromagnets were made from thousands of tons of silver borrowed from the U.S. Treasury.
# Uranium isotope separation
The world did not lack methods for separating isotopes when it discovered the possible utility of a kilogram of uranium-235 (235U). Known techniques, pursued simultaneously in Germany and the United States, included ultra-centrifugation, diffusion across thermal or osmotic pressure barriers, and deflection in electric and magnetic fields. The last method appealed to Lawrence, who had made his reputation on the precise control of beams of charged particles. In principle the technique is simple. When passing between the poles of a magnet, a monoenergetic beam of ions of naturally occurring uranium splits into several streams according to their momentum, one per isotope, each characterized by a particular radius of curvature. Collecting cups at the ends of the semicircular trajectories catch the homogeneous streams.
Most physicists in 1941 doubted that electromagnetic separation would succeed in practice because they expected that the mutual repulsion of the like-charged ions (the space charge effect) would prevent the formation of narrow beams. But Lawrence, who had seen a line of positively charged ions pour from his cyclotron, guessed that negative particles formed in the air kept the beam from dispersing under its own electrical influence. He had the 37-inch (94 cm) cyclotron modified to demonstrate the feasibility of electromagnetic separation of uranium isotopes using the principle of the mass spectrograph. "It will not be a calamity," he wrote Compton, if uranium turned out to have no military applications; but if "fantastically positive and we fail to get them first, the results for our country may well be a tragic disaster." By December 1941 the uranium ion beam was passing 5 microamperes to the collector; a small amount to be sure, but enough to assure Lawrence that space charge would not be a formidable problem.
The fact that beams of uranium ions could be defined well enough to yield small quantities of isotopes suitable for laboratory research by no means assured that electromagnetic separation could be worked on the industrial scale necessary to make a kilogram of 235U. The process has little to work on, only the slight difference in mass-1.25 percent-between uraniums 235 and 238. Because the lighter ions respond slightly more readily to the magnetic field than the heavier, their trajectories bend in a tighter arc. At the end of their semicircular travel, the ions of 235U are relatively more plentiful on the inside than on the outside of the beam. But the maximum separation even in the ideal case is small, only one-tenth inch for an arc with a diameter of 37 inches (94 cm). Actual beams are far from ideal.
# The alpha calutron
Many technical problems had to be solved before even a prototype could be tested in the field of the nearly completed 184-inch (4.67 m) magnet. The beams, though small, could melt the collectors during long hours of operation; the staff therefore installed water cooling for the collectors and tank liner. They contrived electric arcs to ionize the uranium tetrachloride feed. They devised ways to extract the enriched uranium that collected at the receiver, and the still valuable feed material that condensed along with chloride "gunk" (to use their technical term) all over the inside of the tank. They made scrapers to clean the exit slits of the feed sources regularly lest the accumulated "crud" (another word of art) cut down beam strength. Lawrence's optimistic conclusion: by the fall of 1942 ten calutrons, each with a 100-milliampere source and all operating within the 184-inch field, would produce four grams of enriched uranium a day. The S-1 Uranium Committee that oversaw the uranium project for Office of Scientific Research and Development recommended expending $12 million to create a plant with 25 times that capacity before the fall of 1943. Lawrence did not doubt that other means, particularly reactor production of fissile plutonium, might ultimately be the most efficient way to a bomb. But in mid-1942 no reactor worked, and the calutron did.
The calutron design settled on in 1942, called "alpha," provided for enrichment of natural uranium to about 15 percent 235U. Extravagant effort went into designing powerful ion sources and aptly shaped, eventually parabolic collecting slots. The many modifications and security codes proliferated whimsical names: sources Plato, Cyclops, Bicyclops, and Goofy mated with receivers Gloria, Irene, Mona, or Zulu. Ions from Plato and his friends traversed an arc 48 inches (1.22 m) in radius to reach collector slits placed 0.6 inch (15 mm) apart. The guiding magnetic field was shimmed not by the old black art but in obedience to calculations. Accurately machined and installed, the shims greatly increased the usable beam that reached the collectors.
# Scaling up at Oak Ridge
Among results obtained with the 184-inch magnet was a design superior to it for large-scale calutrons, the so-called "XA." The prototype of the magnets to be installed at Oak Ridge, XA was a rectangular, three-coil magnet giving a horizontal field in which the calutron tanks could stand side-by-side. It had room for four alpha tanks, each with a double source. By the spring of 1943, convinced that the Germans might be ahead, General Leslie Groves decided to skip the scheduled pilot plant; from the XA and a scale model of the production magnet alone would come procedures for alpha operation at Oak Ridge. Tests of the first, full-scale system installed there, the XAX, were scheduled for July.
The spring and early summer of 1943 brought hundreds of trainees to Berkeley from Tennessee- Eastman Company, the operator for the Oak Ridge plant. The Laboratory labored to ensure that the test XA magnet system and alpha units were working by April in spite of delays in delivery of steel. Between April and July the training sessions ran continuously. In June a migration that by 1944 would reach 200 started for Oak Ridge. Laboratory expenditures exceeded half a million dollars a month.
The first wave of Berkeley workers at Oak Ridge had to see that the XAX magnet worked. Then runs could begin on the first production system, or "racetrack;" a 24-fold magnification of the XA that could hold 96 calutron alpha tanks. To minimize magnetic losses and steel consumption, the assembly was curved into an oval 122 feet (37 m) long, 77 feet (23 m) wide and 15 feet (4.6 m) high. Want of copper for the large coils to produce the magnetic fields prompted a solution possible only in wartime: Groves drafted 14,700 tons (13,300 tonne) of pure silver from a government vault for the purpose. Late in the summer of 1943 the XAX was ready for testing. After a week of difficulty, it cleared the hurdle for full-scale racetrack runs.
The first two of five projected racetracks started up in November and failed from contaminated cooling oil; the second was limping in January, but produced 200 grams of uranium enriched to 12 percent 235U by the end of February 1944, its fifth of the total goal of one kilogram of enriched uranium per month. By April four racetracks were functioning, including the repaired number 1. They required constant attention. Many people from the Laboratory helped modify the units to reach production goals.
The calutrons were initially operated by scientists from Berkeley to remove bugs and achieve a reasonable operating rate. Then Tennessee Eastman operators who had only a high school education took over. Kenneth Nichols compared unit production data, and pointed out to Ernest Lawrence that the young “hill-billy” girl operators were outproducing his Ph.Ds. They agreed to a production race and Lawrence lost, a morale boost for the Tennessee Eastman workers and supervisors. The girls were trained like soldiers not to reason why, while “the scientists could not refrain from time-consuming investigation of the cause of even minor fluctuations of the dials” Responsibility for operation passed entirely to Tennessee Eastman after the spring of 1944, and the Laboratory staff at Oak Ridge turned their attention to redesigning the calutron system for higher efficiency.
# The beta calutrons
Many at the Laboratory, especially Edward Lofgren and Martin Kamen, thought that a second stage would be necessary to reach the required enrichment. Groves approved the idea. In the spring of 1943, during training at Berkeley for alpha operations, design began on the second or beta stage. Because beta would have only the enriched product of alpha as feed, it would process proportionately less material; its beam therefore did not need to be as broad, nor its dimensions as large, as alpha's. Beta design emphasized recovery, not only of the further enriched output but also of the already enriched feed. The first units were tried at Oak Ridge in late February 1944, but the sources had to be redesigned, and even by June difficulties persisted in recovering the precious beta feed strewn throughout the calutron. Process efficiencies stayed low: only 4 or 5 percent of the 235U in the feed ended up in the output. A better source of enriched uranium feed would have to be found to create the 10 kilograms or so of 90 percent 235U that Robert Oppenheimer thought necessary for a bomb.
The gaseous diffusion procedure for separation of uranium isotopes, which had consumed more money even than the calutron, had not met its design goals by late 1944. Groves decided that it could not be counted on to produce high enrichment, and that whatever it did produce would have to be supplemented with other slightly enriched uranium and processed through beta calutrons. To augment the calutron feed, the Manhattan Engineering District constructed still another plant at Oak Ridge, this one working by thermal diffusion, a method developed by Philip Abelson.
# Weapons grade uranium
In the critical production period in the first months of 1945, the calutrons, particularly the six betas of 36 tanks each, produced weapons-grade 235U using feed from the modified alpha calutrons, the small output from the gaseous diffusion plant, and whatever the new thermal process had to offer. Virtually all the 235U sent by courier on the train to Chicago and on to Los Alamos, New Mexico had passed through the beta calutrons. From these shipments Oppenheimer's physicists assembled the bomb that was to destroy Hiroshima.
# Modern calutrons
After the 1990 Gulf War, UNSCOM determined that Iraq had been pursuing a calutron program to enrich uranium.
# Calutron patents
The main Calutron patents are Methods of and apparatus for separating materials (Ernest O. Lawrence), Magnetic shims (Robert Oppenheimer and Stanley Frankel), and Calutron system (Ernest O. Lawrence). | Calutron
Template:Nofootnotes
A Calutron was a mass spectrometer used for separating the isotopes of uranium developed by Ernest O. Lawrence[1] during the Manhattan Project and was similar to the Cyclotron invented by Lawrence. Its name is a concatenation of Cal. U.-tron, in tribute to the University of California, Lawrence's institution and the contractor of the Los Alamos laboratory.[2] They were implemented for industrial scale uranium enrichment at the Oak Ridge, Tennessee Y-12 plant established during the war and provided much of the uranium used for the "Little Boy" nuclear weapon, which was dropped onto Hiroshima in 1945.
In a mass spectrometer, a vaporised quantity of a sample is bombarded with high energy electrons which causes them to become positively charged ions. They are then accelerated and subsequently deflected by magnetic fields. They then collide with a plate, producing a measurable electric current. The mass of the ions can be calculated according to the strength of the field and the charge of the ions.
To maximize the separation and the use of the required large electromagnet, multiple Calutrons were arranged around the magnet in a massive oval, which resembled (and were called) race tracks. Two types of Calutrons were created, known as Alpha and Beta, as the technology was improved. Magnetic separation was later abandoned in favor of the more complicated, but more effective, gaseous diffusion method. Due to the copper shortage during WWII, the electromagnets were made from thousands of tons of silver borrowed from the U.S. Treasury.[3][4]
# Uranium isotope separation
The world did not lack methods for separating isotopes when it discovered the possible utility of a kilogram of uranium-235 (235U). Known techniques, pursued simultaneously in Germany and the United States, included ultra-centrifugation, diffusion across thermal or osmotic pressure barriers, and deflection in electric and magnetic fields. The last method appealed to Lawrence, who had made his reputation on the precise control of beams of charged particles. In principle the technique is simple. When passing between the poles of a magnet, a monoenergetic beam of ions of naturally occurring uranium splits into several streams according to their momentum, one per isotope, each characterized by a particular radius of curvature. Collecting cups at the ends of the semicircular trajectories catch the homogeneous streams.
Most physicists in 1941 doubted that electromagnetic separation would succeed in practice because they expected that the mutual repulsion of the like-charged ions (the space charge effect) would prevent the formation of narrow beams. But Lawrence, who had seen a line of positively charged ions pour from his cyclotron, guessed that negative particles formed in the air kept the beam from dispersing under its own electrical influence. He had the 37-inch (94 cm) cyclotron modified to demonstrate the feasibility of electromagnetic separation of uranium isotopes using the principle of the mass spectrograph. "It will not be a calamity," he wrote Compton, if uranium turned out to have no military applications; but if "fantastically positive and we fail to get them first, the results for our country may well be a tragic disaster." By December 1941 the uranium ion beam was passing 5 microamperes to the collector; a small amount to be sure, but enough to assure Lawrence that space charge would not be a formidable problem.
The fact that beams of uranium ions could be defined well enough to yield small quantities of isotopes suitable for laboratory research by no means assured that electromagnetic separation could be worked on the industrial scale necessary to make a kilogram of 235U. The process has little to work on, only the slight difference in mass-1.25 percent-between uraniums 235 and 238. Because the lighter ions respond slightly more readily to the magnetic field than the heavier, their trajectories bend in a tighter arc. At the end of their semicircular travel, the ions of 235U are relatively more plentiful on the inside than on the outside of the beam. But the maximum separation even in the ideal case is small, only one-tenth inch for an arc with a diameter of 37 inches (94 cm). Actual beams are far from ideal.
# The alpha calutron
Many technical problems had to be solved before even a prototype could be tested in the field of the nearly completed 184-inch (4.67 m) magnet. The beams, though small, could melt the collectors during long hours of operation; the staff therefore installed water cooling for the collectors and tank liner. They contrived electric arcs to ionize the uranium tetrachloride feed. They devised ways to extract the enriched uranium that collected at the receiver, and the still valuable feed material that condensed along with chloride "gunk" (to use their technical term) all over the inside of the tank. They made scrapers to clean the exit slits of the feed sources regularly lest the accumulated "crud" (another word of art) cut down beam strength. Lawrence's optimistic conclusion: by the fall of 1942 ten calutrons, each with a 100-milliampere source and all operating within the 184-inch field, would produce four grams of enriched uranium a day. The S-1 Uranium Committee that oversaw the uranium project for Office of Scientific Research and Development recommended expending $12 million to create a plant with 25 times that capacity before the fall of 1943. Lawrence did not doubt that other means, particularly reactor production of fissile plutonium, might ultimately be the most efficient way to a bomb. But in mid-1942 no reactor worked, and the calutron did.
The calutron design settled on in 1942, called "alpha," provided for enrichment of natural uranium to about 15 percent 235U. Extravagant effort went into designing powerful ion sources and aptly shaped, eventually parabolic collecting slots. The many modifications and security codes proliferated whimsical names: sources Plato, Cyclops, Bicyclops, and Goofy mated with receivers Gloria, Irene, Mona, or Zulu. Ions from Plato and his friends traversed an arc 48 inches (1.22 m) in radius to reach collector slits placed 0.6 inch (15 mm) apart. The guiding magnetic field was shimmed not by the old black art but in obedience to calculations. Accurately machined and installed, the shims greatly increased the usable beam that reached the collectors.
# Scaling up at Oak Ridge
Among results obtained with the 184-inch magnet was a design superior to it for large-scale calutrons, the so-called "XA." The prototype of the magnets to be installed at Oak Ridge, XA was a rectangular, three-coil magnet giving a horizontal field in which the calutron tanks could stand side-by-side. It had room for four alpha tanks, each with a double source. By the spring of 1943, convinced that the Germans might be ahead, General Leslie Groves decided to skip the scheduled pilot plant; from the XA and a scale model of the production magnet alone would come procedures for alpha operation at Oak Ridge. Tests of the first, full-scale system installed there, the XAX, were scheduled for July.
The spring and early summer of 1943 brought hundreds of trainees to Berkeley from Tennessee- Eastman Company, the operator for the Oak Ridge plant. The Laboratory labored to ensure that the test XA magnet system and alpha units were working by April in spite of delays in delivery of steel. Between April and July the training sessions ran continuously. In June a migration that by 1944 would reach 200 started for Oak Ridge. Laboratory expenditures exceeded half a million dollars a month.
The first wave of Berkeley workers at Oak Ridge had to see that the XAX magnet worked. Then runs could begin on the first production system, or "racetrack;" a 24-fold magnification of the XA that could hold 96 calutron alpha tanks. To minimize magnetic losses and steel consumption, the assembly was curved into an oval 122 feet (37 m) long, 77 feet (23 m) wide and 15 feet (4.6 m) high. Want of copper for the large coils to produce the magnetic fields prompted a solution possible only in wartime: Groves drafted 14,700 tons (13,300 tonne) of pure silver from a government vault for the purpose. Late in the summer of 1943 the XAX was ready for testing. After a week of difficulty, it cleared the hurdle for full-scale racetrack runs.
The first two of five projected racetracks started up in November and failed from contaminated cooling oil; the second was limping in January, but produced 200 grams of uranium enriched to 12 percent 235U by the end of February 1944, its fifth of the total goal of one kilogram of enriched uranium per month. By April four racetracks were functioning, including the repaired number 1. They required constant attention. Many people from the Laboratory helped modify the units to reach production goals.
The calutrons were initially operated by scientists from Berkeley to remove bugs and achieve a reasonable operating rate. Then Tennessee Eastman operators who had only a high school education took over. Kenneth Nichols compared unit production data, and pointed out to Ernest Lawrence that the young “hill-billy” girl operators were outproducing his Ph.Ds. They agreed to a production race and Lawrence lost, a morale boost for the Tennessee Eastman workers and supervisors. The girls were trained like soldiers not to reason why, while “the scientists could not refrain from time-consuming investigation of the cause of even minor fluctuations of the dials” [6] Responsibility for operation passed entirely to Tennessee Eastman after the spring of 1944, and the Laboratory staff at Oak Ridge turned their attention to redesigning the calutron system for higher efficiency.
# The beta calutrons
Many at the Laboratory, especially Edward Lofgren and Martin Kamen, thought that a second stage would be necessary to reach the required enrichment. Groves approved the idea. In the spring of 1943, during training at Berkeley for alpha operations, design began on the second or beta stage. Because beta would have only the enriched product of alpha as feed, it would process proportionately less material; its beam therefore did not need to be as broad, nor its dimensions as large, as alpha's. Beta design emphasized recovery, not only of the further enriched output but also of the already enriched feed. The first units were tried at Oak Ridge in late February 1944, but the sources had to be redesigned, and even by June difficulties persisted in recovering the precious beta feed strewn throughout the calutron. Process efficiencies stayed low: only 4 or 5 percent of the 235U in the feed ended up in the output. A better source of enriched uranium feed would have to be found to create the 10 kilograms or so of 90 percent 235U that Robert Oppenheimer thought necessary for a bomb.
The gaseous diffusion procedure for separation of uranium isotopes, which had consumed more money even than the calutron, had not met its design goals by late 1944. Groves decided that it could not be counted on to produce high enrichment, and that whatever it did produce would have to be supplemented with other slightly enriched uranium and processed through beta calutrons. To augment the calutron feed, the Manhattan Engineering District constructed still another plant at Oak Ridge, this one working by thermal diffusion, a method developed by Philip Abelson.
# Weapons grade uranium
In the critical production period in the first months of 1945, the calutrons, particularly the six betas of 36 tanks each, produced weapons-grade 235U using feed from the modified alpha calutrons, the small output from the gaseous diffusion plant, and whatever the new thermal process had to offer. Virtually all the 235U sent by courier on the train to Chicago and on to Los Alamos, New Mexico had passed through the beta calutrons. From these shipments Oppenheimer's physicists assembled the bomb that was to destroy Hiroshima.
# Modern calutrons
After the 1990 Gulf War, UNSCOM determined that Iraq had been pursuing a calutron program to enrich uranium.[7]
# Calutron patents
The main Calutron patents are Methods of and apparatus for separating materials (Ernest O. Lawrence),[8] Magnetic shims (Robert Oppenheimer and Stanley Frankel),[9] and Calutron system (Ernest O. Lawrence).[10] | https://www.wikidoc.org/index.php/Calutron | |
4f08f37614634589a2ff1fb10366e6559e6cf91e | wikidoc | Cambrian | Cambrian
The Cambrian is a geologic period and system that began about Template:Period startTemplate:Period start error Ma (million years ago) at the end of the Proterozoic eon and ended about Template:Period endTemplate:Period start error Ma with the beginning of the Ordovician period Template:ICS 2004. It was the first period of the Paleozoic era of the Phanerozoic eon. The Cambrian takes its name from Cambria, the classical name for Wales, the area where rocks from this time period were first studied.
The Cambrian is the earliest period in whose rocks are found numerous large, distinctly fossilizable multicellular organisms. This sudden appearance of hard body fossils is referred to as the Cambrian explosion. Despite the long recognition of its distinction from younger Ordovician rocks and older Precambrian rocks it was not until 1994 that this time period was internationally ratified. The base of the Cambrian is defined on a complex assemblage of trace fossils known as the Trichophycus pedum assemblage. This assemblage is distinct from anything in the Precambrian as it has ecologically tiered vertical burrows which are absent from the Precambrian.
# Cambrian subdivisions
The Cambrian period follows the Ediacaran and is followed by the Ordovician period. The Cambrian is divided into three epochs — the Early Cambrian (Caerfai or Waucoban), Middle Cambrian (St Davids or Albertian) and Furongian (also known as Late Cambrian, Merioneth or Croixan). Rocks of these epochs are referred to as belonging to the Lower, Middle, or Upper Cambrian.
Each of the epochs are divided into several stages. Only one, the Paibian, has been recognized by the International Commission on Stratigraphy, and others are still unnamed. However, the Cambrian is divided into several regional faunal stages of which the Russian-Kazakhian system is most used in international parlance:
## Cambrian dating
The time range for the Cambrian has classically been thought to have been from about 500 mya to about 570 mya. The lower boundary of the Cambrian was traditionally set at the earliest appearance of early arthropods known as trilobites and also unusual forms known as archeocyathids (literally 'ancient cup') that are thought to be the earliest sponges and also the first non-microbial reef builders.
The end of the period was eventually set at a fairly definite faunal change now identified as an extinction event. Fossil discoveries and radiometric dating in the last quarter of the 20th century have called these dates into question. Date inconsistencies as large as 20 Ma are common between authors. Framing dates of ca. () 545 to 490 mya were proposed by the International Subcommission on Global Stratigraphy as recently as 2002.
A radiometric date from New Brunswick puts the end of the first stage of the Cambrian around 511 mya. This leaves 21 Ma for the other two stages of the Cambrian.
A more precise date of 542 ± 0.3 mya for the extinction event at the beginning of the Cambrian has recently been submitted. The rationale for this precise dating is interesting in itself as an example of paleological deductive reasoning. Exactly at the Cambrian boundary there is a marked fall in the abundance of carbon-13, a "reverse spike" that paleontologists call an excursion. It is so widespread that it is the best indicator of the position of the Precambrian-Cambrian boundary in stratigraphic sequences of roughly this age. One of the places that this well-established carbon-13 excursion occurs is in Oman. Amthor (2003) describes evidence from Oman that indicates the carbon-isotope excursion relates to a mass extinction: the disappearance of distinctive fossils from the Precambrian coincides exactly with the carbon-13 anomaly. Fortunately, in the Oman sequence, so too does a volcanic ash horizon from which zircons provide a very precise age of 542 ± 0.3 Ma (calculated on the decay rate of uranium to lead). This new and precise date tallies with the less precise dates for the carbon-13 anomaly, derived from sequences in Siberia and Namibia. It is presented here as likely to become accepted as the definitive age for the start of the Phanerozoic eon, and thus the start of the Paleozoic era and the Cambrian period.
# Cambrian paleogeography
Cambrian continents are thought to have resulted from the breakup of a Neoproterozoic supercontinent called Pannotia. The waters of the Cambrian period appear to have been widespread and shallow. Gondwana remained the largest supercontinent after the breakup of Pannotia. It is thought that Cambrian climates were significantly warmer than those of preceding times that experienced extensive ice ages discussed as the Varanger glaciation. Also there was no glaciation at the poles. Continental drift rates in the Cambrian may have been anomalously high. Laurentia, Baltica and Siberia remained independent continents since the break-up of the supercontinent of Pannotia. Gondwana started to drift towards the South Pole. Panthalassa covered most of the southern hemisphere, and minor oceans included the Proto-Tethys Ocean, Iapetus Ocean, and Khanty Ocean, all of which expanded by this time.
# Cambrian fauna
Of those modern animal phyla that fossilize easily, all save the bryozoans have claimed representatives in the Cambrian. Many extinct phyla and odd animals that have unclear relationships to other animals also appear in the Cambrian. The apparent "sudden" appearance of very diverse faunas over a period of no more than a few tens of millions of years is referred to as the "Cambrian Explosion". Also, the first possible tracks on land, such as Protichnites and Climactichnites, dating to about 530 mya and found in Ontario, Canada, and northern United States, appeared at this time. The conodonts, small predatory primitive chordates known from their fossilised teeth, also appeared during the Furongian epoch of the Cambrian period. The conodonts thrived throughout the Paleozoic and the early Mesozoic until they completely disappeared during the Late Triassic period when the first mammals were evolving.
The best studied sites where the soft parts of organisms have fossilized are in the Burgess shale of British Columbia. They represent strata from the Middle Cambrian and provide us with a wealth of information on early animal diversity. Similar faunas have subsequently been found in a number of other places — most importantly in very early Cambrian shales in the People's Republic of China's Yunnan Province (see Maotianshan shales). Fairly extensive Precambrian Ediacaran faunas have been identified in the past 50 years, but their relationships to Cambrian forms are quite obscure.
## Cambrian flora
Generally it is accepted that there were no land plants at this time although molecular dating suggests that land plant ancestors diverged from the algae much earlier, in the Neoproterozoic about 700 ma, and that fungi diverged from the animals about 1 billion years ago. The land at this time was barren, mostly desert and badlands. | Cambrian
Template:Geological period
The Cambrian is a geologic period and system that began about Template:Period startTemplate:Period start error Ma (million years ago) at the end of the Proterozoic eon and ended about Template:Period endTemplate:Period start error Ma with the beginning of the Ordovician period Template:ICS 2004. It was the first period of the Paleozoic era of the Phanerozoic eon. The Cambrian takes its name from Cambria, the classical name for Wales, the area where rocks from this time period were first studied.
The Cambrian is the earliest period in whose rocks are found numerous large, distinctly fossilizable multicellular organisms. This sudden appearance of hard body fossils is referred to as the Cambrian explosion. Despite the long recognition of its distinction from younger Ordovician rocks and older Precambrian rocks it was not until 1994 that this time period was internationally ratified. The base of the Cambrian is defined on a complex assemblage of trace fossils known as the Trichophycus pedum assemblage. This assemblage is distinct from anything in the Precambrian as it has ecologically tiered vertical burrows which are absent from the Precambrian.
# Cambrian subdivisions
The Cambrian period follows the Ediacaran and is followed by the Ordovician period. The Cambrian is divided into three epochs — the Early Cambrian (Caerfai or Waucoban), Middle Cambrian (St Davids or Albertian) and Furongian (also known as Late Cambrian, Merioneth or Croixan). Rocks of these epochs are referred to as belonging to the Lower, Middle, or Upper Cambrian.
Each of the epochs are divided into several stages. Only one, the Paibian, has been recognized by the International Commission on Stratigraphy, and others are still unnamed. However, the Cambrian is divided into several regional faunal stages of which the Russian-Kazakhian system is most used in international parlance:
## Cambrian dating
The time range for the Cambrian has classically been thought to have been from about 500 mya to about 570 mya. The lower boundary of the Cambrian was traditionally set at the earliest appearance of early arthropods known as trilobites and also unusual forms known as archeocyathids (literally 'ancient cup') that are thought to be the earliest sponges and also the first non-microbial reef builders.
The end of the period was eventually set at a fairly definite faunal change now identified as an extinction event. Fossil discoveries and radiometric dating in the last quarter of the 20th century have called these dates into question. Date inconsistencies as large as 20 Ma are common between authors. Framing dates of ca. () 545 to 490 mya were proposed by the International Subcommission on Global Stratigraphy as recently as 2002.
A radiometric date from New Brunswick puts the end of the first stage of the Cambrian around 511 mya. This leaves 21 Ma for the other two stages of the Cambrian.
A more precise date of 542 ± 0.3 mya for the extinction event at the beginning of the Cambrian has recently been submitted.[1] The rationale for this precise dating is interesting in itself as an example of paleological deductive reasoning. Exactly at the Cambrian boundary there is a marked fall in the abundance of carbon-13, a "reverse spike" that paleontologists call an excursion. It is so widespread that it is the best indicator of the position of the Precambrian-Cambrian boundary in stratigraphic sequences of roughly this age. One of the places that this well-established carbon-13 excursion occurs is in Oman. Amthor (2003) describes evidence from Oman that indicates the carbon-isotope excursion relates to a mass extinction: the disappearance of distinctive fossils from the Precambrian coincides exactly with the carbon-13 anomaly. Fortunately, in the Oman sequence, so too does a volcanic ash horizon from which zircons provide a very precise age of 542 ± 0.3 Ma (calculated on the decay rate of uranium to lead). This new and precise date tallies with the less precise dates for the carbon-13 anomaly, derived from sequences in Siberia and Namibia. It is presented here as likely to become accepted as the definitive age for the start of the Phanerozoic eon, and thus the start of the Paleozoic era and the Cambrian period.
# Cambrian paleogeography
Cambrian continents are thought to have resulted from the breakup of a Neoproterozoic supercontinent called Pannotia. The waters of the Cambrian period appear to have been widespread and shallow. Gondwana remained the largest supercontinent after the breakup of Pannotia. It is thought that Cambrian climates were significantly warmer than those of preceding times that experienced extensive ice ages discussed as the Varanger glaciation. Also there was no glaciation at the poles. Continental drift rates in the Cambrian may have been anomalously high. Laurentia, Baltica and Siberia remained independent continents since the break-up of the supercontinent of Pannotia. Gondwana started to drift towards the South Pole. Panthalassa covered most of the southern hemisphere, and minor oceans included the Proto-Tethys Ocean, Iapetus Ocean, and Khanty Ocean, all of which expanded by this time.
# Cambrian fauna
Of those modern animal phyla that fossilize easily, all save the bryozoans have claimed representatives in the Cambrian. Many extinct phyla and odd animals that have unclear relationships to other animals also appear in the Cambrian. The apparent "sudden" appearance of very diverse faunas over a period of no more than a few tens of millions of years is referred to as the "Cambrian Explosion". Also, the first possible tracks on land, such as Protichnites and Climactichnites, dating to about 530 mya and found in Ontario, Canada, and northern United States, appeared at this time. The conodonts, small predatory primitive chordates known from their fossilised teeth, also appeared during the Furongian epoch of the Cambrian period. The conodonts thrived throughout the Paleozoic and the early Mesozoic until they completely disappeared during the Late Triassic period when the first mammals were evolving.
The best studied sites where the soft parts of organisms have fossilized are in the Burgess shale of British Columbia. They represent strata from the Middle Cambrian and provide us with a wealth of information on early animal diversity. Similar faunas have subsequently been found in a number of other places — most importantly in very early Cambrian shales in the People's Republic of China's Yunnan Province (see Maotianshan shales). Fairly extensive Precambrian Ediacaran faunas have been identified in the past 50 years, but their relationships to Cambrian forms are quite obscure.
## Cambrian flora
Generally it is accepted that there were no land plants at this time although molecular dating suggests that land plant ancestors diverged from the algae much earlier, in the Neoproterozoic about 700 ma[citation needed], and that fungi diverged from the animals about 1 billion years ago[citation needed]. The land at this time was barren, mostly desert and badlands. | https://www.wikidoc.org/index.php/Cambrian | |
eb6ca047fe126cc597f20d18c857752d57ebd7ba | wikidoc | Ligament | Ligament
# Overview
In anatomy, the term ligament is used to denote three different types of structures:
- Fibrous tissue that connects bones to other bones. They are sometimes called "articular ligaments", "fibrous ligaments", or "true ligaments".
- A fold of peritoneum or other membrane
- The remnants of a tubular structure from the fetal period of life
The first meaning is most commonly what is meant by the term "ligament". After briefly discussing the other two types of ligaments, the remainder of this article will focus upon the first type.
# Peritoneal ligaments
Certain folds of peritoneum are referred to as ligaments.
Examples include:
- The hepatoduodenal ligament surrounds the hepatic portal vein and other vessels as they travel from the duodenum to the liver.
- The broad ligament of the uterus is also a fold of peritoneum.
- The suspensory ligament of the ovary
# Fetal remnant ligaments
Certain tubular structures from the fetal period are referred to as ligaments after they close up and turn into cord-like structures:
# Articular ligaments
In its most common use, a ligament is a short band of tough fibrous dense regular connective tissue composed mainly of long, stringy collagen fibres. Ligaments connect bones to other bones to form a joint. (They do not connect muscles to bones; that is the function of tendons.) Some ligaments limit the mobility of articulations, or prevent certain movements altogether.
Capsular ligaments are part of the articular capsule that surrounds synovial joints. They act as mechanical reinforcements. Extra-capsular ligaments join bones together and provide joint stability.
Ligaments are only slightly elastic; when under tension, they gradually lengthen. (Unlike tendons which are very elastic). This is one reason why dislocated joints must be set as quickly as possible: if the ligaments lengthen too much, then the joint will be weakened, becoming prone to future dislocations. Athletes, gymnasts, dancers, and martial artists perform stretching exercises to lengthen their ligaments, making their joints more supple. The term double-jointed refers to people who have more elastic ligaments, allowing their joints to stretch and contort further. The medical term for describing such double-jointed persons is hyperlaxity and double-jointed is a synonym of hyperlax.
The study of ligaments is known as desmology.
The consequence of a broken ligament can be instability of the joint. Not all broken ligaments need surgery, but if surgery is needed to stabilise the joint, the broken ligament can be joined. Scar tissue may prevent this. If it is not possible to fix the broken ligament, other procedures such as the Brunelli Procedure can correct the instability. Instability of a joint can over time lead to wear of the cartilage and eventually to osteoarthritis.
## Examples
### Knee
- Anterior cruciate ligament (ACL)
- Lateral collateral ligament (LCL)
- Posterior cruciate ligament (PCL)
- Medial collateral ligament (MCL)
- Cranial cruciate ligament (CrCL) - quadruped equivalent of ACL
- Caudal cruciate ligament (CaCL) - quadruped equivalent of PCL
### Head and neck
- Cricothyroid ligament
- Periodontal ligament
- Suspensory ligament of the lens
### Pelvis
- Anterior sacroiliac ligament
- Posterior sacroiliac ligament
- Sacrotuberous ligament
- Sacrospinous ligament
- Inferior pubic ligament
- Superior pubic ligament
- Suspensory ligament of the penis
### Thorax
- Suspensory ligament of the breast
### Wrist
- See Wrist#Ligaments | Ligament
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In anatomy, the term ligament is used to denote three different types of structures: [1]
- Fibrous tissue that connects bones to other bones. They are sometimes called "articular ligaments"[2], "fibrous ligaments", or "true ligaments".
- A fold of peritoneum or other membrane
- The remnants of a tubular structure from the fetal period of life
The first meaning is most commonly what is meant by the term "ligament". After briefly discussing the other two types of ligaments, the remainder of this article will focus upon the first type.
# Peritoneal ligaments
Certain folds of peritoneum are referred to as ligaments.
Examples include:
- The hepatoduodenal ligament surrounds the hepatic portal vein and other vessels as they travel from the duodenum to the liver.
- The broad ligament of the uterus is also a fold of peritoneum.
- The suspensory ligament of the ovary
# Fetal remnant ligaments
Certain tubular structures from the fetal period are referred to as ligaments after they close up and turn into cord-like structures:
# Articular ligaments
In its most common use, a ligament is a short band of tough fibrous dense regular connective tissue composed mainly of long, stringy collagen fibres. Ligaments connect bones to other bones to form a joint. (They do not connect muscles to bones; that is the function of tendons.) Some ligaments limit the mobility of articulations, or prevent certain movements altogether.
Capsular ligaments are part of the articular capsule that surrounds synovial joints. They act as mechanical reinforcements. Extra-capsular ligaments join bones together and provide joint stability.
Ligaments are only slightly elastic; when under tension, they gradually lengthen. (Unlike tendons which are very elastic). This is one reason why dislocated joints must be set as quickly as possible: if the ligaments lengthen too much, then the joint will be weakened, becoming prone to future dislocations. Athletes, gymnasts, dancers, and martial artists perform stretching exercises to lengthen their ligaments, making their joints more supple. The term double-jointed refers to people who have more elastic ligaments, allowing their joints to stretch and contort further. The medical term for describing such double-jointed persons is hyperlaxity and double-jointed is a synonym of hyperlax.
The study of ligaments is known as desmology.
The consequence of a broken ligament can be instability of the joint. Not all broken ligaments need surgery, but if surgery is needed to stabilise the joint, the broken ligament can be joined. Scar tissue may prevent this. If it is not possible to fix the broken ligament, other procedures such as the Brunelli Procedure can correct the instability. Instability of a joint can over time lead to wear of the cartilage and eventually to osteoarthritis.
## Examples
### Knee
- Anterior cruciate ligament (ACL)
- Lateral collateral ligament (LCL)
- Posterior cruciate ligament (PCL)
- Medial collateral ligament (MCL)
- Cranial cruciate ligament (CrCL) - quadruped equivalent of ACL
- Caudal cruciate ligament (CaCL) - quadruped equivalent of PCL
### Head and neck
- Cricothyroid ligament
- Periodontal ligament
- Suspensory ligament of the lens
### Pelvis
- Anterior sacroiliac ligament
- Posterior sacroiliac ligament
- Sacrotuberous ligament
- Sacrospinous ligament
- Inferior pubic ligament
- Superior pubic ligament
- Suspensory ligament of the penis
### Thorax
- Suspensory ligament of the breast
### Wrist
- See Wrist#Ligaments | https://www.wikidoc.org/index.php/Capsular_ligaments | |
c57123e96fe1ab079bf11f200066b673d59ee15f | wikidoc | Methanol | Methanol
# Overview
Methanol, also known as methyl alcohol, carbinol, wood alcohol, wood naphtha or wood spirits, is a chemical compound with chemical formula CH3OH (often abbreviated MeOH). It is the simplest alcohol, and is a light, volatile, colourless, flammable, poisonous liquid with a distinctive odor that is somewhat milder and sweeter than ethanol (ethyl alcohol). At room temperature it is a polar liquid and is used as an antifreeze, solvent, fuel, and as a denaturant for ethyl alcohol. It is also used for producing biodiesel via transesterification reaction.
Methanol is produced naturally in the anaerobic metabolism of many varieties of bacteria. As a result, there is a small fraction of methanol vapor in the atmosphere. Over the course of several days, atmospheric methanol is oxidized by oxygen with the help of sunlight to carbon dioxide and water.
Methanol burns in air forming carbon dioxide and water:
A methanol flame is almost colorless, causing an additional safety hazard around open methanol flames.
Because of its poisonous properties, methanol is frequently used as a denaturant additive for ethanol manufactured for industrial uses— this addition of a poison economically exempts industrial ethanol from the rather significant 'liquor' taxes that would otherwise be levied as it is the essence of all potable alcoholic beverages. Methanol is often called wood alcohol because it was once produced chiefly as a byproduct of the destructive distillation of wood. It is now produced synthetically by a multi-step process: natural gas and steam are reformed in a furnace to produce hydrogen and carbon monoxide; then, hydrogen and carbon monoxide gases react under pressure in the presence of a catalyst.
An entire methanol economy, based on methanol as a primary energy-storage medium and fuel, has been seriously proposed.
# History
In their embalming process, the ancient Egyptians used a mixture of substances, including methanol, which they obtained from the pyrolysis of wood. Pure methanol, however, was first isolated in 1661 by Robert Boyle, who called it spirit of box, because he produced it via the distillation of boxwood. It later became known as pyroxylic spirit. In 1834, the French chemists Jean-Baptiste Dumas and Eugene Peligot determined its elemental composition. They also introduced the word methylene to organic chemistry, forming it from Greek methy = "wine" + hȳlē = wood (patch of trees). Its intended origin was "alcohol made from wood (substance)," but it has Greek language errors. The term "methyl" was derived in about 1840 by back-formation from methylene, and was then applied to describe "methyl alcohol." This was shortened to "methanol" in 1892 by the International Conference on Chemical Nomenclature. The suffix -yl used in organic chemistry to form names of radicals, was extracted from the word "methyl."
In 1923, the German chemists Matthias and Pier, working for BASF developed a means to convert synthesis gas (a mixture of carbon oxides and hydrogen) into methanol. A patent was filed Jan 12 1926 (reference no. 1,569,775). This process used a chromium and manganese oxid catalyst, and required extremely vigorous conditions—pressures ranging from 50 to 220 atm), and temperatures up to 450 °C. Modern methanol production has been made more efficient through use of catalysts (commonly copper) capable of operating at lower pressures.
The use of methanol as a motor fuel received attention during the oil crises of the 1970s due to its availability and low cost. Problems occurred early in the development of gasoline-methanol blends. As a result of its low price, some gasoline marketers over-blended. Others used improper blending and handling techniques.
In 2006 astronomers using the MERLIN array of radio telescopes at Jodrell Bank Observatory discovered a large cloud of methanol in space, 300 billion miles across.
# Production
Today, synthesis gas is most commonly produced from the methane component in natural gas rather than from coal. Three processes are commercially practiced. At moderate pressures of 1 to 2 MPa (10–20 atm) and high temperatures (around 850 °C), methane reacts with steam on a nickel catalyst to produce syngas according to the chemical equation:
This reaction, commonly called steam-methane reforming or SMR, is endothermic and the heat transfer limitations place limits on the size of and pressure in the catalytic reactors used. Methane can also undergo partial oxidation with molecular oxygen to produce syngas, as the following equation shows:
this reaction is exothermic and the heat given off can be used in-situ to drive the steam-methane reforming reaction. When the two processes are combined, it is referred to as autothermal reforming. The ratio of CO and H2 can be adjusted to some extent by the water-gas shift reaction,
to provide the appropriate stoichiometry for methanol synthesis.
The carbon monoxide and hydrogen then react on a second catalyst to produce methanol. Today, the most widely used catalyst is a mixture of copper, zinc oxide, and alumina first used by ICI in 1966. At 5–10 MPa (50–100 atm) and 250 °C, it can catalyze the production of methanol from carbon monoxide and hydrogen with high selectivity
It is worth noting that the production of synthesis gas from methane produces 3 moles of hydrogen for every mole of carbon monoxide, while the methanol synthesis consumes only 2 moles of hydrogen for every mole of carbon monoxide. One way of dealing with the excess hydrogen is to inject carbon dioxide into the methanol synthesis reactor, where it, too, reacts to form methanol according to the chemical equation
Although natural gas is the most economical and widely used feedstock for methanol production, other feedstocks can be used. Where natural gas is unavailable, light petroleum products can be used in its place.
# Occurrence
## Human metabolite
Methanol is poisonous to the central nervous system and may cause blindness, coma, and death. However, in small amounts, methanol is a natural endogenous compound found in normal, healthy human individuals. A study found a mean of 4.5 ppm in the exhaled breath of subjects. The mean endogenous methanol production in humans of 0.45 g/d may be metabolized from pectin found in fruit; one kilogram of apple produces up to 1.4 g methanol.
# Toxicity
Methanol has a high toxicity in humans. If as little as 10 mL of pure methanol is ingested, for example, it can break down into formic acid, which can cause permanent blindness by destruction of the optic nerve, and 30 mL is potentially fatal, although the median lethal dose is typically 100 mL (3.4 fl oz) (i.e. 1–2 mL/kg body weight of pure methanol). Reference dose for methanol is 2 mg/kg/day. Toxic effects take hours to start, and effective antidotes can often prevent permanent damage. Because of its similarities in both appearance and odor to ethanol (the alcohol in beverages), it is difficult to differentiate between the two (such is also the case with denatured alcohol). However, there are cases of methanol resistance, such as that of Mike Malloy, who was the victim of a failed murder attempt by methanol in the early 1930s.
Methanol is toxic by two mechanisms. First, methanol (whether it enters the body by ingestion, inhalation, or absorption through the skin) can be fatal due to its CNS depressant properties in the same manner as ethanol poisoning. Second, in a process of toxication, it is metabolized to formic acid (which is present as the formate ion) via formaldehyde in a process initiated by the enzyme alcohol dehydrogenase in the liver. Methanol is converted to formaldehyde via alcohol dehydrogenase (ADH) and formaldehyde is converted to formic acid (formate) via aldehyde dehydrogenase (ALDH). The conversion to formate via ALDH proceeds completely, with no detectable formaldehyde remaining. Formate is toxic because it inhibits mitochondrial cytochrome c oxidase, causing the symptoms of hypoxia at the cellular level, and also causing metabolic acidosis, among a variety of other metabolic disturbances.
Methanol poisoning can be treated with fomepizole, or if unavailable, ethanol. Both drugs act to reduce the action of alcohol dehydrogenase on methanol by means of competitive inhibition, so it is excreted by the kidneys rather than being transformed into toxic metabolites. Further treatment may include giving sodium bicarbonate for metabolic acidosis, and hemodialysis or hemodiafiltration can be used to remove methanol and formate from the blood. Folinic acid or folic acid is also administered to enhance the metabolism of formate.
The initial symptoms of methanol intoxication include central nervous system depression, headache, dizziness, nausea, lack of coordination, and confusion. Sufficiently large doses can cause unconsciousness and death. The initial symptoms of methanol exposure are usually less severe than the symptoms resulting from the ingestion of a similar quantity of ethanol. Once the initial symptoms have passed, a second set of symptoms arises, 10 to as many as 30 hours after the initial exposure to methanol, including blurring or complete loss of vision, acidosis and putaminal hemorrhages, an uncommon but serious complication. These symptoms result from the accumulation of toxic levels of formate in the blood, and may progress to death by respiratory failure. Physical examination may show tachypnea, and ophthalmologic examination may show dilated pupils with hyperemia of the optic disc and retinal edema.
Ethanol is sometimes denatured (adulterated), and made poisonous, by the addition of methanol. The result is known as methylated spirit, "meths" (British use) or "metho" (Australian slang). These are not to be confused with "meth", a common abbreviation for methamphetamine, and an abbreviation for methadone in Britain.
Small amounts of methanol are produced by the metabolism of food and are generally harmless, being metabolized quickly and completely.
# Applications
Methanol is a common laboratory solvent. It is especially useful for HPLC and UV/VIS spectroscopy due to its low UV cutoff.
## Feedstock
The largest use of methanol by far, is in making other chemicals. About 40% of methanol is converted to formaldehyde, and from there into products as diverse as plastics, plywood, paints, explosives, and permanent press textiles.
Also in the early 1970s, a Methanol to gasoline process was developed by Mobil for producing gasoline ready for use in vehicles. One such industrial facility was built in New Zealand in the 1980s. In the 1990s, large amounts of methanol were used in the United States to produce the gasoline additive methyl tert-butyl ether (MTBE), though leakage has led to many states banning it. In addition to direct use as a fuel, methanol (or less commonly, ethanol) is used as a component in the transesterification of triglycerides to yield a form of biodiesel.
Other chemical derivatives of methanol include dimethyl ether, which has replaced chlorofluorocarbons as an aerosol spray propellant, and acetic acid.
## Automotive fuel
Methanol is used on a limited basis to fuel internal combustion engines, mainly by virtue of the fact that it is not nearly as flammable as gasoline. Pure methanol is required by rule to be used in Champcars, USAC sprint cars (as well as midgets, modifieds, etc.), and other dirt track series such as World of Outlaws. Methanol is also used in radio controlled model airplanes (required in the "glow-plug" engines that primarily power them), cars and trucks. Drag racers and mud racers also use methanol as their primary fuel source. Methanol is required with a supercharged engine in a Top Alcohol Dragster and, until the end of the 2006 season, all vehicles in the Indianapolis 500 had to run methanol. Mud racers have mixed methanol with gasoline and nitrous oxide to produce more power than gasoline and nitrous oxide alone.
One of the drawbacks of methanol as a fuel is its corrosivity to some metals, including aluminium. Methanol, although a weak acid, attacks the oxide coating that normally protects the aluminium from corrosion:
The resulting methoxide salts are soluble in methanol, resulting in clean aluminum surface, which is readily oxidised by some dissolved oxygen. Also the methanol can act as an oxidizer:
This reciprocal process effectively fuels corrosion until either the metal is eaten away or the concentration of CH3OH is negligible.
When produced from wood or other organic materials, the resulting organic methanol (bioalcohol) has been suggested as renewable alternative to petroleum-based hydrocarbons. However, one cannot use pure methanol in modern petroleum cars without modification, due to potential damage to metal piping and rubber seals.
## Other applications
Methanol is a traditional denaturant for ethanol, thus giving the term methylated spirit.
Methanol is also used as a solvent, and as an antifreeze in pipelines and windshield washer fluid.
In some wastewater treatment plants, a small amount of methanol is added to wastewater to provide a food source of carbon for the denitrifying bacteria, which convert nitrates to nitrogen.
During World War II, methanol was used as a fuel in several German military rocket designs, under name M-Stoff, and in a mixture as C-Stoff.
Methanol is used as a denaturing agent in polyacrylamide gel electrophoresis.
Direct-methanol fuel cells are unique in their low temperature, atmospheric pressure operation, allowing them to be miniaturized to an unprecedented degree. This, combined with the relatively easy and safe storage and handling of methanol may open the possibility of fuel cell-powered consumer electronics, such as for laptop computers.
# Health and safety
Methanol is toxic by two mechanisms. Firstly, methanol (whether it enters the body by ingestion, inhalation, or absorption through the skin) can be fatal due to its CNS depressant properties in the same manner as ethanol poisoning. Secondly, it is toxic by its breakdown (toxication) by the enzyme alcohol dehydrogenase in the liver by forming formic acid and formaldehyde which cause permanent blindness by destruction of the optic nerve. Fetal tissue will not tolerate methanol. Dangerous doses will build up if a person is regularly exposed to vapors or handles liquid without skin protection. If methanol has been ingested, a doctor should be contacted immediately. The usual fatal dose is 100–125 mL (4 fl oz). Toxic effects take hours to start, and effective antidotes can often prevent permanent damage. This is treated using ethanol or fomepizole. Either of these drugs acts to slow down the action of alcohol dehydrogenase on methanol by means of competitive inhibition, so that it is excreted by the kidneys rather than being transformed into toxic metabolites.
The initial symptoms of methanol intoxication are those of central nervous system depression: headache, dizziness, nausea, lack of coordination, confusion, drowsiness, and with sufficiently large doses, unconsciousness and death. The initial symptoms of methanol exposure are usually less severe than the symptoms resulting from the ingestion of a similar quantity of ethyl alcohol.
Once the initial symptoms have passed, a second set of symptoms arises 10–30 hours after the initial exposure to methanol: blurring or complete loss of vision, together with acidosis. These symptoms result from the accumulation of toxic levels of formate in the bloodstream, and may progress to death by respiratory failure. The ester derivatives of methanol do not share this toxicity.
Ethanol is sometimes denatured (adulterated), and thus made undrinkable, by the addition of methanol. The result is known as methylated spirit or "meths" (UK use). (The latter should not be confused with meth, a common abbreviation for methamphetamine.)
Pure methanol has been used in open wheel auto racing since the mid-1960s. Unlike petroleum fires, methanol fires can be extinguished with plain water. A methanol-based fire burns invisibly, unlike gasoline, which burns with visible smoke. If a fire occurs on the track, there is no smoke to obstruct the view of fast approaching drivers, but this can also delay visual detection of the fire and the initiation of fire suppression actions. The decision to permanently switch to methanol in American IndyCar racing was a result of the devastating crash and explosion at the 1964 Indianapolis 500 which killed drivers Eddie Sachs and Dave MacDonald.
One concern with the addition of methanol to automotive fuels is highlighted by recent groundwater impacts from the fuel additive methyl tert-butyl ether (MTBE). Leaking underground gasoline storage tanks created MTBE plumes in groundwater that eventually contaminated well water. Methanol's high solubility in water raises concerns that similar well water contamination could arise from the widespread use of methanol as an automotive fuel. | Methanol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Jyostna Chouturi, M.B.B.S [2]
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# Overview
Methanol, also known as methyl alcohol, carbinol, wood alcohol, wood naphtha or wood spirits, is a chemical compound with chemical formula CH3OH (often abbreviated MeOH). It is the simplest alcohol, and is a light, volatile, colourless, flammable, poisonous liquid with a distinctive odor that is somewhat milder and sweeter than ethanol (ethyl alcohol). At room temperature it is a polar liquid and is used as an antifreeze, solvent, fuel, and as a denaturant for ethyl alcohol. It is also used for producing biodiesel via transesterification reaction.
Methanol is produced naturally in the anaerobic metabolism of many varieties of bacteria. As a result, there is a small fraction of methanol vapor in the atmosphere. Over the course of several days, atmospheric methanol is oxidized by oxygen with the help of sunlight to carbon dioxide and water.
Methanol burns in air forming carbon dioxide and water:
A methanol flame is almost colorless, causing an additional safety hazard around open methanol flames.
Because of its poisonous properties, methanol is frequently used as a denaturant additive for ethanol manufactured for industrial uses— this addition of a poison economically exempts industrial ethanol from the rather significant 'liquor' taxes that would otherwise be levied as it is the essence of all potable alcoholic beverages. Methanol is often called wood alcohol because it was once produced chiefly as a byproduct of the destructive distillation of wood. It is now produced synthetically by a multi-step process: natural gas and steam are reformed in a furnace to produce hydrogen and carbon monoxide; then, hydrogen and carbon monoxide gases react under pressure in the presence of a catalyst.
An entire methanol economy, based on methanol as a primary energy-storage medium and fuel, has been seriously proposed.
# History
In their embalming process, the ancient Egyptians used a mixture of substances, including methanol, which they obtained from the pyrolysis of wood. Pure methanol, however, was first isolated in 1661 by Robert Boyle, who called it spirit of box, because he produced it via the distillation of boxwood. It later became known as pyroxylic spirit. In 1834, the French chemists Jean-Baptiste Dumas and Eugene Peligot determined its elemental composition. They also introduced the word methylene to organic chemistry, forming it from Greek methy = "wine" + hȳlē = wood (patch of trees). Its intended origin was "alcohol made from wood (substance)," but it has Greek language errors. The term "methyl" was derived in about 1840 by back-formation from methylene, and was then applied to describe "methyl alcohol." This was shortened to "methanol" in 1892 by the International Conference on Chemical Nomenclature. The suffix -yl used in organic chemistry to form names of radicals, was extracted from the word "methyl."
In 1923, the German chemists Matthias and Pier, working for BASF developed a means to convert synthesis gas (a mixture of carbon oxides and hydrogen) into methanol. A patent was filed Jan 12 1926 (reference no. 1,569,775). This process used a chromium and manganese oxid catalyst, and required extremely vigorous conditions—pressures ranging from 50 to 220 atm), and temperatures up to 450 °C. Modern methanol production has been made more efficient through use of catalysts (commonly copper) capable of operating at lower pressures.
The use of methanol as a motor fuel received attention during the oil crises of the 1970s due to its availability and low cost. Problems occurred early in the development of gasoline-methanol blends. As a result of its low price, some gasoline marketers over-blended. Others used improper blending and handling techniques.
In 2006 astronomers using the MERLIN array of radio telescopes at Jodrell Bank Observatory discovered a large cloud of methanol in space, 300 billion miles across.
# Production
Today, synthesis gas is most commonly produced from the methane component in natural gas rather than from coal. Three processes are commercially practiced. At moderate pressures of 1 to 2 MPa (10–20 atm) and high temperatures (around 850 °C), methane reacts with steam on a nickel catalyst to produce syngas according to the chemical equation:
This reaction, commonly called steam-methane reforming or SMR, is endothermic and the heat transfer limitations place limits on the size of and pressure in the catalytic reactors used. Methane can also undergo partial oxidation with molecular oxygen to produce syngas, as the following equation shows:
this reaction is exothermic and the heat given off can be used in-situ to drive the steam-methane reforming reaction. When the two processes are combined, it is referred to as autothermal reforming. The ratio of CO and H2 can be adjusted to some extent by the water-gas shift reaction,
to provide the appropriate stoichiometry for methanol synthesis.
The carbon monoxide and hydrogen then react on a second catalyst to produce methanol. Today, the most widely used catalyst is a mixture of copper, zinc oxide, and alumina first used by ICI in 1966. At 5–10 MPa (50–100 atm) and 250 °C, it can catalyze the production of methanol from carbon monoxide and hydrogen with high selectivity
It is worth noting that the production of synthesis gas from methane produces 3 moles of hydrogen for every mole of carbon monoxide, while the methanol synthesis consumes only 2 moles of hydrogen for every mole of carbon monoxide. One way of dealing with the excess hydrogen is to inject carbon dioxide into the methanol synthesis reactor, where it, too, reacts to form methanol according to the chemical equation
Although natural gas is the most economical and widely used feedstock for methanol production, other feedstocks can be used. Where natural gas is unavailable, light petroleum products can be used in its place.
# Occurrence
## Human metabolite
Methanol is poisonous to the central nervous system and may cause blindness, coma, and death. However, in small amounts, methanol is a natural endogenous compound found in normal, healthy human individuals. A study found a mean of 4.5 ppm in the exhaled breath of subjects.[1] The mean endogenous methanol production in humans of 0.45 g/d may be metabolized from pectin found in fruit; one kilogram of apple produces up to 1.4 g methanol.[2]
# Toxicity
Methanol has a high toxicity in humans. If as little as 10 mL of pure methanol is ingested, for example, it can break down into formic acid, which can cause permanent blindness by destruction of the optic nerve, and 30 mL is potentially fatal,[3] although the median lethal dose is typically 100 mL (3.4 fl oz) (i.e. 1–2 mL/kg body weight of pure methanol[4]). Reference dose for methanol is 2 mg/kg/day.[5] Toxic effects take hours to start, and effective antidotes can often prevent permanent damage.[3] Because of its similarities in both appearance and odor to ethanol (the alcohol in beverages), it is difficult to differentiate between the two (such is also the case with denatured alcohol). However, there are cases of methanol resistance, such as that of Mike Malloy, who was the victim of a failed murder attempt by methanol in the early 1930s.[6]
Methanol is toxic by two mechanisms. First, methanol (whether it enters the body by ingestion, inhalation, or absorption through the skin) can be fatal due to its CNS depressant properties in the same manner as ethanol poisoning. Second, in a process of toxication, it is metabolized to formic acid (which is present as the formate ion) via formaldehyde in a process initiated by the enzyme alcohol dehydrogenase in the liver.[7] Methanol is converted to formaldehyde via alcohol dehydrogenase (ADH) and formaldehyde is converted to formic acid (formate) via aldehyde dehydrogenase (ALDH). The conversion to formate via ALDH proceeds completely, with no detectable formaldehyde remaining.[8] Formate is toxic because it inhibits mitochondrial cytochrome c oxidase, causing the symptoms of hypoxia at the cellular level, and also causing metabolic acidosis, among a variety of other metabolic disturbances.[9]
Methanol poisoning can be treated with fomepizole, or if unavailable, ethanol.[7][10][11] Both drugs act to reduce the action of alcohol dehydrogenase on methanol by means of competitive inhibition, so it is excreted by the kidneys rather than being transformed into toxic metabolites.[7] Further treatment may include giving sodium bicarbonate for metabolic acidosis, and hemodialysis or hemodiafiltration can be used to remove methanol and formate from the blood.[7] Folinic acid or folic acid is also administered to enhance the metabolism of formate.[7]
The initial symptoms of methanol intoxication include central nervous system depression, headache, dizziness, nausea, lack of coordination, and confusion. Sufficiently large doses can cause unconsciousness and death. The initial symptoms of methanol exposure are usually less severe than the symptoms resulting from the ingestion of a similar quantity of ethanol.[12] Once the initial symptoms have passed, a second set of symptoms arises, 10 to as many as 30 hours after the initial exposure to methanol, including blurring or complete loss of vision, acidosis and putaminal hemorrhages, an uncommon but serious complication.[7][13] These symptoms result from the accumulation of toxic levels of formate in the blood, and may progress to death by respiratory failure. Physical examination may show tachypnea, and ophthalmologic examination may show dilated pupils with hyperemia of the optic disc and retinal edema.
Ethanol is sometimes denatured (adulterated), and made poisonous, by the addition of methanol. The result is known as methylated spirit, "meths" (British use) or "metho" (Australian slang). These are not to be confused with "meth", a common abbreviation for methamphetamine, and an abbreviation for methadone in Britain.
Small amounts of methanol are produced by the metabolism of food and are generally harmless, being metabolized quickly and completely.
# Applications
Methanol is a common laboratory solvent. It is especially useful for HPLC and UV/VIS spectroscopy due to its low UV cutoff.
## Feedstock
The largest use of methanol by far, is in making other chemicals. About 40% of methanol is converted to formaldehyde, and from there into products as diverse as plastics, plywood, paints, explosives, and permanent press textiles.
Also in the early 1970s, a Methanol to gasoline process was developed by Mobil for producing gasoline ready for use in vehicles. One such industrial facility was built in New Zealand in the 1980s. In the 1990s, large amounts of methanol were used in the United States to produce the gasoline additive methyl tert-butyl ether (MTBE), though leakage has led to many states banning it. In addition to direct use as a fuel, methanol (or less commonly, ethanol) is used as a component in the transesterification of triglycerides to yield a form of biodiesel.
Other chemical derivatives of methanol include dimethyl ether, which has replaced chlorofluorocarbons as an aerosol spray propellant, and acetic acid.
## Automotive fuel
Methanol is used on a limited basis to fuel internal combustion engines, mainly by virtue of the fact that it is not nearly as flammable as gasoline. Pure methanol is required by rule to be used in Champcars, USAC sprint cars (as well as midgets, modifieds, etc.), and other dirt track series such as World of Outlaws. Methanol is also used in radio controlled model airplanes (required in the "glow-plug" engines that primarily power them), cars and trucks. Drag racers and mud racers also use methanol as their primary fuel source. Methanol is required with a supercharged engine in a Top Alcohol Dragster and, until the end of the 2006 season, all vehicles in the Indianapolis 500 had to run methanol. Mud racers have mixed methanol with gasoline and nitrous oxide to produce more power than gasoline and nitrous oxide alone.
One of the drawbacks of methanol as a fuel is its corrosivity to some metals, including aluminium. Methanol, although a weak acid, attacks the oxide coating that normally protects the aluminium from corrosion:
The resulting methoxide salts are soluble in methanol, resulting in clean aluminum surface, which is readily oxidised by some dissolved oxygen. Also the methanol can act as an oxidizer:
This reciprocal process effectively fuels corrosion until either the metal is eaten away or the concentration of CH3OH is negligible.
When produced from wood or other organic materials, the resulting organic methanol (bioalcohol) has been suggested as renewable alternative to petroleum-based hydrocarbons. However, one cannot use pure methanol in modern petroleum cars without modification, due to potential damage to metal piping and rubber seals.
## Other applications
Methanol is a traditional denaturant for ethanol, thus giving the term methylated spirit.
Methanol is also used as a solvent, and as an antifreeze in pipelines and windshield washer fluid.
In some wastewater treatment plants, a small amount of methanol is added to wastewater to provide a food source of carbon for the denitrifying bacteria, which convert nitrates to nitrogen.
During World War II, methanol was used as a fuel in several German military rocket designs, under name M-Stoff, and in a mixture as C-Stoff.
Methanol is used as a denaturing agent in polyacrylamide gel electrophoresis.
Direct-methanol fuel cells are unique in their low temperature, atmospheric pressure operation, allowing them to be miniaturized to an unprecedented degree. This, combined with the relatively easy and safe storage and handling of methanol may open the possibility of fuel cell-powered consumer electronics, such as for laptop computers.[14]
# Health and safety
Methanol is toxic by two mechanisms. Firstly, methanol (whether it enters the body by ingestion, inhalation, or absorption through the skin) can be fatal due to its CNS depressant properties in the same manner as ethanol poisoning. Secondly, it is toxic by its breakdown (toxication) by the enzyme alcohol dehydrogenase in the liver by forming formic acid and formaldehyde which cause permanent blindness by destruction of the optic nerve.[15] Fetal tissue will not tolerate methanol. Dangerous doses will build up if a person is regularly exposed to vapors or handles liquid without skin protection. If methanol has been ingested, a doctor should be contacted immediately. The usual fatal dose is 100–125 mL (4 fl oz). Toxic effects take hours to start, and effective antidotes can often prevent permanent damage. This is treated using ethanol or fomepizole.[16] Either of these drugs acts to slow down the action of alcohol dehydrogenase on methanol by means of competitive inhibition, so that it is excreted by the kidneys rather than being transformed into toxic metabolites.
The initial symptoms of methanol intoxication are those of central nervous system depression: headache, dizziness, nausea, lack of coordination, confusion, drowsiness, and with sufficiently large doses, unconsciousness and death. The initial symptoms of methanol exposure are usually less severe than the symptoms resulting from the ingestion of a similar quantity of ethyl alcohol.
Once the initial symptoms have passed, a second set of symptoms arises 10–30 hours after the initial exposure to methanol: blurring or complete loss of vision, together with acidosis. These symptoms result from the accumulation of toxic levels of formate in the bloodstream, and may progress to death by respiratory failure. The ester derivatives of methanol do not share this toxicity.
Ethanol is sometimes denatured (adulterated), and thus made undrinkable, by the addition of methanol. The result is known as methylated spirit or "meths" (UK use). (The latter should not be confused with meth, a common abbreviation for methamphetamine.)
Pure methanol has been used in open wheel auto racing since the mid-1960s. Unlike petroleum fires, methanol fires can be extinguished with plain water. A methanol-based fire burns invisibly, unlike gasoline, which burns with visible smoke. If a fire occurs on the track, there is no smoke to obstruct the view of fast approaching drivers, but this can also delay visual detection of the fire and the initiation of fire suppression actions. The decision to permanently switch to methanol in American IndyCar racing was a result of the devastating crash and explosion at the 1964 Indianapolis 500 which killed drivers Eddie Sachs and Dave MacDonald.[17]
One concern with the addition of methanol to automotive fuels is highlighted by recent groundwater impacts from the fuel additive methyl tert-butyl ether (MTBE). Leaking underground gasoline storage tanks created MTBE plumes in groundwater that eventually contaminated well water. Methanol's high solubility in water raises concerns that similar well water contamination could arise from the widespread use of methanol as an automotive fuel. | https://www.wikidoc.org/index.php/Carbinol | |
de562fb4f25041094f2607e8ea30a3d5ba9e94b5 | wikidoc | Carbogen | Carbogen
Carbogen, also called Meduna's Mixture after its inventor Ladislas J. Meduna, is a life-supporting mixture of carbon dioxide and oxygen gas. Meduna's original formula was 30% CO2 and 70% oxygen, but carbogen can refer to any mixture of these two gases, from 1.5% to 50% CO2.
# Mechanism
When carbogen is inhaled, the increase of carbon dioxide in the lungs causes a perception, both psychological and physiological, of suffocation because the brain perceives an increase in carbon dioxide levels in the lungs as a decrease in oxygen levels. In nature, this is generally true, and has evolved as an evolutionary mechanism to prevent all mammals from drowning by failing to surface in water. Therefore, inhalation of carbogen causes the body to react as if it were not receiving sufficient oxygen. Breathing quickens and deepens, heart rate increases, and cells release alkaline buffering agents to remove carbonic acid from the bloodstream. Not surprisingly, the sensation of inhaling carbogen is highly unpleasant and is likely to cause panic, near-death experiences, and other discomfort.
# Psychotherapy
Carbogen was once used in psychology and psychedelic psychotherapy to determine how a patient would react to an altered state of consciousness or to a sensation of loss of control. Individuals who reacted especially negatively to carbogen were generally not administered other psychotheraputic drugs for fear of similar reactions. Meduna administered carbogen to his patients to induce abreaction, which, with proper preparation and administration, he found could help clients become free of their neuroses. Carbogen users are said to have discovered unconscious contents of their mind, with the experience clearing away repressed material and freeing the subject for a smoother, more profound psychedelic experience.
One subject reported:
"After the second breath came an onrush of color, first a predominant sheet of beautiful rosy-red, following which came successive sheets of brilliant color and design, some geometric, some fanciful and graceful …. Then the colors separated; my soul drawing apart from the physical being, was drawn upward seemingly to leave the earth and to go upward where it reached a greater Spirit with Whom there was a communion, producing a remarkable, new relaxation and deep security."
Carbogen is rarely used in therapy anymore, largely due to the decline in psychotherapeutics.
# Modern Uses
Carbogen is used in biology research to study in vivo oxygen and carbon dioxide flows.
# Notes
- ↑ Prisman E, Slessarev M, Azami T, Nayot D, Milosevic M, and Fisher J. (2007). Modified oxygen mask to induce target levels of hyperoxia and hypercarbia during radiotherapy: a more effective alternative to carbogen. International Journal of Radiation Biology. Jul;83(7):457-62.
- ↑ Jump up to: 3.0 3.1 3.2 Walsh, Roger N. (2005). Higher Wisdom: Eminent Elders Explore the Continuing Impact of Psychedelics. State University of New York Press. pp. 57–58, 98. ISBN 0791465179. Unknown parameter |coauthor= ignored (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Markoff, John (2005). What the Dormouse Said. Penguin. pp. 25, 62. ISBN 0-670-03382-0.
- ↑ Meduna, Ladislas J. (1950). Carbon Dioxide Therapy. Charles Thomas.
- ↑ Arnold JF, Kotas M, Fidler F, Pracht ED, Flentje M, Jakob PM. (2007). Quantitative regional oxygen transfer imaging of the human lung. Journal of Magnetic Resonance Imaging. Aug 8;26(3):637-645
de:Carbogen
et:Meditsiiniline karbogeen | Carbogen
Carbogen, also called Meduna's Mixture after its inventor Ladislas J. Meduna, is a life-supporting mixture of carbon dioxide and oxygen gas. Meduna's original formula was 30% CO2 and 70% oxygen, but carbogen can refer to any mixture of these two gases, from 1.5%[1] to 50%[2] CO2.
# Mechanism
When carbogen is inhaled, the increase of carbon dioxide in the lungs causes a perception, both psychological and physiological, of suffocation because the brain perceives an increase in carbon dioxide levels in the lungs as a decrease in oxygen levels.[3] In nature, this is generally true, and has evolved as an evolutionary mechanism to prevent all mammals from drowning by failing to surface in water. Therefore, inhalation of carbogen causes the body to react as if it were not receiving sufficient oxygen. Breathing quickens and deepens, heart rate increases, and cells release alkaline buffering agents to remove carbonic acid from the bloodstream. Not surprisingly, the sensation of inhaling carbogen is highly unpleasant and is likely to cause panic, near-death experiences, and other discomfort.[3]
# Psychotherapy
Carbogen was once used in psychology and psychedelic psychotherapy to determine how a patient would react to an altered state of consciousness or to a sensation of loss of control.[4] Individuals who reacted especially negatively to carbogen were generally not administered other psychotheraputic drugs for fear of similar reactions. Meduna administered carbogen to his patients to induce abreaction, which, with proper preparation and administration, he found could help clients become free of their neuroses. Carbogen users are said to have discovered unconscious contents of their mind, with the experience clearing away repressed material and freeing the subject for a smoother, more profound psychedelic experience.[3]
One subject reported:
"After the second breath came an onrush of color, first a predominant sheet of beautiful rosy-red, following which came successive sheets of brilliant color and design, some geometric, some fanciful and graceful …. Then the colors separated; my soul drawing apart from the physical being, was drawn upward seemingly to leave the earth and to go upward where it reached a greater Spirit with Whom there was a communion, producing a remarkable, new relaxation and deep security."[5]
Carbogen is rarely used in therapy anymore, largely due to the decline in psychotherapeutics.
# Modern Uses
Carbogen is used in biology research to study in vivo oxygen and carbon dioxide flows.[6]
# Notes
- ↑ Prisman E, Slessarev M, Azami T, Nayot D, Milosevic M, and Fisher J. (2007). Modified oxygen mask to induce target levels of hyperoxia and hypercarbia during radiotherapy: a more effective alternative to carbogen. International Journal of Radiation Biology. Jul;83(7):457-62.
- ↑ http://www.erowid.org/chemicals/carbogen/carbogen_basics.shtml
- ↑ Jump up to: 3.0 3.1 3.2 Walsh, Roger N. (2005). Higher Wisdom: Eminent Elders Explore the Continuing Impact of Psychedelics. State University of New York Press. pp. 57–58, 98. ISBN 0791465179. Unknown parameter |coauthor= ignored (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Markoff, John (2005). What the Dormouse Said. Penguin. pp. 25, 62. ISBN 0-670-03382-0.
- ↑ Meduna, Ladislas J. (1950). Carbon Dioxide Therapy. Charles Thomas.
- ↑ Arnold JF, Kotas M, Fidler F, Pracht ED, Flentje M, Jakob PM. (2007). Quantitative regional oxygen transfer imaging of the human lung. Journal of Magnetic Resonance Imaging. Aug 8;26(3):637-645
de:Carbogen
et:Meditsiiniline karbogeen | https://www.wikidoc.org/index.php/Carbogen | |
931b8ba1fd9f8d9731663ccd74ad45019fe1fe30 | wikidoc | Carbonyl | Carbonyl
# Overview
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom : C=O.
The term carbonyl can also refer to carbon monoxide as a ligand in an inorganic or organometallic complex (a metal carbonyl, e.g. nickel carbonyl); in this situation, carbon is triple-bonded to oxygen : C≡O.
The remainder of this article concerns itself with the organic chemistry definition of carbonyl.
# Carbonyl compounds
A carbonyl group characterizes the following types of compounds (where -CO denotes a C=O carbonyl group):
Other organic carbonyls are urea and carbamates. Examples of inorganic carbonyl compounds are carbon dioxide, carbonyl sulfide and phosgene
# Reactivity
Oxygen is more electronegative than carbon, and thus pulls electron density away from carbon to increase the bond's polarity. Therefore, the carbonyl carbon becomes electrophilic, and thus more reactive with nucleophiles. Also, the electronegative oxygen can react with an electrophile; for example a proton in an acidic solution or other Lewis Acid.
The alpha hydrogen in a carbonyl compound is much more acidic (~1030 times more acidic) than a typical CH bond. For example the pKa values of acetaldehyde and acetone are 16.7 and 19, respectively.
Amides are the most stable of the carbonyl couplings due to their high resonance stabilization between the Nitrogen-Carbon and Carbon-Oxygen bonds.
Carbonyl groups can be reduced by reaction with hydride reagents such as NaBH4 and LiAlH4, and by organometallic reagents such as organolithium reagents and Grignard reagents.
Other important reactions include:
- Wolff-Kishner reduction
- Clemmensen reduction
- Conversion into thioacetals
- Hydration to hemiacetals and hemiketals, and then to acetals and ketals
- Reaction with ammonia and primary amines to form imines
- Reaction with hydroxylamines to form oximes
- Reaction with cyanide anion to form cyanohydrins
- Oxidation with oxaziridines to acyloins
- Reaction with Tebbe's reagent and phosphonium ylides to alkenes.
- Perkin reaction
- Tishchenko reaction
- Aldol condensation
- Cannizaro's reaction
# α,β-Unsaturated carbonyl compounds
α,β-Unsaturated carbonyl compounds are an important class of carbonyl compounds with the general structure Cβ=Cα−C=O. In these compounds the carbonyl group is conjugated with an alkene (hence the adjective unsaturated), from which they derive special properties. Examples of unsaturated carbonyls are acrolein, mesityl oxide, acrylic acid and maleic acid. Unsaturated carbonyls can be prepared in the laboratory in an aldol reaction and in the Perkin reaction.
The carbonyl group, be it an aldehyde or acid, draws electrons away from the alkene and the alkene group in unsaturated carbonyls are therefore deactived towards an electrophile such as bromine or hydrochloric acid. As a general rule with unsymmetric electrophiles hydrogen attaches itself at the α position in an electrophilic addition.
On the other hand, these compounds are activated towards nucleophiles in nucleophilic addition.
# Spectroscopy
- Infrared spectroscopy: the C=O double bond absorbs infrared light at wavenumbers between approximately 1600–1900 cm−1. The exact location of the absorption is well understood with respect to the geometry of the molecule. This absorption is known as the "carbonyl stretch" when displayed on an infrared absorption spectrum.
- Nuclear magnetic resonance: the C=O double-bond exhibits different resonances depending on surrounding atoms, generally a downfield shift. The 13C NMR of a carbonyl carbon is in the range of 160-220 ppm. | Carbonyl
# Overview
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom : C=O.
The term carbonyl can also refer to carbon monoxide as a ligand in an inorganic or organometallic complex (a metal carbonyl, e.g. nickel carbonyl); in this situation, carbon is triple-bonded to oxygen : C≡O.
The remainder of this article concerns itself with the organic chemistry definition of carbonyl.
# Carbonyl compounds
A carbonyl group characterizes the following types of compounds (where -CO denotes a C=O carbonyl group):
Other organic carbonyls are urea and carbamates. Examples of inorganic carbonyl compounds are carbon dioxide, carbonyl sulfide and phosgene
# Reactivity
Oxygen is more electronegative than carbon, and thus pulls electron density away from carbon to increase the bond's polarity. Therefore, the carbonyl carbon becomes electrophilic, and thus more reactive with nucleophiles. Also, the electronegative oxygen can react with an electrophile; for example a proton in an acidic solution or other Lewis Acid.
The alpha hydrogen in a carbonyl compound is much more acidic (~1030 times more acidic) than a typical CH bond. For example the pKa values of acetaldehyde and acetone are 16.7 and 19, respectively.[1]
Amides are the most stable of the carbonyl couplings due to their high resonance stabilization between the Nitrogen-Carbon and Carbon-Oxygen bonds.
Carbonyl groups can be reduced by reaction with hydride reagents such as NaBH4 and LiAlH4, and by organometallic reagents such as organolithium reagents and Grignard reagents.
Other important reactions include:
- Wolff-Kishner reduction
- Clemmensen reduction
- Conversion into thioacetals
- Hydration to hemiacetals and hemiketals, and then to acetals and ketals
- Reaction with ammonia and primary amines to form imines
- Reaction with hydroxylamines to form oximes
- Reaction with cyanide anion to form cyanohydrins
- Oxidation with oxaziridines to acyloins
- Reaction with Tebbe's reagent and phosphonium ylides to alkenes.
- Perkin reaction
- Tishchenko reaction
- Aldol condensation
- Cannizaro's reaction
# α,β-Unsaturated carbonyl compounds
α,β-Unsaturated carbonyl compounds are an important class of carbonyl compounds with the general structure Cβ=Cα−C=O. In these compounds the carbonyl group is conjugated with an alkene (hence the adjective unsaturated), from which they derive special properties. Examples of unsaturated carbonyls are acrolein, mesityl oxide, acrylic acid and maleic acid. Unsaturated carbonyls can be prepared in the laboratory in an aldol reaction and in the Perkin reaction.
The carbonyl group, be it an aldehyde or acid, draws electrons away from the alkene and the alkene group in unsaturated carbonyls are therefore deactived towards an electrophile such as bromine or hydrochloric acid. As a general rule with unsymmetric electrophiles hydrogen attaches itself at the α position in an electrophilic addition.
On the other hand, these compounds are activated towards nucleophiles in nucleophilic addition.
# Spectroscopy
- Infrared spectroscopy: the C=O double bond absorbs infrared light at wavenumbers between approximately 1600–1900 cm−1. The exact location of the absorption is well understood with respect to the geometry of the molecule. This absorption is known as the "carbonyl stretch" when displayed on an infrared absorption spectrum.[2]
- Nuclear magnetic resonance: the C=O double-bond exhibits different resonances depending on surrounding atoms, generally a downfield shift. The 13C NMR of a carbonyl carbon is in the range of 160-220 ppm. | https://www.wikidoc.org/index.php/Carbonyl | |
66a69de5e5f772731eae740037eb7a8b41563772 | wikidoc | Cardamom | Cardamom
The name cardamom is used for herbs within two genera of the ginger family Zingiberaceae, namely Elettaria and Amomum. Both varieties take the form of a small seedpod, triangular in cross-section and spindle-shaped, with a thin papery outer shell and small black seeds. Elettaria pods are light green in color, while Amomum pods are larger and dark brown.
# Types of cardamom and their distribution
The two main genera of the ginger family that are named as forms of cardamom are distributed as follows:
- Elettaria (commonly called cardamom, green cardamom, or true cardamom) is distributed from India to Malaysia.
- Amomum (commonly known as black cardamom, brown cardamom, Kravan, Java cardamom, Bengal cardamom, Siamese cardamom, white or red cardamom) is distributed mainly in Asia and Australia.
# Uses
All the different cardamom species and varieties are used mainly as cooking spices and as medicines. In general,
- Elettaria cardamomum (the usual type of cardamom) is used as a spice, a masticatory, and in medicine; it is also sometimes smoked; it is used as a food plant by the larva of the moth Endoclita hosei.
- Amomum is used as an ingredient in traditional systems of medicine in China, India, Korea, Japan, and Vietnam.
- In the Middle East and Turkey, green cardamom powder is used as a spice for sweet dishes as well as traditional flavouring in coffee and tea. It is also used to some extent in some dish recipes. In Arabic, cardamom is called al-Hayl.
- In South Asia green cardamom is often used in traditional Indian sweets and in tea, or chai. Black cardamom is sometimes used in garam masala for curries. It is often referred to by its size as being 'Moti Elaichi' or fat cardamom. In Hindi and Urdu cardamom is called elaichi. It is called Elakka in Malayalam, language of kerala which contributes 70% of Indian cardamom.
- In Northern Europe, cardamom is commonly used in sweet foods.
- It has also been known to be used for making gin.
# Uses in cuisines around the world
Cardamom has a strong, unique taste, with an intensely aromatic fragrance. It is a common ingredient in Indian cooking, and is often used in baking in Nordic countries. One of the most expensive spices by weight, little is needed to impart the flavour. Cardamom is best stored in pod form, because once the seeds are exposed or ground, they quickly lose their flavour. However, high-quality ground cardamom is often more readily (and cheaply) available, and is an acceptable substitute. For recipes requiring whole cardamom pods, a generally accepted equivalent is 10 pods equals 1½ teaspoons of ground cardamom.
## In traditional medicine
In South Asia, green cardamom called "Elaichi", in Hindi and Urdu, is broadly used to treat infections in teeth and gums, to prevent and treat throat troubles, congestion of the lungs and pulmonary tuberculosis, inflammation of eyelids and also digestive disorders. It is also reportedly used as an antidote for both snake and scorpion venom.
Species in the genus Amomum are also used in traditional Indian medicine. Among other species, varieties and cultivars, Amomum villosum is used in traditional Chinese medicine to treat stomach-aches, constipation, dysentery, and other digestion problems. "Tsaoko" cardamom is cultivated in Yunnan, China, both for medicinal purposes and as a spice.
# Gallery
- Cardamom fruit and seeds
Cardamom fruit and seeds
- Cardamom fruit and seeds close up
Cardamom fruit and seeds close up
- Black and green cardamom
Black and green cardamom | Cardamom
The name cardamom is used for herbs within two genera of the ginger family Zingiberaceae, namely Elettaria and Amomum. Both varieties take the form of a small seedpod, triangular in cross-section and spindle-shaped, with a thin papery outer shell and small black seeds. Elettaria pods are light green in color, while Amomum pods are larger and dark brown.
# Types of cardamom and their distribution
The two main genera of the ginger family that are named as forms of cardamom are distributed as follows:
- Elettaria (commonly called cardamom, green cardamom, or true cardamom) is distributed from India to Malaysia.
- Amomum (commonly known as black cardamom, brown cardamom, Kravan, Java cardamom, Bengal cardamom, Siamese cardamom, white or red cardamom) is distributed mainly in Asia and Australia.
# Uses
All the different cardamom species and varieties are used mainly as cooking spices and as medicines. In general,
- Elettaria cardamomum (the usual type of cardamom) is used as a spice, a masticatory, and in medicine; it is also sometimes smoked; it is used as a food plant by the larva of the moth Endoclita hosei.
- Amomum is used as an ingredient in traditional systems of medicine in China, India, Korea, Japan, and Vietnam.
- In the Middle East and Turkey, green cardamom powder is used as a spice for sweet dishes as well as traditional flavouring in coffee and tea. It is also used to some extent in some dish recipes. In Arabic, cardamom is called al-Hayl.
- In South Asia green cardamom is often used in traditional Indian sweets and in tea, or chai. Black cardamom is sometimes used in garam masala for curries. It is often referred to by its size as being 'Moti Elaichi' or fat cardamom. In Hindi and Urdu cardamom is called elaichi. It is called Elakka in Malayalam, language of kerala which contributes 70% of Indian cardamom.[1]
- In Northern Europe, cardamom is commonly used in sweet foods.
- It has also been known to be used for making gin.
# Uses in cuisines around the world
Cardamom has a strong, unique taste, with an intensely aromatic fragrance. It is a common ingredient in Indian cooking, and is often used in baking in Nordic countries. One of the most expensive spices by weight, little is needed to impart the flavour. Cardamom is best stored in pod form, because once the seeds are exposed or ground, they quickly lose their flavour. However, high-quality ground cardamom is often more readily (and cheaply) available, and is an acceptable substitute. For recipes requiring whole cardamom pods, a generally accepted equivalent is 10 pods equals 1½ teaspoons of ground cardamom.
## In traditional medicine
In South Asia, green cardamom called "Elaichi", in Hindi and Urdu, is broadly used to treat infections in teeth and gums, to prevent and treat throat troubles, congestion of the lungs and pulmonary tuberculosis, inflammation of eyelids and also digestive disorders. It is also reportedly used as an antidote for both snake and scorpion venom.
Species in the genus Amomum are also used in traditional Indian medicine. Among other species, varieties and cultivars, Amomum villosum is used in traditional Chinese medicine to treat stomach-aches, constipation, dysentery, and other digestion problems. "Tsaoko" cardamom is cultivated in Yunnan, China, both for medicinal purposes and as a spice.
# Gallery
- Cardamom fruit and seeds
Cardamom fruit and seeds
- Cardamom fruit and seeds close up
Cardamom fruit and seeds close up
- Black and green cardamom
Black and green cardamom | https://www.wikidoc.org/index.php/Cardamom | |
2c04f2d39fe12864d37bddd36150934091db6bde | wikidoc | Catheter | Catheter
Steven C. Campbell, M.D., Ph.D.
# Overview
In medicine a catheter is a tube that can be inserted into a body cavity, duct or vessel. Catheters thereby allow drainage or injection of fluids or access by surgical instruments. The process of inserting a catheter is catheterisation. In most uses a catheter is a thin, flexible tube: a "soft" catheter; in some uses, it is a larger, solid tube: a "hard" catheter.
# History and etymology
The ancient Egyptians created catheters from reeds. "Katheter" originally referred to an instrument that was inserted such as a plug. The word "katheter" in turn came from "kathiemai" meaning "to sound" with a probe. The ancient Greeks inserted a hollow metal tube through the urethra into the bladder to empty it and the tube came to be known as a "katheter"
# Uses
Placement of a catheter into a particular part of the body may allow:
- draining urine from the urinary bladder as in urinary catheterization, e.g., the Foley catheter or even when the urethra is damaged as in suprapubic catheterisation.
- drainage of urine from the kidney pelvis by percutaneous nephrostomy
- drainage of fluid collections, e.g. an abdominal abscess
- administration of intravenous fluids, medication or parenteral nutrition
- angioplasty, angiography, balloon septostomy, balloon sinuplasty. Often Seldinger technique is used.
- direct measurement of blood pressure in an artery or vein
- direct measurement of intracranial pressure
- administration of anaesthetic medication into the epidural space, the subarachnoid space, or around a major nerve bundle such as the brachial plexus
- subcutaneous administration of insulin or other medications, with the use of an infusion set and insulin pump
- Can be administered as sexual torture in a consensual BDSM context.
A central venous catheter is a conduit for giving drugs or fluids into a large-bore catheter positioned either in a vein near the heart or just inside the atrium. A Swan-Ganz catheter is a special type of catheter placed into the pulmonary artery for measuring pressures in the heart.
A Touhy borst adapter is a medical device used for attaching catheters to various other devices.
An external male condom catheter (Slang term: Texas Condom) is not a true catheter, as it is not inserted into a body cavity duct or vessel. Rather, this is a condom-like device with a plug where the condom's reservoir tip would be, and an adhesive at the base. This device allows for urinary catheterization without the insertion of a true catheter, and forms part of a Stadium buddy.
# Inventors
The modern application of the catheter was in use at least by 1868 when Dr. N.B.Sornborger patented the Syringe and Catheter (patent #73402) with features for fastening it to the body and controlling the depth of insertion.
David S. Sheridan was the inventor of the modern disposable catheter in the 1940s. In his lifetime he started and sold four catheter companies and was dubbed the "Catheter King" by Forbes Magazine in 1988. He is also credited with the invention of the modern "disposable" plastic endotracheal tube now used routinely in surgery. Prior to his invention, red rubber tubes were used, sterilized, and then re-used which often led to the spread of disease and also held a high risk of infection. As a result Mr Sheridan is credited with saving thousands of lives.
In the early 1900s, a Dubliner named Walsh and a famous Scottish urinologist called Norman Gibbon teamed together to create the standard catheter used in hospitals today. Named after the two creators, it was called the Gibbon-Walsh catheter.
The Gibbon catheter and the Walsh catheter have been described and their advantages over other catheters shown. The Walsh catheter is particularly useful after prostatectomy for it drains the bladder without infection or clot retention. The Gibbon catheter has largely removed the necessity of emergency prostatectomy. It is also very useful in cases of urethral fistula. A simple procedure such as dilatation of the urethra and passage of a Gibbon catheter often causes the fistula to close. This catheter is also of use in the treatment of urethral stricture and, as a temporary measure, in the treatment of retention of urine caused by carcinoma of the prostate | Catheter
Template:Search infobox
Steven C. Campbell, M.D., Ph.D.
# Overview
In medicine a catheter is a tube that can be inserted into a body cavity, duct or vessel. Catheters thereby allow drainage or injection of fluids or access by surgical instruments. The process of inserting a catheter is catheterisation. In most uses a catheter is a thin, flexible tube: a "soft" catheter; in some uses, it is a larger, solid tube: a "hard" catheter.
# History and etymology
The ancient Egyptians created catheters from reeds. "Katheter" originally referred to an instrument that was inserted such as a plug. The word "katheter" in turn came from "kathiemai" meaning "to sound" with a probe. The ancient Greeks inserted a hollow metal tube through the urethra into the bladder to empty it and the tube came to be known as a "katheter"
# Uses
Placement of a catheter into a particular part of the body may allow:
- draining urine from the urinary bladder as in urinary catheterization, e.g., the Foley catheter or even when the urethra is damaged as in suprapubic catheterisation.
- drainage of urine from the kidney pelvis by percutaneous nephrostomy[1]
- drainage of fluid collections, e.g. an abdominal abscess
- administration of intravenous fluids, medication or parenteral nutrition
- angioplasty, angiography, balloon septostomy, balloon sinuplasty. Often Seldinger technique is used.
- direct measurement of blood pressure in an artery or vein
- direct measurement of intracranial pressure
- administration of anaesthetic medication into the epidural space, the subarachnoid space, or around a major nerve bundle such as the brachial plexus
- subcutaneous administration of insulin or other medications, with the use of an infusion set and insulin pump
- Can be administered as sexual torture in a consensual BDSM context.
A central venous catheter is a conduit for giving drugs or fluids into a large-bore catheter positioned either in a vein near the heart or just inside the atrium. A Swan-Ganz catheter is a special type of catheter placed into the pulmonary artery for measuring pressures in the heart.
A Touhy borst adapter is a medical device used for attaching catheters to various other devices.
An external male condom catheter (Slang term: Texas Condom) is not a true catheter, as it is not inserted into a body cavity duct or vessel. Rather, this is a condom-like device with a plug where the condom's reservoir tip would be, and an adhesive at the base. This device allows for urinary catheterization without the insertion of a true catheter, and forms part of a Stadium buddy.
# Inventors
The modern application of the catheter was in use at least by 1868 when Dr. N.B.Sornborger patented the Syringe and Catheter (patent #73402) with features for fastening it to the body and controlling the depth of insertion.
David S. Sheridan was the inventor of the modern disposable catheter in the 1940s. In his lifetime he started and sold four catheter companies and was dubbed the "Catheter King" by Forbes Magazine in 1988. He is also credited with the invention of the modern "disposable" plastic endotracheal tube now used routinely in surgery. Prior to his invention, red rubber tubes were used, sterilized, and then re-used which often led to the spread of disease and also held a high risk of infection. As a result Mr Sheridan is credited with saving thousands of lives.
In the early 1900s, a Dubliner named Walsh and a famous Scottish urinologist called Norman Gibbon teamed together to create the standard catheter used in hospitals today. Named after the two creators, it was called the Gibbon-Walsh catheter.
The Gibbon catheter and the Walsh catheter have been described and their advantages over other catheters shown. The Walsh catheter is particularly useful after prostatectomy for it drains the bladder without infection or clot retention. The Gibbon catheter has largely removed the necessity of emergency prostatectomy. It is also very useful in cases of urethral fistula. A simple procedure such as dilatation of the urethra and passage of a Gibbon catheter often causes the fistula to close. This catheter is also of use in the treatment of urethral stricture and, as a temporary measure, in the treatment of retention of urine caused by carcinoma of the prostate | https://www.wikidoc.org/index.php/Cardiac_catheter | |
f38ffb1280a802500759667aa56f13147c760e7c | wikidoc | Catalase | Catalase
Catalase is a common enzyme found in nearly all living organisms exposed to oxygen (such as bacteria, plants, and animals). It catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in protecting the cell from oxidative damage by reactive oxygen species (ROS). Likewise, catalase has one of the highest turnover numbers of all enzymes; one catalase molecule can convert millions of hydrogen peroxide molecules to water and oxygen each second.
Catalase is a tetramer of four polypeptide chains, each over 500 amino acids long. It contains four iron-containing heme groups that allow the enzyme to react with the hydrogen peroxide. The optimum pH for human catalase is approximately 7, and has a fairly broad maximum: the rate of reaction does not change appreciably between pH 6.8 and 7.5. The pH optimum for other catalases varies between 4 and 11 depending on the species. The optimum temperature also varies by species.
# Structure
Human catalase forms a tetramer composed of four subunits, each of which can be conceptually divided into four domains. The extensive core of each subunit is generated by an eight-stranded antiparallel b-barrel (b1-8), with nearest neighbor connectivity capped by b-barrel loops on one side and a9 loops on the other. A helical domain at one face of the b-barrel is composed of four C-terminal helices (a16, a17, a18, and a19) and four helices derived from residues between b4 and b5 (a4, a5, a6, and a7). Alternative splicing may result in different protein variants.
# History
Catalase was not noticed until 1818 when Louis Jacques Thénard, who discovered H2O2 (hydrogen peroxide), suggested its breakdown is caused by an unknown substance. In 1900, Oscar Loew was the first to give it the name catalase, and found it in many plants and animals. In 1937 catalase from beef liver was crystallised by James B. Sumner and Alexander Dounce and the molecular weight was found in 1938.
The amino acid sequence of bovine catalase was determined in 1969, and the three-dimensional structure in 1981.
# Function
## Reaction
The presence of catalase in a microbial or tissue sample can be demonstrated by adding hydrogen peroxide and observing the reaction. The production of oxygen can be seen by the formation of bubbles. This easy test, which can be seen with the naked eye, without the aid of instruments, is possible because catalase has a very high specific activity, which produces a detectable response, as well as the fact that one of the products is a gas.
## Molecular mechanism
While the complete mechanism of catalase is not currently known, the reaction is believed to occur in two stages:
Here Fe()-E represents the iron center of the heme group attached to the enzyme. Fe(IV)-E(.+) is a mesomeric form of Fe(V)-E, meaning the iron is not completely oxidized to +V, but receives some stabilising electron density from the heme ligand, which is then shown as a radical cation (.+).
As hydrogen peroxide enters the active site, it interacts with the amino acids Asn148 (asparagine at position 148) and His75, causing a proton (hydrogen ion) to transfer between the oxygen atoms. The free oxygen atom coordinates, freeing the newly formed water molecule and Fe(IV)=O. Fe(IV)=O reacts with a second hydrogen peroxide molecule to reform Fe(III)-E and produce water and oxygen. The reactivity of the iron center may be improved by the presence of the phenolate ligand of Tyr358 in the fifth coordination position, which can assist in the oxidation of the Fe(III) to Fe(IV). The efficiency of the reaction may also be improved by the interactions of His75 and Asn148 with reaction intermediates. In general, the rate of the reaction can be determined by the Michaelis-Menten equation.
Catalase can also catalyze the oxidation, by hydrogen peroxide, of various metabolites and toxins, including formaldehyde, formic acid, phenols, acetaldehyde and alcohols. It does so according to the following reaction:
The exact mechanism of this reaction is not known.
Any heavy metal ion (such as copper cations in copper(II) sulfate) can act as a noncompetitive inhibitor of catalase. Furthermore, the poison cyanide is a noncompetitive inhibitor of catalase at high concentrations of hydrogen peroxide.
Arsenate acts as an activator. Three-dimensional protein structures of the peroxidated catalase intermediates are available at the Protein Data Bank.
## Cellular role
Hydrogen peroxide is a harmful byproduct of many normal metabolic processes; to prevent damage to cells and tissues, it must be quickly converted into other, less dangerous substances. To this end, catalase is frequently used by cells to rapidly catalyze the decomposition of hydrogen peroxide into less-reactive gaseous oxygen and water molecules.
Mice genetically engineered to lack catalase are initially phenotypically normal., however, catalase deficiency in mice may increase the likelihood of developing obesity, fatty liver, and type 2 diabetes. Some humans have very low levels of catalase (acatalasia), yet show few ill effects.
The increased oxidative stress that occurs with aging in mice is alleviated by over-expression of catalase. Over-expressing mice do not exhibit the age-associated loss of spermatozoa, testicular germ and Sertoli cells seen in wild-type mice. Oxidative stress in wild-type mice ordinarily induces oxidative DNA damage (measured as 8-oxodG) in sperm with aging, but these damages are significantly reduced in aged catalase over-expressing mice. Furthermore, these over-expressing mice show no decrease in age-dependent number of pups per litter. Overexpression of catalase targeted to mitochondria extends the lifespan of mice.
Catalase is usually located in a cellular organelle called the peroxisome. Peroxisomes in plant cells are involved in photorespiration (the use of oxygen and production of carbon dioxide) and symbiotic nitrogen fixation (the breaking apart of diatomic nitrogen (N2) to reactive nitrogen atoms). Hydrogen peroxide is used as a potent antimicrobial agent when cells are infected with a pathogen. Catalase-positive pathogens, such as Mycobacterium tuberculosis, Legionella pneumophila, and Campylobacter jejuni, make catalase to deactivate the peroxide radicals, thus allowing them to survive unharmed within the host.
Like alcohol dehydrogenase, catalase converts ethanol to acetaldehyde, but it is unlikely that this reaction is physiologically significant.
# Distribution among organisms
The large majority of known organisms use catalase in every organ, with particularly high concentrations occurring in the liver in mammals.Almost all aerobic microorganisms use catalase. It is also present in some anaerobic microorganisms, such as Methanosarcina barkeri. Catalase is also universal among plants and occurs in most fungi.
One unique use of catalase occurs in the bombardier beetle. This beetle has two sets of liquids that are stored separately in two paired glands. The larger of the pair, the storage chamber or reservoir, contains hydroquinones and hydrogen peroxide, while the smaller, the reaction chamber, contains catalases and peroxidases. To activate the noxious spray, the beetle mixes the contents of the two compartments, causing oxygen to be liberated from hydrogen peroxide. The oxygen oxidizes the hydroquinones and also acts as the propellant. The oxidation reaction is very exothermic (ΔH = −202.8 kJ/mol) and rapidly heats the mixture to the boiling point.
Long-lived queens of the termite Reticulitermes speratus have significantly lower oxidative damage to their DNA than non-reproductive individuals (workers and soldiers). Queens have more than two times higher catalase activity and seven times higher expression levels of the catalase gene RsCAT1 than workers. It appears that the efficient antioxidant capability of termite queens can partly explain how they attain longer life.
Catalase enzymes from various species have vastly differing optimum temperatures. Poikilothermic animals typically have catalases with optimum temperatures in the range of 15-25 °C, while mammalian or avian catalases might have optimum temperatures above 35 °C, and catalases from plants vary depending on their growth habit. In contrast, catalase isolated from the hyperthermophile archaeon Pyrobaculum calidifontis has a temperature optimum of 90 °C.
# Clinical significance and application
Catalase is used in the food industry for removing hydrogen peroxide from milk prior to cheese production. Another use is in food wrappers where it prevents food from oxidizing. Catalase is also used in the textile industry, removing hydrogen peroxide from fabrics to make sure the material is peroxide-free.
A minor use is in contact lens hygiene – a few lens-cleaning products disinfect the lens using a hydrogen peroxide solution; a solution containing catalase is then used to decompose the hydrogen peroxide before the lens is used again.
## Bacterial identification (catalase test)
The catalase test is one of the three main tests used by microbiologists to identify species of bacteria. If the bacteria possess catalase (i.e., are catalase-positive), when a small amount of bacterial isolate is added to hydrogen peroxide, bubbles of oxygen are observed. The catalase test is done by placing a drop of hydrogen peroxide on a microscope slide. An applicator stick is touched to the colony, and the tip is then smeared onto the hydrogen peroxide drop.
- If the mixture produces bubbles or froth, the organism is said to be 'catalase-positive'. Staphylococci and Micrococci are catalase-positive. Other catalase-positive organisms include Listeria, Corynebacterium diphtheriae, Burkholderia cepacia, Nocardia, the family Enterobacteriaceae (Citrobacter, E. coli, Enterobacter, Klebsiella, Shigella, Yersinia, Proteus, Salmonella, Serratia), Pseudomonas, Mycobacterium tuberculosis, Aspergillus, Cryptococcus, and Rhodococcus equi.
- If not, the organism is 'catalase-negative'. Streptococcus and Enterococcus spp. are catalase-negative.
While the catalase test alone cannot identify a particular organism, it can aid identification when combined with other tests such as antibiotic resistance. The presence of catalase in bacterial cells depends on both the growth condition and the medium used to grow the cells.
Capillary tubes may also be used. A small sample of bacteria is collected on the end of the capillary tube, without blocking the tube, to avoid false negative results. The opposite end is then dipped into hydrogen peroxide, which is drawn into the tube through capillary action, and turned upside down, so that the bacterial points downwards. The hand holding the tube is then tapped on the bench, moving the hydrogen peroxide down until it touches the bacteria. If bubbles form on contact, this indicates a positive catalase result. This test can detect catalase-positive bacteria at concentrations above about 105 cells/mL, and is simple to use.
## Bacterial virulence
Neutrophils and other phagocytes use peroxide to kill bacteria. The enzyme NADPH oxidase generates superoxide within the phagosome, which is converted via hydrogen peroxide to other oxidising substances like hypochlorous acid which kill phagocytosed pathogens. In individuals with chronic granulomatous disease (CGD) there is a defect in producing peroxide via mutations in phagocyte oxidases such as myeloperoxidase. Normal cellular metabolism will still produce a small amount of peroxide and this peroxide can be used to produce hypochlorous acid to eradicate the bacterial infection. However, if individuals with CGD are infected with catalase-positive bacteria, the bacterial catalase can destroy the excess peroxide before it can be used to produce other oxidising substances. In these individuals the pathogen survives and becomes a chronic infection. This chronic infection is typically surrounded by macrophages in an attempt to isolate the infection. This wall of macrophages surrounding a pathogen is called a granuloma. Many bacteria are catalase positive, but some are better catalase-producers than others. The mnemonic "cats Need PLACESS to Belch their Hairballs" can be used to memorise the catalase-positive bacteria: nocardia, pseudomonas, listeria, aspergillus, candida, E. coli, staphylococcus, serratia, B. cepacia and H. pylori.
## Acatalasia
Acatalasia is a condition caused by homozygous mutations in CAT, resulting in a lack of catalase. Symptoms are mild and include oral ulcers. A heterozygous CAT mutation results in lower, but still present catalase.
## Gray hair
Low levels of catalase may play a role in the graying process of human hair. Hydrogen peroxide is naturally produced by the body and broken down by catalase. If catalase levels decline, hydrogen peroxide cannot be broken down so well. The hydrogen peroxide interferes with the production of melanin, the pigment that gives hair its color.
# Interactions
Catalase has been shown to interact with the ABL2 and Abl genes. Infection with the murine leukemia virus causes catalase activity to decline in the lungs, heart and kidneys of mice. Conversely, dietary fish oil increased catalase activity in the heart, and kidneys of mice. | Catalase
Catalase is a common enzyme found in nearly all living organisms exposed to oxygen (such as bacteria, plants, and animals). It catalyzes the decomposition of hydrogen peroxide to water and oxygen.[1] It is a very important enzyme in protecting the cell from oxidative damage by reactive oxygen species (ROS). Likewise, catalase has one of the highest turnover numbers of all enzymes; one catalase molecule can convert millions of hydrogen peroxide molecules to water and oxygen each second.[2]
Catalase is a tetramer of four polypeptide chains, each over 500 amino acids long.[3] It contains four iron-containing heme groups that allow the enzyme to react with the hydrogen peroxide. The optimum pH for human catalase is approximately 7,[4] and has a fairly broad maximum: the rate of reaction does not change appreciably between pH 6.8 and 7.5.[5] The pH optimum for other catalases varies between 4 and 11 depending on the species.[6] The optimum temperature also varies by species.[7]
# Structure
Human catalase forms a tetramer composed of four subunits, each of which can be conceptually divided into four domains.[8] The extensive core of each subunit is generated by an eight-stranded antiparallel b-barrel (b1-8), with nearest neighbor connectivity capped by b-barrel loops on one side and a9 loops on the other.[8] A helical domain at one face of the b-barrel is composed of four C-terminal helices (a16, a17, a18, and a19) and four helices derived from residues between b4 and b5 (a4, a5, a6, and a7).[8] Alternative splicing may result in different protein variants.
# History
Catalase was not noticed until 1818 when Louis Jacques Thénard, who discovered H2O2 (hydrogen peroxide), suggested its breakdown is caused by an unknown substance. In 1900, Oscar Loew was the first to give it the name catalase, and found it in many plants and animals.[9] In 1937 catalase from beef liver was crystallised by James B. Sumner and Alexander Dounce[10] and the molecular weight was found in 1938.[11]
The amino acid sequence of bovine catalase was determined in 1969,[12] and the three-dimensional structure in 1981.[13]
# Function
## Reaction
The presence of catalase in a microbial or tissue sample can be demonstrated by adding hydrogen peroxide and observing the reaction. The production of oxygen can be seen by the formation of bubbles. This easy test, which can be seen with the naked eye, without the aid of instruments, is possible because catalase has a very high specific activity, which produces a detectable response, as well as the fact that one of the products is a gas.
## Molecular mechanism
While the complete mechanism of catalase is not currently known,[14] the reaction is believed to occur in two stages:
Here Fe()-E represents the iron center of the heme group attached to the enzyme. Fe(IV)-E(.+) is a mesomeric form of Fe(V)-E, meaning the iron is not completely oxidized to +V, but receives some stabilising electron density from the heme ligand, which is then shown as a radical cation (.+).
As hydrogen peroxide enters the active site, it interacts with the amino acids Asn148 (asparagine at position 148) and His75, causing a proton (hydrogen ion) to transfer between the oxygen atoms. The free oxygen atom coordinates, freeing the newly formed water molecule and Fe(IV)=O. Fe(IV)=O reacts with a second hydrogen peroxide molecule to reform Fe(III)-E and produce water and oxygen.[14] The reactivity of the iron center may be improved by the presence of the phenolate ligand of Tyr358 in the fifth coordination position, which can assist in the oxidation of the Fe(III) to Fe(IV). The efficiency of the reaction may also be improved by the interactions of His75 and Asn148 with reaction intermediates.[14] In general, the rate of the reaction can be determined by the Michaelis-Menten equation.[15]
Catalase can also catalyze the oxidation, by hydrogen peroxide, of various metabolites and toxins, including formaldehyde, formic acid, phenols, acetaldehyde and alcohols. It does so according to the following reaction:
The exact mechanism of this reaction is not known.
Any heavy metal ion (such as copper cations in copper(II) sulfate) can act as a noncompetitive inhibitor of catalase. Furthermore, the poison cyanide is a noncompetitive inhibitor[16] of catalase at high concentrations of hydrogen peroxide.[17]
Arsenate acts as an activator.[18] Three-dimensional protein structures of the peroxidated catalase intermediates are available at the Protein Data Bank.
## Cellular role
Hydrogen peroxide is a harmful byproduct of many normal metabolic processes; to prevent damage to cells and tissues, it must be quickly converted into other, less dangerous substances. To this end, catalase is frequently used by cells to rapidly catalyze the decomposition of hydrogen peroxide into less-reactive gaseous oxygen and water molecules.[19]
Mice genetically engineered to lack catalase are initially phenotypically normal.,[20] however, catalase deficiency in mice may increase the likelihood of developing obesity, fatty liver,[21] and type 2 diabetes.[22] Some humans have very low levels of catalase (acatalasia), yet show few ill effects.
The increased oxidative stress that occurs with aging in mice is alleviated by over-expression of catalase.[23] Over-expressing mice do not exhibit the age-associated loss of spermatozoa, testicular germ and Sertoli cells seen in wild-type mice. Oxidative stress in wild-type mice ordinarily induces oxidative DNA damage (measured as 8-oxodG) in sperm with aging, but these damages are significantly reduced in aged catalase over-expressing mice.[23] Furthermore, these over-expressing mice show no decrease in age-dependent number of pups per litter. Overexpression of catalase targeted to mitochondria extends the lifespan of mice.[24]
Catalase is usually located in a cellular organelle called the peroxisome.[25] Peroxisomes in plant cells are involved in photorespiration (the use of oxygen and production of carbon dioxide) and symbiotic nitrogen fixation (the breaking apart of diatomic nitrogen (N2) to reactive nitrogen atoms). Hydrogen peroxide is used as a potent antimicrobial agent when cells are infected with a pathogen. Catalase-positive pathogens, such as Mycobacterium tuberculosis, Legionella pneumophila, and Campylobacter jejuni, make catalase to deactivate the peroxide radicals, thus allowing them to survive unharmed within the host.[26]
Like alcohol dehydrogenase, catalase converts ethanol to acetaldehyde, but it is unlikely that this reaction is physiologically significant.[27]
# Distribution among organisms
The large majority of known organisms use catalase in every organ, with particularly high concentrations occurring in the liver in mammals.[28]Almost all aerobic microorganisms use catalase. It is also present in some anaerobic microorganisms, such as Methanosarcina barkeri.[29] Catalase is also universal among plants and occurs in most fungi.[30]
One unique use of catalase occurs in the bombardier beetle. This beetle has two sets of liquids that are stored separately in two paired glands. The larger of the pair, the storage chamber or reservoir, contains hydroquinones and hydrogen peroxide, while the smaller, the reaction chamber, contains catalases and peroxidases. To activate the noxious spray, the beetle mixes the contents of the two compartments, causing oxygen to be liberated from hydrogen peroxide. The oxygen oxidizes the hydroquinones and also acts as the propellant.[31] The oxidation reaction is very exothermic (ΔH = −202.8 kJ/mol) and rapidly heats the mixture to the boiling point.[32]
Long-lived queens of the termite Reticulitermes speratus have significantly lower oxidative damage to their DNA than non-reproductive individuals (workers and soldiers).[33] Queens have more than two times higher catalase activity and seven times higher expression levels of the catalase gene RsCAT1 than workers.[33] It appears that the efficient antioxidant capability of termite queens can partly explain how they attain longer life.
Catalase enzymes from various species have vastly differing optimum temperatures. Poikilothermic animals typically have catalases with optimum temperatures in the range of 15-25 °C, while mammalian or avian catalases might have optimum temperatures above 35 °C,[34][35] and catalases from plants vary depending on their growth habit.[34] In contrast, catalase isolated from the hyperthermophile archaeon Pyrobaculum calidifontis has a temperature optimum of 90 °C.[36]
# Clinical significance and application
Catalase is used in the food industry for removing hydrogen peroxide from milk prior to cheese production.[37] Another use is in food wrappers where it prevents food from oxidizing.[38] Catalase is also used in the textile industry, removing hydrogen peroxide from fabrics to make sure the material is peroxide-free.[39]
A minor use is in contact lens hygiene – a few lens-cleaning products disinfect the lens using a hydrogen peroxide solution; a solution containing catalase is then used to decompose the hydrogen peroxide before the lens is used again.[40]
## Bacterial identification (catalase test)
The catalase test is one of the three main tests used by microbiologists to identify species of bacteria. If the bacteria possess catalase (i.e., are catalase-positive), when a small amount of bacterial isolate is added to hydrogen peroxide, bubbles of oxygen are observed. The catalase test is done by placing a drop of hydrogen peroxide on a microscope slide. An applicator stick is touched to the colony, and the tip is then smeared onto the hydrogen peroxide drop.
- If the mixture produces bubbles or froth, the organism is said to be 'catalase-positive'. Staphylococci[41] and Micrococci[42] are catalase-positive. Other catalase-positive organisms include Listeria, Corynebacterium diphtheriae, Burkholderia cepacia, Nocardia, the family Enterobacteriaceae (Citrobacter, E. coli, Enterobacter, Klebsiella, Shigella, Yersinia, Proteus, Salmonella, Serratia), Pseudomonas, Mycobacterium tuberculosis, Aspergillus, Cryptococcus, and Rhodococcus equi.
- If not, the organism is 'catalase-negative'. Streptococcus[43] and Enterococcus spp. are catalase-negative.
While the catalase test alone cannot identify a particular organism, it can aid identification when combined with other tests such as antibiotic resistance. The presence of catalase in bacterial cells depends on both the growth condition and the medium used to grow the cells.
Capillary tubes may also be used. A small sample of bacteria is collected on the end of the capillary tube, without blocking the tube, to avoid false negative results. The opposite end is then dipped into hydrogen peroxide, which is drawn into the tube through capillary action, and turned upside down, so that the bacterial points downwards. The hand holding the tube is then tapped on the bench, moving the hydrogen peroxide down until it touches the bacteria. If bubbles form on contact, this indicates a positive catalase result. This test can detect catalase-positive bacteria at concentrations above about 105 cells/mL,[44] and is simple to use.
## Bacterial virulence
Neutrophils and other phagocytes use peroxide to kill bacteria. The enzyme NADPH oxidase generates superoxide within the phagosome, which is converted via hydrogen peroxide to other oxidising substances like hypochlorous acid which kill phagocytosed pathogens.[45] In individuals with chronic granulomatous disease (CGD) there is a defect in producing peroxide via mutations in phagocyte oxidases such as myeloperoxidase.[46] Normal cellular metabolism will still produce a small amount of peroxide and this peroxide can be used to produce hypochlorous acid to eradicate the bacterial infection. However, if individuals with CGD are infected with catalase-positive bacteria, the bacterial catalase can destroy the excess peroxide before it can be used to produce other oxidising substances. In these individuals the pathogen survives and becomes a chronic infection. This chronic infection is typically surrounded by macrophages in an attempt to isolate the infection. This wall of macrophages surrounding a pathogen is called a granuloma. Many bacteria are catalase positive, but some are better catalase-producers than others. The mnemonic "cats Need PLACESS to Belch their Hairballs" can be used to memorise the catalase-positive bacteria: nocardia, pseudomonas, listeria, aspergillus, candida, E. coli, staphylococcus, serratia, B. cepacia and H. pylori.[47]
## Acatalasia
Acatalasia is a condition caused by homozygous mutations in CAT, resulting in a lack of catalase. Symptoms are mild and include oral ulcers. A heterozygous CAT mutation results in lower, but still present catalase.[48]
## Gray hair
Low levels of catalase may play a role in the graying process of human hair. Hydrogen peroxide is naturally produced by the body and broken down by catalase. If catalase levels decline, hydrogen peroxide cannot be broken down so well. The hydrogen peroxide interferes with the production of melanin, the pigment that gives hair its color.[49][50]
# Interactions
Catalase has been shown to interact with the ABL2[51] and Abl genes.[51] Infection with the murine leukemia virus causes catalase activity to decline in the lungs, heart and kidneys of mice. Conversely, dietary fish oil increased catalase activity in the heart, and kidneys of mice.[52] | https://www.wikidoc.org/index.php/Catalase | |
751f3a8856e6e8f4fb9bbbe4833fcf186fec0358 | wikidoc | Catechin | Catechin
Catechins are polyphenolic antioxidant plant metabolites, specifically flavonoids called flavan-3-ols. Although present in numerous plant species, the largest source in the human diet is from various teas derived from the tea-plant Camellia sinensis.
# Catechin, epicatechin, gallocatechin, epigallocatechin, and the gallates
Catechin and epicatechin are epimers, with (-)-epicatechin and (+)-catechin being the most common optical isomers found in nature. Catechin was first isolated from the plant extract catechu, from which it derives its name. Heating catechin past its point of decomposition releases pyrocatechol, which explains the common origin of the names of these compounds.
Epigallocatechin and gallocatechin contain an additional phenolic hydroxyl group when compared to epicatechin and catechin, respectively, similar to the difference in pyrogallol compared to pyrocatechol.
Catechin gallates are gallic acid esters of the catechins; such as EGCG (epigallocatechin gallate), which is commonly the most abundant catechin in tea.
# Sources of catechins
Catechins constitute about 25% of the dry weight of fresh tea leaf, although total catechin content varies widely depending on clonal variation, growing location, seasonal/ light variation, and altitude. They are present in nearly all teas made from Camellia sinensis, including white tea, green tea, black tea and Oolong tea.
Catechins are also present in the human diet in chocolate, fruits, vegetables and wine and are found in many other plant species.
# Health benefits of catechins
The health benefits of catechins have been studied extensively in humans and in animal models. Reduction in atherosclerotic plaques was seen in animal models. Reduction in carcinogenesis was seen in vitro.
Many studies on health benefits have been linked to the catechin content.
According to Norman Hollenberg, professor of medicine at Harvard Medical School, epicatechin can reduce the risk of four of the major health problems: stroke, heart failure, cancer and diabetes. He studied the Kuna people in Panama, who drink up to 40 cups of cocoa a week, and found that the prevalence of the "big four" is less than 10%. He believes that epicatechin should be considered essential to the diet and thus classed as a vitamin.Science Daily March 12, 2007
According to one researcher epigallocatechin-3-gallate is an antioxidant that helps protect the skin from UV radiation-induced damage and tumor formation.
A study on green-tea catechins is reviewed here: | Catechin
Catechins are polyphenolic antioxidant plant metabolites, specifically flavonoids called flavan-3-ols. Although present in numerous plant species, the largest source in the human diet is from various teas derived from the tea-plant Camellia sinensis.
# Catechin, epicatechin, gallocatechin, epigallocatechin, and the gallates
Catechin and epicatechin are epimers, with (-)-epicatechin and (+)-catechin being the most common optical isomers found in nature. Catechin was first isolated from the plant extract catechu, from which it derives its name. Heating catechin past its point of decomposition releases pyrocatechol, which explains the common origin of the names of these compounds.
Epigallocatechin and gallocatechin contain an additional phenolic hydroxyl group when compared to epicatechin and catechin, respectively, similar to the difference in pyrogallol compared to pyrocatechol.
Catechin gallates are gallic acid esters of the catechins; such as EGCG (epigallocatechin gallate), which is commonly the most abundant catechin in tea.
# Sources of catechins
Catechins constitute about 25% of the dry weight of fresh tea leaf[1], although total catechin content varies widely depending on clonal variation, growing location, seasonal/ light variation, and altitude. They are present in nearly all teas made from Camellia sinensis, including white tea, green tea, black tea and Oolong tea.
Catechins are also present in the human diet in chocolate[2], fruits, vegetables and wine[3] and are found in many other plant species[4].
# Health benefits of catechins
The health benefits of catechins have been studied extensively in humans and in animal models. Reduction in atherosclerotic plaques was seen in animal models.[5] Reduction in carcinogenesis was seen in vitro.[6]
Many studies on health benefits have been linked to the catechin content.
According to Norman Hollenberg, professor of medicine at Harvard Medical School, epicatechin can reduce the risk of four of the major health problems: stroke, heart failure, cancer and diabetes. He studied the Kuna people in Panama, who drink up to 40 cups of cocoa a week, and found that the prevalence of the "big four" is less than 10%. He believes that epicatechin should be considered essential to the diet and thus classed as a vitamin.[1]Science Daily March 12, 2007
According to one researcher[7] epigallocatechin-3-gallate is an antioxidant that helps protect the skin from UV radiation-induced damage and tumor formation.
A study on green-tea catechins is reviewed here: http://www.sciencedaily.com/releases/2007/08/070810194923.htm | https://www.wikidoc.org/index.php/Catechin | |
eeb97e8be29d814f6de96e2bd79cd13e9037d618 | wikidoc | Caveolin | Caveolin
In molecular biology caveolins are a family of integral membrane proteins that are the principal components of caveolae membranes and involved in receptor-independent endocytosis. Caveolins may act as scaffolding proteins within caveolar membranes by compartmentalizing and concentrating signaling molecules. They also induce positive (inward) membrane curvature by way of oligomerization, and hairpin insertion. Various classes of signaling molecules, including G-protein subunits, receptor and non-receptor tyrosine kinases, endothelial nitric oxide synthase (eNOS), and small GTPases, bind Cav-1 through its 'caveolin-scaffolding domain'.
The caveolin gene family has three members in vertebrates: CAV1, CAV2, and CAV3, coding for the proteins caveolin-1, caveolin-2, and caveolin-3, respectively. All three members are membrane proteins with similar structure. Caveolin forms oligomers and associates with cholesterol and sphingolipids in certain areas of the cell membrane, leading to the formation of caveolae.
# Structure and expression
The caveolins are similar in structure. They all form hairpin loops that are inserted into the cell membrane. Both the C-terminus and the N-terminus face the cytoplasmic side of the membrane. There are two isoforms of caveolin-1: caveolin-1α and caveolin-1β, the latter lacking a part of the N-terminus.
Caveolins are found in the majority of adherent, mammalian cells.
- Caveolin-1 is most prominently expressed in endothelial, fibrous, and adipose tissue.
- The expression pattern of caveolin-2 is similar to that of caveolin-1; it seems to be co-expressed with caveolin-1.
- The expression of caveolin-3 is restricted to striated and smooth muscle.
# Function
The functions of caveolins are still under intensive investigation. They are best known for their role in the formation of 50-nanometer-size invaginations of the plasma membrane, called caveolae. Oligomers of caveolin form the coat of these domains. Cells that lack caveolins also lack caveolae. Many functions are ascribed to these domains, ranging from endocytosis and transcytosis to signal transduction.
Caveolin-1 has also been shown to play a role in the integrin signaling. The tyrosine phosphorylated form of caveolin-1 colocalizes with focal adhesions, suggesting a role for caveolin-1 in migration. Indeed, downregulation of caveolin-1 leads to less efficient migration in vitro.
Genetically engineered mice that lack caveolin-1 and caveolin-2 are viable and fertile, showing that neither the caveolins nor the caveolae are essential in embryonic development or reproduction of these animals. However, knock-out animals do develop abnormal, hypertrophic lungs, and cardiac myopathy, leading to a reduction in lifespan. Mice lacking caveolins also suffer from impaired angiogenic responses as well as abnormal responses to vasoconstrictive stimuli. In zebrafish, lack of caveolins leads to embryonic lethality, suggesting that higher vertebrates (as exemplified by mice) have developed compensation or redundancy for the functions of caveolins.
# Role in disease
## Cancer
Caveolins have a paradoxical role in the development of this disease. They have been implicated in both tumor suppression and oncogenesis. High expression of caveolins leads to inhibition of cancer-related pathways, such as growth factor signaling pathways. However, certain cancer cells that express caveolins have been shown to be more aggressive and metastatic, because of a potential for anchorage-independent growth.
## Cardiovascular diseases
Caveolins are thought to play an important role during the development of atherosclerosis. Furthermore, caveolin-3 has been associated with Long QT syndrome.
## Muscular dystrophy
Caveolin-3 has been implicated in the development of certain types of muscular dystrophy (Limb-girdle muscular dystrophy). | Caveolin
In molecular biology caveolins are a family of integral membrane proteins that are the principal components of caveolae membranes and involved in receptor-independent endocytosis.[1][2][3] Caveolins may act as scaffolding proteins within caveolar membranes by compartmentalizing and concentrating signaling molecules. They also induce positive (inward) membrane curvature by way of oligomerization, and hairpin insertion. Various classes of signaling molecules, including G-protein subunits, receptor and non-receptor tyrosine kinases, endothelial nitric oxide synthase (eNOS), and small GTPases, bind Cav-1 through its 'caveolin-scaffolding domain'.
The caveolin gene family has three members in vertebrates: CAV1, CAV2, and CAV3, coding for the proteins caveolin-1, caveolin-2, and caveolin-3, respectively. All three members are membrane proteins with similar structure. Caveolin forms oligomers and associates with cholesterol and sphingolipids in certain areas of the cell membrane, leading to the formation of caveolae.
# Structure and expression
The caveolins are similar in structure. They all form hairpin loops that are inserted into the cell membrane. Both the C-terminus and the N-terminus face the cytoplasmic side of the membrane. There are two isoforms of caveolin-1: caveolin-1α and caveolin-1β, the latter lacking a part of the N-terminus.
Caveolins are found in the majority of adherent, mammalian cells.
- Caveolin-1 is most prominently expressed in endothelial, fibrous, and adipose tissue.
- The expression pattern of caveolin-2 is similar to that of caveolin-1; it seems to be co-expressed with caveolin-1.
- The expression of caveolin-3 is restricted to striated and smooth muscle.
# Function
The functions of caveolins are still under intensive investigation. They are best known for their role in the formation of 50-nanometer-size invaginations of the plasma membrane, called caveolae. Oligomers of caveolin form the coat of these domains. Cells that lack caveolins also lack caveolae. Many functions are ascribed to these domains, ranging from endocytosis and transcytosis to signal transduction.
Caveolin-1 has also been shown to play a role in the integrin signaling. The tyrosine phosphorylated form of caveolin-1 colocalizes with focal adhesions, suggesting a role for caveolin-1 in migration. Indeed, downregulation of caveolin-1 leads to less efficient migration in vitro.
Genetically engineered mice that lack caveolin-1 and caveolin-2 are viable and fertile, showing that neither the caveolins nor the caveolae are essential in embryonic development or reproduction of these animals. However, knock-out animals do develop abnormal, hypertrophic lungs, and cardiac myopathy, leading to a reduction in lifespan. Mice lacking caveolins also suffer from impaired angiogenic responses as well as abnormal responses to vasoconstrictive stimuli. In zebrafish, lack of caveolins leads to embryonic lethality, suggesting that higher vertebrates (as exemplified by mice) have developed compensation or redundancy for the functions of caveolins.
# Role in disease
## Cancer
Caveolins have a paradoxical role in the development of this disease. They have been implicated in both tumor suppression and oncogenesis.[4] High expression of caveolins leads to inhibition of cancer-related pathways, such as growth factor signaling pathways. However, certain cancer cells that express caveolins have been shown to be more aggressive and metastatic, because of a potential for anchorage-independent growth.
## Cardiovascular diseases
Caveolins are thought to play an important role during the development of atherosclerosis.[5] Furthermore, caveolin-3 has been associated with Long QT syndrome.[6]
## Muscular dystrophy
Caveolin-3 has been implicated in the development of certain types of muscular dystrophy (Limb-girdle muscular dystrophy).[7] | https://www.wikidoc.org/index.php/Caveolin | |
b75e3a03bba4622fa18845d1497406419566c318 | wikidoc | Ccdc109b | Ccdc109b
Coiled-coil domain containing 109B (CCDC109B) is a potential calcium uniporter protein found in the membrane of human cells and is encoded by the CCDC109B gene. While CCDC109B is a transmembrane protein it is unclear if it is located within the cell membrane or mitochondrial membrane.
# Gene information
CCDC109B is located at 4q25 and is 128,520 base pairs in length. CCDC109B contains eight exons and is located on the positive strand of chromosome four. CCDC109B has nine transcript variants due to alternative splicing. The unspliced version of this gene is the longest and most common variant found in human cells and is 1298 base pairs in length.
# Protein information
When translated, the CCDC109B protein is composed of 336 amino acids and has a molecular weight of 39.1 kDa. The 3' end of this protein is highly conserved and contains domains crucial for protein function.
## Protein domains
- Domain of Unknown Function 607 (DUF607): The function of this domain is largely unknown, although it may serve as a calcium transporter when CCDC109B forms homo-oligimers. DUF607 is conserved in orthologs and is located closer to the 3' end of this protein, even though DUF607 is present for most of the protein's length.
- Transmembrane Region: CCDC109B contains two transmembrane regions, located within DUF607, making it a multipass membrane protein. Since there are two transmembrane regions, both the N-terminus and C-terminus are located on one side of the membrane and have been localized to the cytosolic side of the cell membrane.
- DIME Motif: This motif is a completely conserved region found in all orthologs of this protein and is found within DUF607 and between the transmembrane domains. The DIME motif is a sequence of 23 amino acids that has the sequence: QxGxLAxLTWWxYSWDIMEPVTYF, where letters correspond to actual amino acid residule and "x" represents amino acids that are not conserved within this sequence. Throughout the entire CCDC109B protein there are no other conserved amino acid sequences that are greater than three amino acids in length. The DIME Motif has a hypothesized role in calcium transport and is most likely essential in DUF607.
## Post-translational modifications
### Phosphorylation sites
The CCDC109B protein contains several likely phosphorylation sites on serine, threonine, and tyrosine residues.
- Serine Phosphorylation Sites: Amino acid positions 77, 213, 315, and 322.
- Threonine Phosphorylation Site: Amino acid position 53.
- Tyrosine Phosphorylation Site: Amino acid position 274.
### Sumoylation site
There is one likely sumoylation site within CCDC109B at amino acid residue 306, which is a lysine. This residue is highly conserved among orthologs.
## Tertiary structure
Although it is known that CCDC109B is a transmembrane protein the proper folding of its N-terminus and C-terminus is unclear.
# Homology
CCDC109B shows conservation in vertebrates, including mammals, birds, reptiles, and amphibians. There appears to be some conservation in earlier organisms such as flies, worms, and plants, but the percent identity is very low and these organisms have many orthologus structures that may not be CCDC109B. The orthologs found in non-vertebrate organisms may also actually be the paralog of CCDC109B which is still producing some identity to CCDC109B.
The table below shows CCDC109B conservation among vertebrate organisms:
## Paralog of CCDC109B
CCDC109B has a single paralog in the human genome. This paralog is CCDC109A, which is more commonly known as Mitochondrial Calcium Uniporter (MCU) MCU is located in the inner membrane of the mitochondrion and is found as an oligomer that transports calcium ions into the mitochondria. MCU is an essential component of the mitochondrial membrane and sliencing MCU abolishes calcium uptake. The DIME motif, which is also conserved in CCDC109B, is responsible for calcium uptake and a mutation in this region inhibits this function. CCDC109B and MCU share a 43% identity in which the DIME motif is fully conserved.
# Expression profile
CCDC109B is expressed at high levels in the immune system and the circulatory system. CCDC109B is expressed in B-cells, Dendritic Cells, T-Cells, and Natural Killer Cells. CCDC109B expression is not present in human adipose tissue, adrenal glands, bladder, bone marrow, ear, esophagus, larynx, parathyroid, pituitary gland, spleen, thryroid, trachea, or umbilical cord tissues.
## Role in disease
CCDC109B may contribute to a number of diseases including various lymphomas and leukemias. Changes in CCDC109B expression are also present in other diseases such as glioblastomas, Daudi Burkitt's lymphoma, Duchenne muscular dystrophy, breast carcinomas, and promyelocytic leukemia HL-60. CCDC109B may also contribute to atopic dermatitis skin lesions and Job's Syndrome. However, the mechanisms behind the role of CCDC109B in these diseases are unclear and not well characterized through research.
# Protein-protein interaction
## Transcription factors
CCDC109B has a promoter region that contains sites for transcription factor binding. This promoter region is approximately 500 nucleotides long and is located just prior to the start of translation. Notable transcription factors that bind CCDC109B include:
- Fork Head Domain Factors (FKHD)
- Myeloid Zinc Finger 1 Factors (MZF1)
- Pleomorphic Adenoma Gene (PLAG)
- C2H2 Zinc Finger Transcription Factors 2 (ZF02)
- Vertebrate SMAD Family of Transcription Factors (SMAD)
- Twist Subfamily of Class B bHLH Transcription Factors (HAND)
- CCAAT/Enhance Binding Protein (CEBP)
- Nuclear Factor of Activated T-Cells (NFAT)
## Cellular proteins
CCDC109B interacts with ZBTB16, which is a zinc-finger transcription factor and has a probable role in protein degradation. CCDC109B's interaction with ZBTB16 was determined by a yeast two-hybrid screen It is still unclear how CCDC109B interacts with ZBTB16.
Other proteins that CCDC109B interact with are currently unknown. | Ccdc109b
Coiled-coil domain containing 109B (CCDC109B) is a potential calcium uniporter protein found in the membrane of human cells and is encoded by the CCDC109B gene. While CCDC109B is a transmembrane protein it is unclear if it is located within the cell membrane or mitochondrial membrane.
# Gene information
CCDC109B is located at 4q25 and is 128,520 base pairs in length. CCDC109B contains eight exons and is located on the positive strand of chromosome four. CCDC109B has nine transcript variants due to alternative splicing.[1] The unspliced version of this gene is the longest and most common variant found in human cells and is 1298 base pairs in length.
# Protein information
When translated, the CCDC109B protein is composed of 336 amino acids and has a molecular weight of 39.1 kDa. The 3' end of this protein is highly conserved and contains domains crucial for protein function.
## Protein domains
- Domain of Unknown Function 607 (DUF607): The function of this domain is largely unknown, although it may serve as a calcium transporter when CCDC109B forms homo-oligimers. DUF607 is conserved in orthologs and is located closer to the 3' end of this protein, even though DUF607 is present for most of the protein's length.[2]
- Transmembrane Region: CCDC109B contains two transmembrane regions, located within DUF607, making it a multipass membrane protein. Since there are two transmembrane regions, both the N-terminus and C-terminus are located on one side of the membrane and have been localized to the cytosolic side of the cell membrane.[2]
- DIME Motif: This motif is a completely conserved region found in all orthologs of this protein and is found within DUF607 and between the transmembrane domains. The DIME motif is a sequence of 23 amino acids that has the sequence: QxGxLAxLTWWxYSWDIMEPVTYF, where letters correspond to actual amino acid residule and "x" represents amino acids that are not conserved within this sequence. Throughout the entire CCDC109B protein there are no other conserved amino acid sequences that are greater than three amino acids in length.[2] The DIME Motif has a hypothesized role in calcium transport and is most likely essential in DUF607.[3]
## Post-translational modifications
### Phosphorylation sites
The CCDC109B protein contains several likely phosphorylation sites on serine, threonine, and tyrosine residues.[4]
- Serine Phosphorylation Sites: Amino acid positions 77, 213, 315, and 322.
- Threonine Phosphorylation Site: Amino acid position 53.
- Tyrosine Phosphorylation Site: Amino acid position 274.
### Sumoylation site
There is one likely sumoylation site within CCDC109B at amino acid residue 306, which is a lysine.[5] This residue is highly conserved among orthologs.
## Tertiary structure
Although it is known that CCDC109B is a transmembrane protein the proper folding of its N-terminus and C-terminus is unclear.
# Homology
CCDC109B shows conservation in vertebrates, including mammals, birds, reptiles, and amphibians. There appears to be some conservation in earlier organisms such as flies, worms, and plants, but the percent identity is very low and these organisms have many orthologus structures that may not be CCDC109B. The orthologs found in non-vertebrate organisms may also actually be the paralog of CCDC109B which is still producing some identity to CCDC109B.
The table below shows CCDC109B conservation among vertebrate organisms:
## Paralog of CCDC109B
CCDC109B has a single paralog in the human genome. This paralog is CCDC109A, which is more commonly known as Mitochondrial Calcium Uniporter (MCU)[3] MCU is located in the inner membrane of the mitochondrion and is found as an oligomer that transports calcium ions into the mitochondria. MCU is an essential component of the mitochondrial membrane and sliencing MCU abolishes calcium uptake. The DIME motif, which is also conserved in CCDC109B, is responsible for calcium uptake and a mutation in this region inhibits this function.[3] CCDC109B and MCU share a 43% identity in which the DIME motif is fully conserved.
# Expression profile
CCDC109B is expressed at high levels in the immune system and the circulatory system.[7] CCDC109B is expressed in B-cells, Dendritic Cells, T-Cells, and Natural Killer Cells. CCDC109B expression is not present in human adipose tissue, adrenal glands, bladder, bone marrow, ear, esophagus, larynx, parathyroid, pituitary gland, spleen, thryroid, trachea, or umbilical cord tissues.[8]
## Role in disease
CCDC109B may contribute to a number of diseases including various lymphomas and leukemias.[9] Changes in CCDC109B expression are also present in other diseases such as glioblastomas, Daudi Burkitt's lymphoma, Duchenne muscular dystrophy, breast carcinomas, and promyelocytic leukemia HL-60. CCDC109B may also contribute to atopic dermatitis skin lesions and Job's Syndrome.[10] However, the mechanisms behind the role of CCDC109B in these diseases are unclear and not well characterized through research.
# Protein-protein interaction
## Transcription factors
CCDC109B has a promoter region that contains sites for transcription factor binding. This promoter region is approximately 500 nucleotides long and is located just prior to the start of translation. Notable transcription factors that bind CCDC109B include:[11]
- Fork Head Domain Factors (FKHD)
- Myeloid Zinc Finger 1 Factors (MZF1)
- Pleomorphic Adenoma Gene (PLAG)
- C2H2 Zinc Finger Transcription Factors 2 (ZF02)
- Vertebrate SMAD Family of Transcription Factors (SMAD)
- Twist Subfamily of Class B bHLH Transcription Factors (HAND)
- CCAAT/Enhance Binding Protein (CEBP)
- Nuclear Factor of Activated T-Cells (NFAT)
## Cellular proteins
CCDC109B interacts with ZBTB16, which is a zinc-finger transcription factor and has a probable role in protein degradation. CCDC109B's interaction with ZBTB16 was determined by a yeast two-hybrid screen[12] It is still unclear how CCDC109B interacts with ZBTB16.
Other proteins that CCDC109B interact with are currently unknown. | https://www.wikidoc.org/index.php/Ccdc109b | |
310019ff183c09b2b93cb5763e282abfcd6a6323 | wikidoc | Cefaclor | Cefaclor
# 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
Cefaclor is an antibiotic that is FDA approved for the treatment of otitis media, lower respiratory tract infections, pharyngitis, tonsillitis, Urinary tract infections, skin structure infections. Common adverse reactions include diarrhea,nervousness, insomnia, confusion, hypertonia, dizziness,asthenia, edema , dyspnea, paresthesias, syncope, hypotension.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Cefaclor is indicated in the treatment of the following infections when caused by susceptible strains of the designated microorganisms:
- Otitis media caused by Streptococcus pneumoniae, Haemophilus influenzae, staphylococci, and Streptococcus pyogenes
Note: β-lactamase-negative, ampicillin-resistant (BLNAR) strains of Haemophilus influenzae should be considered resistant to cefaclor despite apparent in vitro susceptibility of some BLNAR strains.
- Lower respiratory tract infections, including pneumonia caused by Streptococcus pneumoniae, Haemophilus influenzae, and Streptococcus pyogenes.
Note: β-lactamase-negative, ampicillin-resistant (BLNAR) strains of Haemophilus influenzae should be considered resistant to cefaclor despite apparent in vitro susceptibility of some BLNAR strains.
- Pharyngitis and Tonsillitis, caused by Streptococcus pyogenes
Note: Penicillin is the usual drug of choice in the treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever. Cefaclor is generally effective in the eradication of streptococci from the nasopharynx; however, substantial data establishing the efficacy of cefaclor in the subsequent prevention of rheumatic fever are not available at present.
- Urinary tract infections, including pyelonephritis and cystitis, caused by Escherichia coli, Proteus mirabilis, Klebsiella spp., and coagulase-negative staphylococci
- Skin and skin structure infections caused by Staphylococcus aureus and Streptococcus pyogenes
- Appropriate culture and susceptibility studies should be performed to determine susceptibility of the causative organism to cefaclor.
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefaclor and other antibacterial drugs, cefaclor should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
# Dosage
- The usual adult dosage is 250 mg every 8 hours. For more severe infections (such as pneumonia) or those caused by less susceptible organisms, doses may be doubled.
- Cefaclor may be administered in the presence of impaired renal function. Under such a condition, the dosage usually is unchanged.
- In the treatment of β-hemolytic streptococcal infections, a therapeutic dosage of cefaclor should be administered for at least 10 days.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cefaclor in adult patients.
### Non–Guideline-Supported Use
# Indications
Gonorrhea
- Dosing
- A loading dose of 1 gram of CEFACLOR followed by 500 mg twice daily for 2 days
- Sinusitis
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
# Indications
- Cefaclor is indicated in the treatment of the following infections when caused by susceptible strains of the designated microorganisms:
- Otitis media caused by Streptococcus pneumoniae, Haemophilus influenzae, staphylococci, and Streptococcus pyogenes
Note: β-lactamase-negative, ampicillin-resistant (BLNAR) strains of Haemophilus influenzae should be considered resistant to cefaclor despite apparent in vitro susceptibility of some BLNAR strains.
- Lower respiratory tract infections, including pneumonia caused by Streptococcus pneumoniae, Haemophilus influenzae, and Streptococcus pyogenes.
Note: β-lactamase-negative, ampicillin-resistant (BLNAR) strains of Haemophilus influenzae should be considered resistant to cefaclor despite apparent in vitro susceptibility of some BLNAR strains.
- Pharyngitis and Tonsillitis, caused by Streptococcus pyogenes
Note: Penicillin is the usual drug of choice in the treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever. Cefaclor is generally effective in the eradication of streptococci from the nasopharynx; however, substantial data establishing the efficacy of cefaclor in the subsequent prevention of rheumatic fever are not available at present.
- Urinary tract infections, including pyelonephritis and cystitis, caused by Escherichia coli, Proteus mirabilis, Klebsiella spp., and coagulase-negative staphylococci
- Skin and skin structure infections caused by Staphylococcus aureus and Streptococcus pyogenes
- Appropriate culture and susceptibility studies should be performed to determine susceptibility of the causative organism to cefaclor.
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefaclor and other antibacterial drugs, cefaclor should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
# Dosage
- The usual recommended daily dosage for pediatric patients is 20 mg/kg/day in divided doses every 8 hours. In more serious infections, otitis media, and infections caused by less susceptible organisms, 40 mg/kg/day are recommended, with a maximum dosage of 1 g/day.
- Cefaclor may be administered in the presence of impaired renal function. Under such a condition, the dosage usually is unchanged.
- In the treatment of β-hemolytic streptococcal infections, a therapeutic dosage of cefaclor should be administered for at least 10 days.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cefaclor in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cefaclor in pediatric patients.
# Contraindications
- Cefaclor is contraindicated in patients with known allergy to the cephalosporin group of antibiotics.
# Warnings
- BEFORE THERAPY WITH CEFACLOR IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFACLOR, CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS PRODUCT IS TO BE GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS-HYPERSENSITIVITY AMONG β-LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY.
- IF AN ALLERGIC REACTION TO CEFACLOR OCCURS, DISCONTINUE THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, INTRAVENOUS FLUIDS, INTRAVENOUS ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.
- Antibiotics, including cefaclor, should be administered cautiously to any patient who has demonstrated some form of allergy, particularly to drugs.
- Pseudomembranous colitis has been reported with nearly all antibacterial agents, including cefaclor, and has ranged in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
- Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of antibiotic-associated colitis.
- After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug effective against C. difficile.
# PRECAUTIONS
General
- Prescribing cefaclor in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
- Prolonged use of cefaclor may result in the overgrowth of non susceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.
- Positive direct Coombs’ tests have been reported during treatment with the cephalosporin antibiotics. It should be recognized that a positive Coombs’ test may be due to the drug, e.g., in hematologic studies or in transfusion cross-matching procedures when antiglobulin tests are performed on the minor side or in Coombs’ testing of newborns whose mothers have received cephalosporin antibiotics before parturition.
- Cefaclor should be administered with caution in the presence of markedly impaired renal function. Since the half-life of cefaclor in anuria is 2.3 to 2.8 hours, dosage adjustments for patients with moderate or severe renal impairment are usually not required. Clinical experience with cefaclor under such conditions is limited; therefore, careful clinical observation and laboratory studies should be made.
- As with other β-lactam antibiotics, the renal excretion of cefaclor is inhibited by probenecid. Antibiotics, including cephalosporins, should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.
# Adverse Reactions
## Clinical Trials Experience
Adverse effects considered to be related to therapy with cefaclor are listed below:
Hypersensitivity reactions have been reported in about 1.5% of patients and include morbilliform eruptions (1 in 100). Pruritus, urticaria, and positive Coombs’ tests each occur in less than 1 in 200 patients.
- Cases of serum-sickness-like reactions have been reported with the use of cefaclor. These are characterized by findings of erythema multiforme, rashes, and other skin manifestations accompanied by arthritis/arthralgia, with or without fever, and differ from classic serum sickness in that there is infrequently associated lymphadenopathy and proteinuria, no circulating immune complexes, and no evidence to date of sequelae of the reaction. Occasionally, solitary symptoms may occur, but do not represent a serum-sickness-like reaction. While further investigation is ongoing, serum-sickness-like reactions appear to be due to hypersensitivity and more often occur during or following a second (or subsequent) course of therapy with cefaclor. Such reactions have been reported more frequently in pediatric ptients than in adults with an overall occurrence ranging from 1 in 200 (0.5%) in one focused trial to 2 in 8,346 (0.024%) in overall clinical trials (with an incidence in pediatric patients in clinical trials of 0.055%) to 1 in 38,000 (0.003%) in spontaneous event reports. Signs and symptoms usually occur a few days after initiation of therapy and subside within a few days after cessation of therapy; occasionally these reactions have resulted in hospitalization, usually of short duration (median hospitalization = 2 to 3 days, based on postmarketing surveillance studies). In those requiring hospitalization, the symptoms have ranged from mild to severe at the time of admission with more of the severe reactions occurring in pediatric patients. Antihistamines and glucocorticoids appear to enhance resolution of the signs and symptoms. No serious sequelae have been reported.
- More severe hypersensitivity reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and anaphylaxis have been reported rarely. Anaphylactoid events may be manifested by solitary symptoms, including angioedema, asthenia, edema (including face and limbs), dyspnea, paresthesias, syncope, hypotension, or vasodilatation. Anaphylaxis may be more common in patients with a history of penicillin allergy.
- Rarely, hypersensitivity symptoms may persist for several months.
Gastrointestinal symptoms occur in about 2.5% of patients and include diarrhea (1 in 70).
- Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. Nausea and vomiting have been reported rarely. As with some penicillins and some other cephalosporins, transient hepatitis and cholestatic jaundice have been reported rarely.
- Other effects considered related to therapy included eosinophilia (1 in 50 patients), genital pruritus , moniliasis or vaginitis (about 1 in 50 patients), and, rarely, thrombocytopenia or reversible interstitial nephritis.
Causal Relationship Uncertain–
CNS–Rarely, reversible hyperactivity, agitation, nervousness, insomnia, confusion, hypertonia, dizziness, hallucinations, and somnolence have been reported.
Transitory abnormalities in clinical laboratory test results have been reported. Although they were of uncertain etiology, they are listed below to serve as alerting information for the physician.
Hepatic–Slight elevations of AST, ALT, or alkaline phosphatase values (1 in 40).
Hematopoietic–As has also been reported with other β-lactam antibiotics, transient lymphocytosis, leukopenia, and, rarely, hemolytic anemia, aplastic anemia, agranulocytosis, and reversible neutropenia of possible clinical significance.
There have been rare reports of increased prothrombin time with or without clinical bleeding in patients receiving cefaclor and warfarin concomitantly.
Renal– Slight elevations in BUN or serum creatinine (less than 1 in 500) or abnormal urinalysis (less than 1 in 200).
Cephalosporin-class Adverse Reactions
In addition to the adverse reactions listed above that have been observed in patients treated with cefaclor, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics: fever, abdominal pain, superinfection, renal dysfunction, toxic nephropathy, hemorrhage, false positive test for urinary glucose, elevated bilirubin, elevated LDH, and pancytopenia.
Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Cefaclor in the drug label.
# Drug Interactions
- There have been reports of increased anticoagulant effect when cefaclor and oral anticoagulants were administered concomitantly.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy–Teratogenic Effects–Pregnancy Category B
- Reproduction studies have been performed in mice and rats at doses up to 12 times the human dose and in ferrets given 3 times the maximum human dose and have revealed no harm to the fetus due to cefaclor. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cefaclor in women who are pregnant.
### Labor and Delivery
- The effect of cefaclor on labor and delivery is unknown.
### Nursing Mothers
- Small amounts of cefaclor have been detected in mother’s milk following administration of single 500 mg doses. Average levels were 0.18, 0.20, 0.21, and 0.16 mcg/mL at 2, 3, 4, and 5 hours respectively. Trace amounts were detected at 1 hour. The effect on nursing infants is not known. Caution should be exercised when cefaclor is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness of this product for use in infants less than 1 month of age have not been established.
### Geriatic Use
- Of the 3703 patients in clinical studies of cefaclor, 594 (16.0%) were 65 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
- This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Cefaclor with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cefaclor with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Cefaclor in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Cefaclor in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cefaclor in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cefaclor in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Cefaclor in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Cefaclor in the drug label.
# Overdosage
Signs and Symptoms –The toxic symptoms following an overdose of cefaclor may include nausea, vomiting, epigastric distress, and diarrhea. The severity of the epigastric distress and the diarrhea are dose related. If other symptoms are present, it is probable that they are secondary to an underlying disease state, an allergic reaction, or the effects of other intoxication.
Treatment–To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.
Unless 5 times the normal dose of cefaclor has been ingested, gastrointestinal decontamination will not be necessary.
Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal.
Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for an overdose of cefaclor.
# Pharmacology
## Mechanism of Action
There is limited information regarding Cefaclor Mechanism of Action in the drug label.
## Structure
- Cefaclor is a semisynthetic cephalosporin antibiotic for oral administration. It is chemically designated as 3-chloro-7-D-(2-phenylglycinamido)-3-cephem-4-carboxylic acid monohydrate. The molecular formula for cefaclor is C15H14ClN3O4SH2O and the molecular weight is 385.82.
- Each capsule contains cefaclor monohydrate equivalent to 250 mg (0.68 mmol) or 500 mg (1.36 mmol) anhydrous cefaclor. The capsules also contain black iron oxide, croscarmellose sodium, FD&C Red No. 3, FD&C Blue No. 2, gelatin, magnesium stearate, corn starch, and titanium dioxide.
- The color of the capsule powder is white to off white.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Cefaclor in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Cefaclor in the drug label.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Studies have not been performed to determine potential for carcinogenicity, mutagenicity, or impairment of fertility.
# Clinical Studies
There is limited information regarding Clinical Studies of Cefaclor in the drug label.
# How Supplied
Capsules:
- Cefaclor Capsules, USP 250 mg: opaque purple and white hard gelatin capsules imprinted with "West Ward 985" in bottles of 15 and bottles of 100.
- Cefaclor Capsules, USP 500 mg: opaque purple and gray hard gelatin capsules imprinted with "West Ward 986" in bottles of 15 and bottles of 100.
## Storage
Store bottles at 20° to 25°C (68° to 77° F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be counseled that antibacterial drugs including cefaclor should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefaclor is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by cefaclor or other antibacterial drugs in the future.
# Precautions with Alcohol
- Alcohol-Cefaclor interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
CEFACLOR
# Look-Alike Drug Names
There is limited information regarding Cefaclor Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Cefaclor
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Cefaclor is an antibiotic that is FDA approved for the treatment of otitis media, lower respiratory tract infections, pharyngitis, tonsillitis, Urinary tract infections, skin structure infections. Common adverse reactions include diarrhea,nervousness, insomnia, confusion, hypertonia, dizziness,asthenia, edema , dyspnea, paresthesias, syncope, hypotension.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Cefaclor is indicated in the treatment of the following infections when caused by susceptible strains of the designated microorganisms:
- Otitis media caused by Streptococcus pneumoniae, Haemophilus influenzae, staphylococci, and Streptococcus pyogenes
Note: β-lactamase-negative, ampicillin-resistant (BLNAR) strains of Haemophilus influenzae should be considered resistant to cefaclor despite apparent in vitro susceptibility of some BLNAR strains.
- Lower respiratory tract infections, including pneumonia caused by Streptococcus pneumoniae, Haemophilus influenzae, and Streptococcus pyogenes.
Note: β-lactamase-negative, ampicillin-resistant (BLNAR) strains of Haemophilus influenzae should be considered resistant to cefaclor despite apparent in vitro susceptibility of some BLNAR strains.
- Pharyngitis and Tonsillitis, caused by Streptococcus pyogenes
Note: Penicillin is the usual drug of choice in the treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever. Cefaclor is generally effective in the eradication of streptococci from the nasopharynx; however, substantial data establishing the efficacy of cefaclor in the subsequent prevention of rheumatic fever are not available at present.
- Urinary tract infections, including pyelonephritis and cystitis, caused by Escherichia coli, Proteus mirabilis, Klebsiella spp., and coagulase-negative staphylococci
- Skin and skin structure infections caused by Staphylococcus aureus and Streptococcus pyogenes
- Appropriate culture and susceptibility studies should be performed to determine susceptibility of the causative organism to cefaclor.
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefaclor and other antibacterial drugs, cefaclor should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
# Dosage
- The usual adult dosage is 250 mg every 8 hours. For more severe infections (such as pneumonia) or those caused by less susceptible organisms, doses may be doubled.
- Cefaclor may be administered in the presence of impaired renal function. Under such a condition, the dosage usually is unchanged.
- In the treatment of β-hemolytic streptococcal infections, a therapeutic dosage of cefaclor should be administered for at least 10 days.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cefaclor in adult patients.
### Non–Guideline-Supported Use
# Indications
Gonorrhea[1]
- Dosing
- A loading dose of 1 gram of CEFACLOR followed by 500 mg twice daily for 2 days
- Sinusitis[2]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
# Indications
- Cefaclor is indicated in the treatment of the following infections when caused by susceptible strains of the designated microorganisms:
- Otitis media caused by Streptococcus pneumoniae, Haemophilus influenzae, staphylococci, and Streptococcus pyogenes
Note: β-lactamase-negative, ampicillin-resistant (BLNAR) strains of Haemophilus influenzae should be considered resistant to cefaclor despite apparent in vitro susceptibility of some BLNAR strains.
- Lower respiratory tract infections, including pneumonia caused by Streptococcus pneumoniae, Haemophilus influenzae, and Streptococcus pyogenes.
Note: β-lactamase-negative, ampicillin-resistant (BLNAR) strains of Haemophilus influenzae should be considered resistant to cefaclor despite apparent in vitro susceptibility of some BLNAR strains.
- Pharyngitis and Tonsillitis, caused by Streptococcus pyogenes
Note: Penicillin is the usual drug of choice in the treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever. Cefaclor is generally effective in the eradication of streptococci from the nasopharynx; however, substantial data establishing the efficacy of cefaclor in the subsequent prevention of rheumatic fever are not available at present.
- Urinary tract infections, including pyelonephritis and cystitis, caused by Escherichia coli, Proteus mirabilis, Klebsiella spp., and coagulase-negative staphylococci
- Skin and skin structure infections caused by Staphylococcus aureus and Streptococcus pyogenes
- Appropriate culture and susceptibility studies should be performed to determine susceptibility of the causative organism to cefaclor.
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefaclor and other antibacterial drugs, cefaclor should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
# Dosage
- The usual recommended daily dosage for pediatric patients is 20 mg/kg/day in divided doses every 8 hours. In more serious infections, otitis media, and infections caused by less susceptible organisms, 40 mg/kg/day are recommended, with a maximum dosage of 1 g/day.
- Cefaclor may be administered in the presence of impaired renal function. Under such a condition, the dosage usually is unchanged.
- In the treatment of β-hemolytic streptococcal infections, a therapeutic dosage of cefaclor should be administered for at least 10 days.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cefaclor in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cefaclor in pediatric patients.
# Contraindications
- Cefaclor is contraindicated in patients with known allergy to the cephalosporin group of antibiotics.
# Warnings
- BEFORE THERAPY WITH CEFACLOR IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFACLOR, CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS PRODUCT IS TO BE GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS-HYPERSENSITIVITY AMONG β-LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY.
- IF AN ALLERGIC REACTION TO CEFACLOR OCCURS, DISCONTINUE THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, INTRAVENOUS FLUIDS, INTRAVENOUS ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.
- Antibiotics, including cefaclor, should be administered cautiously to any patient who has demonstrated some form of allergy, particularly to drugs.
- Pseudomembranous colitis has been reported with nearly all antibacterial agents, including cefaclor, and has ranged in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
- Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of antibiotic-associated colitis.
- After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug effective against C. difficile.
# PRECAUTIONS
General
- Prescribing cefaclor in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
- Prolonged use of cefaclor may result in the overgrowth of non susceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.
- Positive direct Coombs’ tests have been reported during treatment with the cephalosporin antibiotics. It should be recognized that a positive Coombs’ test may be due to the drug, e.g., in hematologic studies or in transfusion cross-matching procedures when antiglobulin tests are performed on the minor side or in Coombs’ testing of newborns whose mothers have received cephalosporin antibiotics before parturition.
- Cefaclor should be administered with caution in the presence of markedly impaired renal function. Since the half-life of cefaclor in anuria is 2.3 to 2.8 hours, dosage adjustments for patients with moderate or severe renal impairment are usually not required. Clinical experience with cefaclor under such conditions is limited; therefore, careful clinical observation and laboratory studies should be made.
- As with other β-lactam antibiotics, the renal excretion of cefaclor is inhibited by probenecid. Antibiotics, including cephalosporins, should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.
# Adverse Reactions
## Clinical Trials Experience
Adverse effects considered to be related to therapy with cefaclor are listed below:
Hypersensitivity reactions have been reported in about 1.5% of patients and include morbilliform eruptions (1 in 100). Pruritus, urticaria, and positive Coombs’ tests each occur in less than 1 in 200 patients.
- Cases of serum-sickness-like reactions have been reported with the use of cefaclor. These are characterized by findings of erythema multiforme, rashes, and other skin manifestations accompanied by arthritis/arthralgia, with or without fever, and differ from classic serum sickness in that there is infrequently associated lymphadenopathy and proteinuria, no circulating immune complexes, and no evidence to date of sequelae of the reaction. Occasionally, solitary symptoms may occur, but do not represent a serum-sickness-like reaction. While further investigation is ongoing, serum-sickness-like reactions appear to be due to hypersensitivity and more often occur during or following a second (or subsequent) course of therapy with cefaclor. Such reactions have been reported more frequently in pediatric ptients than in adults with an overall occurrence ranging from 1 in 200 (0.5%) in one focused trial to 2 in 8,346 (0.024%) in overall clinical trials (with an incidence in pediatric patients in clinical trials of 0.055%) to 1 in 38,000 (0.003%) in spontaneous event reports. Signs and symptoms usually occur a few days after initiation of therapy and subside within a few days after cessation of therapy; occasionally these reactions have resulted in hospitalization, usually of short duration (median hospitalization = 2 to 3 days, based on postmarketing surveillance studies). In those requiring hospitalization, the symptoms have ranged from mild to severe at the time of admission with more of the severe reactions occurring in pediatric patients. Antihistamines and glucocorticoids appear to enhance resolution of the signs and symptoms. No serious sequelae have been reported.
- More severe hypersensitivity reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and anaphylaxis have been reported rarely. Anaphylactoid events may be manifested by solitary symptoms, including angioedema, asthenia, edema (including face and limbs), dyspnea, paresthesias, syncope, hypotension, or vasodilatation. Anaphylaxis may be more common in patients with a history of penicillin allergy.
- Rarely, hypersensitivity symptoms may persist for several months.
Gastrointestinal symptoms occur in about 2.5% of patients and include diarrhea (1 in 70).
- Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. Nausea and vomiting have been reported rarely. As with some penicillins and some other cephalosporins, transient hepatitis and cholestatic jaundice have been reported rarely.
- Other effects considered related to therapy included eosinophilia (1 in 50 patients), genital pruritus , moniliasis or vaginitis (about 1 in 50 patients), and, rarely, thrombocytopenia or reversible interstitial nephritis.
Causal Relationship Uncertain–
CNS–Rarely, reversible hyperactivity, agitation, nervousness, insomnia, confusion, hypertonia, dizziness, hallucinations, and somnolence have been reported.
Transitory abnormalities in clinical laboratory test results have been reported. Although they were of uncertain etiology, they are listed below to serve as alerting information for the physician.
Hepatic–Slight elevations of AST, ALT, or alkaline phosphatase values (1 in 40).
Hematopoietic–As has also been reported with other β-lactam antibiotics, transient lymphocytosis, leukopenia, and, rarely, hemolytic anemia, aplastic anemia, agranulocytosis, and reversible neutropenia of possible clinical significance.
There have been rare reports of increased prothrombin time with or without clinical bleeding in patients receiving cefaclor and warfarin concomitantly.
Renal– Slight elevations in BUN or serum creatinine (less than 1 in 500) or abnormal urinalysis (less than 1 in 200).
Cephalosporin-class Adverse Reactions
In addition to the adverse reactions listed above that have been observed in patients treated with cefaclor, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics: fever, abdominal pain, superinfection, renal dysfunction, toxic nephropathy, hemorrhage, false positive test for urinary glucose, elevated bilirubin, elevated LDH, and pancytopenia.
Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Cefaclor in the drug label.
# Drug Interactions
- There have been reports of increased anticoagulant effect when cefaclor and oral anticoagulants were administered concomitantly.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy–Teratogenic Effects–Pregnancy Category B
- Reproduction studies have been performed in mice and rats at doses up to 12 times the human dose and in ferrets given 3 times the maximum human dose and have revealed no harm to the fetus due to cefaclor. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cefaclor in women who are pregnant.
### Labor and Delivery
- The effect of cefaclor on labor and delivery is unknown.
### Nursing Mothers
- Small amounts of cefaclor have been detected in mother’s milk following administration of single 500 mg doses. Average levels were 0.18, 0.20, 0.21, and 0.16 mcg/mL at 2, 3, 4, and 5 hours respectively. Trace amounts were detected at 1 hour. The effect on nursing infants is not known. Caution should be exercised when cefaclor is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness of this product for use in infants less than 1 month of age have not been established.
### Geriatic Use
- Of the 3703 patients in clinical studies of cefaclor, 594 (16.0%) were 65 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
- This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Cefaclor with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cefaclor with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Cefaclor in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Cefaclor in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cefaclor in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cefaclor in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Cefaclor in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Cefaclor in the drug label.
# Overdosage
Signs and Symptoms –The toxic symptoms following an overdose of cefaclor may include nausea, vomiting, epigastric distress, and diarrhea. The severity of the epigastric distress and the diarrhea are dose related. If other symptoms are present, it is probable that they are secondary to an underlying disease state, an allergic reaction, or the effects of other intoxication.
Treatment–To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.
Unless 5 times the normal dose of cefaclor has been ingested, gastrointestinal decontamination will not be necessary.
Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal.
Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for an overdose of cefaclor.
# Pharmacology
## Mechanism of Action
There is limited information regarding Cefaclor Mechanism of Action in the drug label.
## Structure
- Cefaclor is a semisynthetic cephalosporin antibiotic for oral administration. It is chemically designated as 3-chloro-7-D-(2-phenylglycinamido)-3-cephem-4-carboxylic acid monohydrate. The molecular formula for cefaclor is C15H14ClN3O4S•H2O and the molecular weight is 385.82.
- Each capsule contains cefaclor monohydrate equivalent to 250 mg (0.68 mmol) or 500 mg (1.36 mmol) anhydrous cefaclor. The capsules also contain black iron oxide, croscarmellose sodium, FD&C Red No. 3, FD&C Blue No. 2, gelatin, magnesium stearate, corn starch, and titanium dioxide.
- The color of the capsule powder is white to off white.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Cefaclor in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Cefaclor in the drug label.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Studies have not been performed to determine potential for carcinogenicity, mutagenicity, or impairment of fertility.
# Clinical Studies
There is limited information regarding Clinical Studies of Cefaclor in the drug label.
# How Supplied
Capsules:
- Cefaclor Capsules, USP 250 mg: opaque purple and white hard gelatin capsules imprinted with "West Ward 985" in bottles of 15 and bottles of 100.
- Cefaclor Capsules, USP 500 mg: opaque purple and gray hard gelatin capsules imprinted with "West Ward 986" in bottles of 15 and bottles of 100.
## Storage
Store bottles at 20° to 25°C (68° to 77° F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be counseled that antibacterial drugs including cefaclor should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefaclor is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by cefaclor or other antibacterial drugs in the future.
# Precautions with Alcohol
- Alcohol-Cefaclor interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
CEFACLOR
# Look-Alike Drug Names
There is limited information regarding Cefaclor Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ceclor | |
04b3622d7ed4c1501bc3b4508c88eade2605ea9e | wikidoc | Cefdinir | Cefdinir
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# Overview
Cefdinir is a 3rd generation cephalosporin that is FDA approved for the {{{indicationType}}} of community-acquired pneumonia, acute exacerbations of chronic bronchitis, acute maxillary sinusitis, pharyngitis/tonsillitis and uncomplicated skin and skin structure infections in adults and adolescents, acute bacterial otitis media, pharyngitis/tonsillitis and uncomplicated skin and skin structure infections in children. Common adverse reactions include abdominal pain, diarrhea, nausea, candida vaginitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- 300 mg q12h for 10 days.
- Dosing Information
- 300 mg q12h for 5 to 10 days or 600 mg q24h for 10 days.
- Dosing Information
- 300 mg q12h for 10 days or 600 mg q24h for 10 days
- Dosing Information
- 300 mg q12h for 5 to 10 days or 600 mg q24h for 10 days.
- Dosing Information
- 300 mg q12h for 10 days.
- Patients on Hemodialysis:
- Hemodialysis removes cefdinir from the body. In patients maintained on chronic hemodialysis, the recommended initial dosage regimen is a 300 mg or 7 mg/kg dose every other day. At the conclusion of each hemodialysis session, 300 mg (or 7 mg/kg) should be given. Subsequent doses (300 mg or 7 mg/kg) are then administered every other day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cefdinir in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cefdinir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- 14 mg/kg/day ORALLY in 1 or 2 divided doses for 5 to 7 days (6 to 12 years with mild to moderate illness) or for 7 days (2 to 5 years with mild to moderate illness) or for 10 days (younger than 2 years or severe illness).
- Dosing Information
- 7 mg/kg ORALLY every 12 hr for 5 to 10 days or 14 mg/kg ORALLY every 24 hr for 10 days; maximum 600 mg/day.
- Dosing Information
- 7 mg/kg ORALLY every 12 hr for 10 days; maximum 600 mg/day.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cefdinir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cefdinir in pediatric patients.
# Contraindications
- Cefdinir is contraindicated in patients with known allergy to the cephalosporin class of antibiotics.
# Warnings
- BEFORE THERAPY WITH CEFDINIR IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFDINIR, OTHER CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF CEFDINIR IS TO BE GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS-HYPERSENSITIVITY AMONG Β-LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO CEFDINIR OCCURS, THE DRUG SHOULD BE DISCONTINUED. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, INTRAVENOUS FLUIDS, INTRAVENOUS ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Cefdinir, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
- C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
### Precautions
- General:
- Prescribing cefdinir capsules in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug resistant bacteria.
- As with other broad-spectrum antibiotics, prolonged treatment may result in the possible emergence and overgrowth of resistant organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate alternative therapy should be administered.
- Cefdinir, as with other broad-spectrum antimicrobials (antibiotics), should be prescribed with caution in individuals with a history of colitis.
- In patients with transient or persistent renal insufficiency (creatinine clearance <30 mL/min), the total daily dose of cefdinir should be reduced because high and prolonged plasma concentrations of cefdinir can result following recommended doses (see DOSAGE AND ADMINISTRATION).
# Adverse Reactions
## Clinical Trials Experience
- In clinical trials, 5093 adult and adolescent patients (3841 U.S. and 1252 non-U.S.) were treated with the recommended dose of cefdinir capsules (600 mg/day). Most adverse events were mild and self-limiting. No deaths or permanent disabilities were attributed to cefdinir. One hundred forty-seven of 5093 (3%) patients discontinued medication due to adverse events thought by the investigators to be possibly, probably, or definitely associated with cefdinir therapy. The discontinuations were primarily for gastrointestinal disturbances, usually diarrhea or nausea. Nineteen of 5093 (0.4%) patients were discontinued due to rash thought related to cefdinir administration.
- In the U.S., the following adverse events were thought by investigators to be possibly, probably, or definitely related to cefdinir capsules in multiple-dose clinical trials (N = 3841 cefdinir-treated patients):
- The following laboratory value changes of possible clinical significance, irrespective of relationship to therapy with cefdinir, were seen during clinical trials conducted in the U.S.:
## Postmarketing Experience
- The following adverse experiences and altered laboratory tests, regardless of their relationship to cefdinir, have been reported during extensive postmarketing experience, beginning with approval in Japan in 1991: shock, anaphylaxis with rare cases of fatality, facial and laryngeal edema, feeling of suffocation, serum sickness-like reactions, conjunctivitis, stomatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, erythema nodosum, acute hepatitis, cholestasis, fulminant hepatitis, hepatic failure, jaundice, increased amylase, acute enterocolitis, bloody diarrhea, hemorrhagic colitis, melena, pseudomembranous colitis, pancytopenia, granulocytopenia, leukopenia, thrombocytopenia, idiopathic thrombocytopenic purpura, hemolytic anemia, acute respiratory failure, asthmatic attack, drug-induced pneumonia, eosinophilic pneumonia, idiopathic interstitial pneumonia, fever, acute renal failure, nephropathy, bleeding tendency, coagulation disorder, disseminated intravascular coagulation, upper GI bleed, peptic ulcer, ileus, loss of consciousness, allergic vasculitis, possible cefdinir-diclofenac interaction, cardiac failure, chest pain, myocardial infarction, hypertension, involuntary movements, and rhabdomyolysis.
# Drug Interactions
- Antacids (Aluminum- or Magnesium-Containing):
- Concomitant administration of 300 mg cefdinir capsules with 30 mL Maalox® TC suspension reduces the rate (Cmax) and extent (AUC) of absorption by approximately 40%. Time to reach Cmax is also prolonged by 1 hour. There are no significant effects on cefdinir pharmacokinetics if the antacid is administered 2 hours before or 2 hours after cefdinir. If antacids are required during cefdinir capsules therapy, cefdinir capsules should be taken at least 2 hours before or after the antacid.
- Probenecid:
- As with other β-lactam antibiotics, probenecid inhibits the renal excretion of cefdinir, resulting in an approximate doubling in AUC, a 54% increase in peak cefdinir plasma levels, and a 50% prolongation in the apparent elimination t1/2.
- Iron Supplements and Foods Fortified With Iron:
- Concomitant administration of cefdinir with a therapeutic iron supplement containing 60 mg of elemental iron (as FeSO4) or vitamins supplemented with 10 mg of elemental iron reduced extent of absorption by 80% and 31%, respectively. If iron supplements are required during cefdinir therapy, cefdinir should be taken at least 2 hours before or after the supplement.
- The effect of foods highly fortified with elemental iron (primarily iron-fortified breakfast cereals) on cefdinir absorption has not been studied.
- There have been reports of reddish stools in patients receiving cefdinir. In many cases, patients were also receiving iron-containing products. :*The reddish color is due to the formation of a nonabsorbable complex between cefdinir or its breakdown products and iron in the gastrointestinal tract.
- Drug/Laboratory Test Interactions
- A false-positive reaction for ketones in the urine may occur with tests using nitroprusside, but not with those using nitroferricyanide. The administration of cefdinir may result in a false-positive reaction for glucose in urine using Clinitest®, Benedict’s solution, or Fehling’s solution. It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Clinistix® or Tes-Tape®) be used. Cephalosporins are known to occasionally induce a positive direct Coombs’ test.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Cefdinir was not teratogenic in rats at oral doses up to 1000 mg/kg/day (70 times the human dose based on mg/kg/day, 11 times based on mg/m2/day) or in rabbits at oral doses up to 10 mg/kg/day (0.7 times the human dose based on mg/kg/day, 0.23 times based on mg/m2/day). Maternal toxicity (decreased body weight gain) was observed in rabbits at the maximum tolerated dose of 10 mg/kg/day without adverse effects on offspring. Decreased body weight occurred in rat fetuses at ≥100 mg/kg/day, and in rat offspring at ≥32 mg/kg/day. No effects were observed on maternal reproductive parameters or offspring survival, development, behavior, or reproductive function.
- There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cefdinir in women who are pregnant.
### Labor and Delivery
- Cefdinir has not been studied for use during labor and delivery.
### Nursing Mothers
- Following administration of single 600 mg doses, cefdinir was not detected in human breast milk.
### Pediatric Use
- Safety and efficacy in neonates and infants less than 6 months of age have not been established. Use of cefdinir for the treatment of acute maxillary sinusitis in pediatric patients (age 6 months through 12 years) is supported by evidence from adequate and well-controlled studies in adults and adolescents, the similar pathophysiology of acute sinusitis in adult and pediatric patients, and comparative pharmacokinetic data in the pediatric population.
### Geriatic Use
- Efficacy is comparable in geriatric patients and younger adults. While cefdinir has been well-tolerated in all age groups, in clinical trials geriatric patients experienced a lower rate of adverse events, including diarrhea, than younger adults. Dose adjustment in elderly patients is not necessary unless renal function is markedly compromised (see DOSAGE AND ADMINISTRATION).
### Gender
There is no FDA guidance on the use of Cefdinir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cefdinir with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Cefdinir in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Cefdinir in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cefdinir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cefdinir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Cefdinir in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Cefdinir in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Information on cefdinir overdosage in humans is not available. In acute rodent toxicity studies, a single oral 5600 mg/kg dose produced no adverse effects. Toxic signs and symptoms following overdosage with other β- lactam antibiotics have included nausea, vomiting, epigastric distress, diarrhea, and convulsions.
### Management
- Hemodialysis removes cefdinir from the body. This may be useful in the event of a serious toxic reaction from overdosage, particularly if renal function is compromised.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Cefdinir in the drug label.
# Pharmacology
## Mechanism of Action
- As with other cephalosporins, bactericidal activity of cefdinir results from inhibition of cell wall synthesis. Cefdinir is stable in the presence of some, but not all, β-lactamase enzymes. As a result, many organisms resistant to penicillins and some cephalosporins are susceptible to cefdinir.
## Structure
- Cefdinir capsules contains the active ingredient cefdinir, an extended-spectrum, semisynthetic cephalosporin, for oral administration. Chemically, cefdinir is 6R--7-amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclooct-2-ene-2-carboxylic acid. Cefdinir is a white to slightly brownish-yellow solid. It is slightly soluble in dilute hydrochloric acid and sparingly soluble in 0.1 M pH 7.0 phosphate buffer. The molecular formula is C14H13N5O5S2 and the molecular weight is 395.42. Cefdinir has the structural formula shown below:
- Cefdinir capsules contain 300 mg of cefdinir and the following inactive ingredients: carboxymethylcellulose calcium; colloidal silicon dioxide; and magnesium stearate. The capsule shells contain D&C Red #28; FD&C Blue #1; FD&C Red #40; gelatin and titanium dioxide.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Cefdinir in the drug label.
## Pharmacokinetics
- Absorption:
- Oral Bioavailability: Maximal plasma cefdinir concentrations occur 2 to 4 hours postdose following capsule or suspension administration. Plasma cefdinir concentrations increase with dose, but the increases are less than dose-proportional from 300 mg (7 mg/kg) to 600 mg (14 mg/kg). Following administration of suspension to healthy adults, cefdinir bioavailability is 120% relative to capsules. Estimated bioavailability of cefdinir capsules is 21% following administration of a 300 mg capsule dose, and 16% following administration of a 600 mg capsule dose. Estimated absolute bioavailability of cefdinir suspension is 25%.
- Effect of Food: The Cmax and AUC of cefdinir from the capsules are reduced by 16% and 10%, respectively, when given with a high-fat meal. The magnitude of these reductions is not likely to be clinically significant. Therefore, cefdinir may be taken without regard to food.
- Cefdinir plasma concentrations and pharmacokinetic parameter values following administration of single 300 and 600 mg oral doses of cefdinir to adult subjects are presented in the following table:
- Multiple Dosing: Cefdinir does not accumulate in plasma following once- or twice-daily administration to subjects with normal renal function.
- Distribution:
- The mean volume of distribution (Vdarea) of cefdinir in adult subjects is 0.35 L/kg (±0.29); in pediatric subjects (age 6 months-12 years), cefdinir Vdarea is 0.67 L/kg (±0.38). Cefdinir is 60% to 70% bound to plasma proteins in both adult and pediatric subjects; binding is independent of concentration.
- Skin Blister: In adult subjects, median (range) maximal blister fluid cefdinir concentrations of 0.65 (0.33-1.1) and 1.1 (0.49-1.9) mcg/mL were observed 4 to 5 hours following administration of 300 and 600 mg doses, respectively. Mean (±SD) blister Cmax and AUC (0-∞) values were 48% (±13) and 91% (±18) of corresponding plasma values.
- Tonsil Tissue: In adult patients undergoing elective tonsillectomy, respective median tonsil tissue cefdinir concentrations 4 hours after administration of single 300 and 600 mg doses were 0.25 (0.22-0.46) and 0.36 (0.22-0.80) mcg/g. Mean tonsil tissue concentrations were 24% (±8) of corresponding plasma concentrations.
- Sinus Tissue: In adult patients undergoing elective maxillary and ethmoid sinus surgery, respective median sinus tissue cefdinir concentrations 4 hours after administration of single 300 and 600 mg doses were <0.12 (<0.12-0.46) and 0.21 (<0.12-2.0) mcg/g. Mean sinus tissue concentrations were 16% (±20) of corresponding plasma concentrations.
- Lung Tissue: In adult patients undergoing diagnostic bronchoscopy, respective median bronchial mucosa cefdinir concentrations 4 hours after administration of single 300 and 600 mg doses were 0.78 (<0.06-1.33) and 1.14 (<0.06-1.92) mcg/mL, and were 31% (±18) of corresponding plasma concentrations. Respective median epithelial lining fluid concentrations were 0.29 (<0.3-4.73) and 0.49 (<0.3-0.59) mcg/mL, and were 35% (±83) of corresponding plasma concentrations.
- Middle Ear Fluid: In 14 pediatric patients with acute bacterial otitis media, respective median middle ear fluid cefdinir concentrations 3 hours after administration of single 7 and 14 mg/kg doses were 0.21 (<0.09-0.94) and 0.72 (0.14-1.42) mcg/mL. Mean middle ear fluid concentrations were 15% (±15) of corresponding plasma concentrations.
- CSF: Data on cefdinir penetration into human cerebrospinal fluid are not available.
- Metabolism and Excretion:
- Cefdinir is not appreciably metabolized. Activity is primarily due to parent drug. Cefdinir is eliminated principally via renal excretion with a mean plasma elimination half-life (t1/2) of 1.7 (±0.6) hours. In healthy subjects with normal renal function, renal clearance is 2.0 (±1.0) mL/min/kg, and apparent oral clearance is 11.6 (±6.0) and 15.5 (±5.4) mL/min/kg following doses of 300 and 600 mg, respectively. Mean percent of dose recovered unchanged in the urine following 300 and 600 mg doses is 18.4% (±6.4) and 11.6% (±4.6), respectively. Cefdinir clearance is reduced in patients with renal dysfunction (see Special Populations: Patients with Renal Insufficiency).
- Because renal excretion is the predominant pathway of elimination, dosage should be adjusted in patients with markedly compromised renal function or who are undergoing hemodialysis (see DOSAGE AND ADMINISTRATION).
- Special Populations:
- Patients with Renal Insufficiency: Cefdinir pharmacokinetics were investigated in 21 adult subjects with varying degrees of renal function. Decreases in cefdinir elimination rate, apparent oral clearance (CL/F), and renal clearance were approximately proportional to the reduction in creatinine clearance (CLcr). As a result, plasma cefdinir concentrations were higher and persisted longer in subjects with renal impairment than in those without renal impairment. In subjects with CLcr between 30 and 60 mL/min, Cmax and t1/2 increased by approximately 2-fold and AUC by approximately 3-fold. In subjects with CLcr <30 mL/min, Cmax increased by approximately 2-fold, t1/2 by approximately 5-fold, and AUC by approximately 6-fold. Dosage adjustment is recommended in patients with markedly compromised renal function (creatinine clearance <30 mL/min; see DOSAGE AND ADMINISTRATION).
- Hemodialysis: Cefdinir pharmacokinetics were studied in 8 adult subjects undergoing hemodialysis. Dialysis (4 hours duration) removed 63% of cefdinir from the body and reduced apparent elimination t1/2 from 16 (±3.5) to 3.2 (±1.2) hours. Dosage adjustment is recommended in this patient population (see DOSAGE AND ADMINISTRATION).
- Hepatic Disease: Because cefdinir is predominantly renally eliminated and not appreciably metabolized, studies in patients with hepatic impairment were not conducted. It is not expected that dosage adjustment will be required in this population.
- Geriatric Patients: The effect of age on cefdinir pharmacokinetics after a single 300 mg dose was evaluated in 32 subjects 19 to 91 years of age. Systemic exposure to cefdinir was substantially increased in older subjects (N=16), Cmax by 44% and AUC by 86%. This increase was due to a reduction in cefdinir clearance. The apparent volume of distribution was also reduced, thus no appreciable alterations in apparent elimination t1/2 were observed (elderly: 2.2 ± 0.6 hours vs young: 1.8 ± 0.4 hours). Since cefdinir clearance has been shown to be primarily related to changes in renal function rather than age, elderly patients do not require dosage adjustment unless they have markedly compromised renal function (creatinine clearance <30 mL/min, see Patients with Renal Insufficiency, above).
- Gender and Race: The results of a meta-analysis of clinical pharmacokinetics (N=217) indicated no significant impact of either gender or race on cefdinir pharmacokinetics.
- As with other cephalosporins, bactericidal activity of cefdinir results from inhibition of cell wall synthesis. Cefdinir is stable in the presence of some, but not all, β-lactamase enzymes. As a result, many organisms resistant to penicillins and some cephalosporins are susceptible to cefdinir.
- Cefdinir has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in INDICATIONS AND USAGE.
- Aerobic Gram-Positive Microorganisms:
- Staphylococcus aureus (including β-lactamase producing strains)
- NOTE: Cefdinir is inactive against methicillin-resistant staphylococci.
- Streptococcus pneumoniae (penicillin-susceptible strains only)
- Streptococcus pyogenes
- Aerobic Gram-Negative Microorganisms:
- Haemophilus influenzae (including β-lactamase producing strains)
- Haemophilus parainfluenzae (including β-lactamase producing strains)
- Moraxella catarrhalis (including β-lactamase producing strains)
- The following in vitro data are available, but their clinical significance is unknown.
- Cefdinir exhibits in vitro minimum inhibitory concentrations (MICs) of 1 mcg/mL or less against (≥90%) strains of the following microorganisms; however, the safety and effectiveness of cefdinir in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
- Aerobic Gram-Positive Microorganisms:
- Staphylococcus epidermidis (methicillin-susceptible strains only)
- Streptococcus agalactiae
- Viridans group streptococci
- NOTE: Cefdinir is inactive against Enterococcus and methicillin-resistant Staphylococcus species.
- Aerobic Gram-Negative Microorganisms:
- Citrobacter diversus
- Escherichia coli
- Klebsiella pneumoniae
- Proteus mirabilis
- NOTE: Cefdinir is inactive against Pseudomonas and Enterobacter species.
- Susceptibility Tests:
- Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method(1) (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of cefdinir powder. The MIC values should be interpreted according to the following criteria:
- For Streptococcus spp:
- Streptococcus pneumoniae that are susceptible to penicillin (MIC ≤0.06 mcg/mL), or streptococci other than S. pneumoniae that are susceptible to penicillin (MIC ≤0.12 mcg/mL), can be considered susceptible to cefdinir. Testing of cefdinir against penicillin-intermediate or penicillin-resistant isolates is not recommended. Reliable interpretive criteria for cefdinir are not available.
- A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
- Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of laboratory procedures. Standard cefdinir powder should provide the following MIC values:
- Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure(2) requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5 mcg cefdinir to test the susceptibility of microorganisms to cefdinir.
- Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 mcg cefdinir disk should be interpreted according to the following criteria:
- For Streptococcus spp:
- Isolates of Streptococcus pneumoniae should be tested against a 1 mcg oxacillin disk. Isolates with oxacillin zone sizes ≥20 mm are susceptible to penicillin and can be considered susceptible to cefdinir. Streptococci other than S. pneumoniae should be tested with a 10 unit penicillin disk. Isolates with penicillin zone sizes ≥28 mm are susceptible to penicillin and can be considered susceptible to cefdinir.
- As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms to control the technical aspects of laboratory procedures. For the diffusion technique, the 5 mcg cefdinir disk should provide the following zone diameters in these laboratory quality control strains:
## Nonclinical Toxicology
- The carcinogenic potential of cefdinir has not been evaluated. No mutagenic effects were seen in the bacterial reverse mutation assay (Ames) or point mutation assay at the hypoxanthine-guanine phosphoribosyltransferase locus (HGPRT) in V79 Chinese hamster lung cells. No clastogenic effects were observed in vitro in the structural chromosome aberration assay in V79 Chinese hamster lung cells or in vivo in the micronucleus assay in mouse bone marrow. In rats, fertility and reproductive performance were not affected by cefdinir at oral doses up to 1000 mg/kg/day (70 times the human dose based on mg/kg/day, 11 times based on mg/m2/day).
# Clinical Studies
- Community-Acquired Bacterial Pneumonia:
- In a controlled, double-blind study in adults and adolescents conducted in the U.S., cefdinir BID was compared with cefaclor 500 mg TID. Using strict evaluability and microbiologic/clinical response criteria 6 to 14 days posttherapy, the following clinical cure rates, presumptive microbiologic eradication rates, and statistical outcomes were obtained:
- In a second controlled, investigator-blind study in adults and adolescents conducted primarily in Europe, cefdinir BID was compared with amoxicillin/clavulanate 500/125 mg TID. Using strict evaluability and clinical response criteria 6 to 14 days posttherapy, the following clinical cure rates, presumptive microbiologic eradication rates, and statistical outcomes were obtained:
- Streptococcal Pharyngitis/Tonsillitis:
- In four controlled studies conducted in the U.S., cefdinir was compared with 10 days of penicillin in adult, adolescent, and pediatric patients. Two studies (one in adults and adolescents, the other in pediatric patients) compared 10 days of cefdinir QD or BID to penicillin 250 mg or 10 mg/kg QID. Using strict evaluability and microbiologic/clinical response criteria 5 to 10 days posttherapy, the following clinical cure rates, microbiologic eradication rates, and statistical outcomes were obtained:
- Two studies (one in adults and adolescents, the other in pediatric patients) compared 5 days of cefdinir BID to 10 days of penicillin 250 mg or 10 mg/kg QID. Using strict evaluability and microbiologic/ clinical response criteria 4 to 10 days posttherapy, the following clinical cure rates, microbiologic eradication rates, and statistical outcomes were obtained:
# How Supplied
- Cefdinir capsules USP, 300 mg, size ‘0’ capsules having blue cap imprinted twice with "LUPIN" (in black ink) and purple body imprinted twice with "CEFDINIR" (in white ink) containing off white to creamish granular slug, are available as follows:
- 60 Capsules/Bottle NDC 68180-711-60
- Store the capsules at 20°-25°C (68°-77°F).
## Storage
There is limited information regarding Cefdinir Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be counseled that antibacterial drugs including cefdinir capsules should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefdinir capsules is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by cefdinir capsules or other antibacterial drugs in the future.
- Antacids containing magnesium or aluminum interfere with the absorption of cefdinir. If this type of antacid is required during cefdinir therapy, cefdinir should be taken at least 2 hours before or after the antacid.
- Iron supplements, including multivitamins that contain iron, interfere with the absorption of cefdinir. If iron supplements are required during cefdinir therapy, cefdinir should be taken at least 2 hours before or after the supplement.
- Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
# Precautions with Alcohol
- Alcohol-Cefdinir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Cefdinir®
# Look-Alike Drug Names
There is limited information regarding Cefdinir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Cefdinir
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Cefdinir is a 3rd generation cephalosporin that is FDA approved for the {{{indicationType}}} of community-acquired pneumonia, acute exacerbations of chronic bronchitis, acute maxillary sinusitis, pharyngitis/tonsillitis and uncomplicated skin and skin structure infections in adults and adolescents, acute bacterial otitis media, pharyngitis/tonsillitis and uncomplicated skin and skin structure infections in children. Common adverse reactions include abdominal pain, diarrhea, nausea, candida vaginitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- 300 mg q12h for 10 days.
- Dosing Information
- 300 mg q12h for 5 to 10 days or 600 mg q24h for 10 days.
- Dosing Information
- 300 mg q12h for 10 days or 600 mg q24h for 10 days
- Dosing Information
- 300 mg q12h for 5 to 10 days or 600 mg q24h for 10 days.
- Dosing Information
- 300 mg q12h for 10 days.
- Patients on Hemodialysis:
- Hemodialysis removes cefdinir from the body. In patients maintained on chronic hemodialysis, the recommended initial dosage regimen is a 300 mg or 7 mg/kg dose every other day. At the conclusion of each hemodialysis session, 300 mg (or 7 mg/kg) should be given. Subsequent doses (300 mg or 7 mg/kg) are then administered every other day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cefdinir in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cefdinir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- 14 mg/kg/day ORALLY in 1 or 2 divided doses for 5 to 7 days (6 to 12 years with mild to moderate illness) or for 7 days (2 to 5 years with mild to moderate illness) or for 10 days (younger than 2 years or severe illness).
- Dosing Information
- 7 mg/kg ORALLY every 12 hr for 5 to 10 days or 14 mg/kg ORALLY every 24 hr for 10 days; maximum 600 mg/day.
- Dosing Information
- 7 mg/kg ORALLY every 12 hr for 10 days; maximum 600 mg/day.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cefdinir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cefdinir in pediatric patients.
# Contraindications
- Cefdinir is contraindicated in patients with known allergy to the cephalosporin class of antibiotics.
# Warnings
- BEFORE THERAPY WITH CEFDINIR IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFDINIR, OTHER CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF CEFDINIR IS TO BE GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS-HYPERSENSITIVITY AMONG Β-LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO CEFDINIR OCCURS, THE DRUG SHOULD BE DISCONTINUED. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, INTRAVENOUS FLUIDS, INTRAVENOUS ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Cefdinir, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
- C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
### Precautions
- General:
- Prescribing cefdinir capsules in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug resistant bacteria.
- As with other broad-spectrum antibiotics, prolonged treatment may result in the possible emergence and overgrowth of resistant organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate alternative therapy should be administered.
- Cefdinir, as with other broad-spectrum antimicrobials (antibiotics), should be prescribed with caution in individuals with a history of colitis.
- In patients with transient or persistent renal insufficiency (creatinine clearance <30 mL/min), the total daily dose of cefdinir should be reduced because high and prolonged plasma concentrations of cefdinir can result following recommended doses (see DOSAGE AND ADMINISTRATION).
# Adverse Reactions
## Clinical Trials Experience
- In clinical trials, 5093 adult and adolescent patients (3841 U.S. and 1252 non-U.S.) were treated with the recommended dose of cefdinir capsules (600 mg/day). Most adverse events were mild and self-limiting. No deaths or permanent disabilities were attributed to cefdinir. One hundred forty-seven of 5093 (3%) patients discontinued medication due to adverse events thought by the investigators to be possibly, probably, or definitely associated with cefdinir therapy. The discontinuations were primarily for gastrointestinal disturbances, usually diarrhea or nausea. Nineteen of 5093 (0.4%) patients were discontinued due to rash thought related to cefdinir administration.
- In the U.S., the following adverse events were thought by investigators to be possibly, probably, or definitely related to cefdinir capsules in multiple-dose clinical trials (N = 3841 cefdinir-treated patients):
- The following laboratory value changes of possible clinical significance, irrespective of relationship to therapy with cefdinir, were seen during clinical trials conducted in the U.S.:
## Postmarketing Experience
- The following adverse experiences and altered laboratory tests, regardless of their relationship to cefdinir, have been reported during extensive postmarketing experience, beginning with approval in Japan in 1991: shock, anaphylaxis with rare cases of fatality, facial and laryngeal edema, feeling of suffocation, serum sickness-like reactions, conjunctivitis, stomatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, erythema nodosum, acute hepatitis, cholestasis, fulminant hepatitis, hepatic failure, jaundice, increased amylase, acute enterocolitis, bloody diarrhea, hemorrhagic colitis, melena, pseudomembranous colitis, pancytopenia, granulocytopenia, leukopenia, thrombocytopenia, idiopathic thrombocytopenic purpura, hemolytic anemia, acute respiratory failure, asthmatic attack, drug-induced pneumonia, eosinophilic pneumonia, idiopathic interstitial pneumonia, fever, acute renal failure, nephropathy, bleeding tendency, coagulation disorder, disseminated intravascular coagulation, upper GI bleed, peptic ulcer, ileus, loss of consciousness, allergic vasculitis, possible cefdinir-diclofenac interaction, cardiac failure, chest pain, myocardial infarction, hypertension, involuntary movements, and rhabdomyolysis.
# Drug Interactions
- Antacids (Aluminum- or Magnesium-Containing):
- Concomitant administration of 300 mg cefdinir capsules with 30 mL Maalox® TC suspension reduces the rate (Cmax) and extent (AUC) of absorption by approximately 40%. Time to reach Cmax is also prolonged by 1 hour. There are no significant effects on cefdinir pharmacokinetics if the antacid is administered 2 hours before or 2 hours after cefdinir. If antacids are required during cefdinir capsules therapy, cefdinir capsules should be taken at least 2 hours before or after the antacid.
- Probenecid:
- As with other β-lactam antibiotics, probenecid inhibits the renal excretion of cefdinir, resulting in an approximate doubling in AUC, a 54% increase in peak cefdinir plasma levels, and a 50% prolongation in the apparent elimination t1/2.
- Iron Supplements and Foods Fortified With Iron:
- Concomitant administration of cefdinir with a therapeutic iron supplement containing 60 mg of elemental iron (as FeSO4) or vitamins supplemented with 10 mg of elemental iron reduced extent of absorption by 80% and 31%, respectively. If iron supplements are required during cefdinir therapy, cefdinir should be taken at least 2 hours before or after the supplement.
- The effect of foods highly fortified with elemental iron (primarily iron-fortified breakfast cereals) on cefdinir absorption has not been studied.
- There have been reports of reddish stools in patients receiving cefdinir. In many cases, patients were also receiving iron-containing products. :*The reddish color is due to the formation of a nonabsorbable complex between cefdinir or its breakdown products and iron in the gastrointestinal tract.
- Drug/Laboratory Test Interactions
- A false-positive reaction for ketones in the urine may occur with tests using nitroprusside, but not with those using nitroferricyanide. The administration of cefdinir may result in a false-positive reaction for glucose in urine using Clinitest®, Benedict’s solution, or Fehling’s solution. It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Clinistix® or Tes-Tape®) be used. Cephalosporins are known to occasionally induce a positive direct Coombs’ test.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Cefdinir was not teratogenic in rats at oral doses up to 1000 mg/kg/day (70 times the human dose based on mg/kg/day, 11 times based on mg/m2/day) or in rabbits at oral doses up to 10 mg/kg/day (0.7 times the human dose based on mg/kg/day, 0.23 times based on mg/m2/day). Maternal toxicity (decreased body weight gain) was observed in rabbits at the maximum tolerated dose of 10 mg/kg/day without adverse effects on offspring. Decreased body weight occurred in rat fetuses at ≥100 mg/kg/day, and in rat offspring at ≥32 mg/kg/day. No effects were observed on maternal reproductive parameters or offspring survival, development, behavior, or reproductive function.
- There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cefdinir in women who are pregnant.
### Labor and Delivery
- Cefdinir has not been studied for use during labor and delivery.
### Nursing Mothers
- Following administration of single 600 mg doses, cefdinir was not detected in human breast milk.
### Pediatric Use
- Safety and efficacy in neonates and infants less than 6 months of age have not been established. Use of cefdinir for the treatment of acute maxillary sinusitis in pediatric patients (age 6 months through 12 years) is supported by evidence from adequate and well-controlled studies in adults and adolescents, the similar pathophysiology of acute sinusitis in adult and pediatric patients, and comparative pharmacokinetic data in the pediatric population.
### Geriatic Use
- Efficacy is comparable in geriatric patients and younger adults. While cefdinir has been well-tolerated in all age groups, in clinical trials geriatric patients experienced a lower rate of adverse events, including diarrhea, than younger adults. Dose adjustment in elderly patients is not necessary unless renal function is markedly compromised (see DOSAGE AND ADMINISTRATION).
### Gender
There is no FDA guidance on the use of Cefdinir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cefdinir with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Cefdinir in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Cefdinir in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cefdinir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cefdinir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Cefdinir in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Cefdinir in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Information on cefdinir overdosage in humans is not available. In acute rodent toxicity studies, a single oral 5600 mg/kg dose produced no adverse effects. Toxic signs and symptoms following overdosage with other β- lactam antibiotics have included nausea, vomiting, epigastric distress, diarrhea, and convulsions.
### Management
- Hemodialysis removes cefdinir from the body. This may be useful in the event of a serious toxic reaction from overdosage, particularly if renal function is compromised.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Cefdinir in the drug label.
# Pharmacology
## Mechanism of Action
- As with other cephalosporins, bactericidal activity of cefdinir results from inhibition of cell wall synthesis. Cefdinir is stable in the presence of some, but not all, β-lactamase enzymes. As a result, many organisms resistant to penicillins and some cephalosporins are susceptible to cefdinir.
## Structure
- Cefdinir capsules contains the active ingredient cefdinir, an extended-spectrum, semisynthetic cephalosporin, for oral administration. Chemically, cefdinir is 6R-[6α,7β(Z)]-7-[(2-amino-4 thiazolyl) (hydroxyimino) acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. Cefdinir is a white to slightly brownish-yellow solid. It is slightly soluble in dilute hydrochloric acid and sparingly soluble in 0.1 M pH 7.0 phosphate buffer. The molecular formula is C14H13N5O5S2 and the molecular weight is 395.42. Cefdinir has the structural formula shown below:
- Cefdinir capsules contain 300 mg of cefdinir and the following inactive ingredients: carboxymethylcellulose calcium; colloidal silicon dioxide; and magnesium stearate. The capsule shells contain D&C Red #28; FD&C Blue #1; FD&C Red #40; gelatin and titanium dioxide.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Cefdinir in the drug label.
## Pharmacokinetics
- Absorption:
- Oral Bioavailability: Maximal plasma cefdinir concentrations occur 2 to 4 hours postdose following capsule or suspension administration. Plasma cefdinir concentrations increase with dose, but the increases are less than dose-proportional from 300 mg (7 mg/kg) to 600 mg (14 mg/kg). Following administration of suspension to healthy adults, cefdinir bioavailability is 120% relative to capsules. Estimated bioavailability of cefdinir capsules is 21% following administration of a 300 mg capsule dose, and 16% following administration of a 600 mg capsule dose. Estimated absolute bioavailability of cefdinir suspension is 25%.
- Effect of Food: The Cmax and AUC of cefdinir from the capsules are reduced by 16% and 10%, respectively, when given with a high-fat meal. The magnitude of these reductions is not likely to be clinically significant. Therefore, cefdinir may be taken without regard to food.
- Cefdinir plasma concentrations and pharmacokinetic parameter values following administration of single 300 and 600 mg oral doses of cefdinir to adult subjects are presented in the following table:
- Multiple Dosing: Cefdinir does not accumulate in plasma following once- or twice-daily administration to subjects with normal renal function.
- Distribution:
- The mean volume of distribution (Vdarea) of cefdinir in adult subjects is 0.35 L/kg (±0.29); in pediatric subjects (age 6 months-12 years), cefdinir Vdarea is 0.67 L/kg (±0.38). Cefdinir is 60% to 70% bound to plasma proteins in both adult and pediatric subjects; binding is independent of concentration.
- Skin Blister: In adult subjects, median (range) maximal blister fluid cefdinir concentrations of 0.65 (0.33-1.1) and 1.1 (0.49-1.9) mcg/mL were observed 4 to 5 hours following administration of 300 and 600 mg doses, respectively. Mean (±SD) blister Cmax and AUC (0-∞) values were 48% (±13) and 91% (±18) of corresponding plasma values.
- Tonsil Tissue: In adult patients undergoing elective tonsillectomy, respective median tonsil tissue cefdinir concentrations 4 hours after administration of single 300 and 600 mg doses were 0.25 (0.22-0.46) and 0.36 (0.22-0.80) mcg/g. Mean tonsil tissue concentrations were 24% (±8) of corresponding plasma concentrations.
- Sinus Tissue: In adult patients undergoing elective maxillary and ethmoid sinus surgery, respective median sinus tissue cefdinir concentrations 4 hours after administration of single 300 and 600 mg doses were <0.12 (<0.12-0.46) and 0.21 (<0.12-2.0) mcg/g. Mean sinus tissue concentrations were 16% (±20) of corresponding plasma concentrations.
- Lung Tissue: In adult patients undergoing diagnostic bronchoscopy, respective median bronchial mucosa cefdinir concentrations 4 hours after administration of single 300 and 600 mg doses were 0.78 (<0.06-1.33) and 1.14 (<0.06-1.92) mcg/mL, and were 31% (±18) of corresponding plasma concentrations. Respective median epithelial lining fluid concentrations were 0.29 (<0.3-4.73) and 0.49 (<0.3-0.59) mcg/mL, and were 35% (±83) of corresponding plasma concentrations.
- Middle Ear Fluid: In 14 pediatric patients with acute bacterial otitis media, respective median middle ear fluid cefdinir concentrations 3 hours after administration of single 7 and 14 mg/kg doses were 0.21 (<0.09-0.94) and 0.72 (0.14-1.42) mcg/mL. Mean middle ear fluid concentrations were 15% (±15) of corresponding plasma concentrations.
- CSF: Data on cefdinir penetration into human cerebrospinal fluid are not available.
- Metabolism and Excretion:
- Cefdinir is not appreciably metabolized. Activity is primarily due to parent drug. Cefdinir is eliminated principally via renal excretion with a mean plasma elimination half-life (t1/2) of 1.7 (±0.6) hours. In healthy subjects with normal renal function, renal clearance is 2.0 (±1.0) mL/min/kg, and apparent oral clearance is 11.6 (±6.0) and 15.5 (±5.4) mL/min/kg following doses of 300 and 600 mg, respectively. Mean percent of dose recovered unchanged in the urine following 300 and 600 mg doses is 18.4% (±6.4) and 11.6% (±4.6), respectively. Cefdinir clearance is reduced in patients with renal dysfunction (see Special Populations: Patients with Renal Insufficiency).
- Because renal excretion is the predominant pathway of elimination, dosage should be adjusted in patients with markedly compromised renal function or who are undergoing hemodialysis (see DOSAGE AND ADMINISTRATION).
- Special Populations:
- Patients with Renal Insufficiency: Cefdinir pharmacokinetics were investigated in 21 adult subjects with varying degrees of renal function. Decreases in cefdinir elimination rate, apparent oral clearance (CL/F), and renal clearance were approximately proportional to the reduction in creatinine clearance (CLcr). As a result, plasma cefdinir concentrations were higher and persisted longer in subjects with renal impairment than in those without renal impairment. In subjects with CLcr between 30 and 60 mL/min, Cmax and t1/2 increased by approximately 2-fold and AUC by approximately 3-fold. In subjects with CLcr <30 mL/min, Cmax increased by approximately 2-fold, t1/2 by approximately 5-fold, and AUC by approximately 6-fold. Dosage adjustment is recommended in patients with markedly compromised renal function (creatinine clearance <30 mL/min; see DOSAGE AND ADMINISTRATION).
- Hemodialysis: Cefdinir pharmacokinetics were studied in 8 adult subjects undergoing hemodialysis. Dialysis (4 hours duration) removed 63% of cefdinir from the body and reduced apparent elimination t1/2 from 16 (±3.5) to 3.2 (±1.2) hours. Dosage adjustment is recommended in this patient population (see DOSAGE AND ADMINISTRATION).
- Hepatic Disease: Because cefdinir is predominantly renally eliminated and not appreciably metabolized, studies in patients with hepatic impairment were not conducted. It is not expected that dosage adjustment will be required in this population.
- Geriatric Patients: The effect of age on cefdinir pharmacokinetics after a single 300 mg dose was evaluated in 32 subjects 19 to 91 years of age. Systemic exposure to cefdinir was substantially increased in older subjects (N=16), Cmax by 44% and AUC by 86%. This increase was due to a reduction in cefdinir clearance. The apparent volume of distribution was also reduced, thus no appreciable alterations in apparent elimination t1/2 were observed (elderly: 2.2 ± 0.6 hours vs young: 1.8 ± 0.4 hours). Since cefdinir clearance has been shown to be primarily related to changes in renal function rather than age, elderly patients do not require dosage adjustment unless they have markedly compromised renal function (creatinine clearance <30 mL/min, see Patients with Renal Insufficiency, above).
- Gender and Race: The results of a meta-analysis of clinical pharmacokinetics (N=217) indicated no significant impact of either gender or race on cefdinir pharmacokinetics.
- As with other cephalosporins, bactericidal activity of cefdinir results from inhibition of cell wall synthesis. Cefdinir is stable in the presence of some, but not all, β-lactamase enzymes. As a result, many organisms resistant to penicillins and some cephalosporins are susceptible to cefdinir.
- Cefdinir has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in INDICATIONS AND USAGE.
- Aerobic Gram-Positive Microorganisms:
- Staphylococcus aureus (including β-lactamase producing strains)
- NOTE: Cefdinir is inactive against methicillin-resistant staphylococci.
- Streptococcus pneumoniae (penicillin-susceptible strains only)
- Streptococcus pyogenes
- Aerobic Gram-Negative Microorganisms:
- Haemophilus influenzae (including β-lactamase producing strains)
- Haemophilus parainfluenzae (including β-lactamase producing strains)
- Moraxella catarrhalis (including β-lactamase producing strains)
- The following in vitro data are available, but their clinical significance is unknown.
- Cefdinir exhibits in vitro minimum inhibitory concentrations (MICs) of 1 mcg/mL or less against (≥90%) strains of the following microorganisms; however, the safety and effectiveness of cefdinir in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
- Aerobic Gram-Positive Microorganisms:
- Staphylococcus epidermidis (methicillin-susceptible strains only)
- Streptococcus agalactiae
- Viridans group streptococci
- NOTE: Cefdinir is inactive against Enterococcus and methicillin-resistant Staphylococcus species.
- Aerobic Gram-Negative Microorganisms:
- Citrobacter diversus
- Escherichia coli
- Klebsiella pneumoniae
- Proteus mirabilis
- NOTE: Cefdinir is inactive against Pseudomonas and Enterobacter species.
- Susceptibility Tests:
- Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method(1) (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of cefdinir powder. The MIC values should be interpreted according to the following criteria:
- For Streptococcus spp:
- Streptococcus pneumoniae that are susceptible to penicillin (MIC ≤0.06 mcg/mL), or streptococci other than S. pneumoniae that are susceptible to penicillin (MIC ≤0.12 mcg/mL), can be considered susceptible to cefdinir. Testing of cefdinir against penicillin-intermediate or penicillin-resistant isolates is not recommended. Reliable interpretive criteria for cefdinir are not available.
- A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
- Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of laboratory procedures. Standard cefdinir powder should provide the following MIC values:
- Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure(2) requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5 mcg cefdinir to test the susceptibility of microorganisms to cefdinir.
- Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 mcg cefdinir disk should be interpreted according to the following criteria:
- For Streptococcus spp:
- Isolates of Streptococcus pneumoniae should be tested against a 1 mcg oxacillin disk. Isolates with oxacillin zone sizes ≥20 mm are susceptible to penicillin and can be considered susceptible to cefdinir. Streptococci other than S. pneumoniae should be tested with a 10 unit penicillin disk. Isolates with penicillin zone sizes ≥28 mm are susceptible to penicillin and can be considered susceptible to cefdinir.
- As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms to control the technical aspects of laboratory procedures. For the diffusion technique, the 5 mcg cefdinir disk should provide the following zone diameters in these laboratory quality control strains:
## Nonclinical Toxicology
- The carcinogenic potential of cefdinir has not been evaluated. No mutagenic effects were seen in the bacterial reverse mutation assay (Ames) or point mutation assay at the hypoxanthine-guanine phosphoribosyltransferase locus (HGPRT) in V79 Chinese hamster lung cells. No clastogenic effects were observed in vitro in the structural chromosome aberration assay in V79 Chinese hamster lung cells or in vivo in the micronucleus assay in mouse bone marrow. In rats, fertility and reproductive performance were not affected by cefdinir at oral doses up to 1000 mg/kg/day (70 times the human dose based on mg/kg/day, 11 times based on mg/m2/day).
# Clinical Studies
- Community-Acquired Bacterial Pneumonia:
- In a controlled, double-blind study in adults and adolescents conducted in the U.S., cefdinir BID was compared with cefaclor 500 mg TID. Using strict evaluability and microbiologic/clinical response criteria 6 to 14 days posttherapy, the following clinical cure rates, presumptive microbiologic eradication rates, and statistical outcomes were obtained:
- In a second controlled, investigator-blind study in adults and adolescents conducted primarily in Europe, cefdinir BID was compared with amoxicillin/clavulanate 500/125 mg TID. Using strict evaluability and clinical response criteria 6 to 14 days posttherapy, the following clinical cure rates, presumptive microbiologic eradication rates, and statistical outcomes were obtained:
- Streptococcal Pharyngitis/Tonsillitis:
- In four controlled studies conducted in the U.S., cefdinir was compared with 10 days of penicillin in adult, adolescent, and pediatric patients. Two studies (one in adults and adolescents, the other in pediatric patients) compared 10 days of cefdinir QD or BID to penicillin 250 mg or 10 mg/kg QID. Using strict evaluability and microbiologic/clinical response criteria 5 to 10 days posttherapy, the following clinical cure rates, microbiologic eradication rates, and statistical outcomes were obtained:
- Two studies (one in adults and adolescents, the other in pediatric patients) compared 5 days of cefdinir BID to 10 days of penicillin 250 mg or 10 mg/kg QID. Using strict evaluability and microbiologic/ clinical response criteria 4 to 10 days posttherapy, the following clinical cure rates, microbiologic eradication rates, and statistical outcomes were obtained:
# How Supplied
- Cefdinir capsules USP, 300 mg, size ‘0’ capsules having blue cap imprinted twice with "LUPIN" (in black ink) and purple body imprinted twice with "CEFDINIR" (in white ink) containing off white to creamish granular slug, are available as follows:
- 60 Capsules/Bottle NDC 68180-711-60
- Store the capsules at 20°-25°C (68°-77°F).
## Storage
There is limited information regarding Cefdinir Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be counseled that antibacterial drugs including cefdinir capsules should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefdinir capsules is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by cefdinir capsules or other antibacterial drugs in the future.
- Antacids containing magnesium or aluminum interfere with the absorption of cefdinir. If this type of antacid is required during cefdinir therapy, cefdinir should be taken at least 2 hours before or after the antacid.
- Iron supplements, including multivitamins that contain iron, interfere with the absorption of cefdinir. If iron supplements are required during cefdinir therapy, cefdinir should be taken at least 2 hours before or after the supplement.
- Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
# Precautions with Alcohol
- Alcohol-Cefdinir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Cefdinir®[1]
# Look-Alike Drug Names
There is limited information regarding Cefdinir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cefdinir | |
8c7877c92d3ecdc7b0edaae90c6869dbffacd24f | wikidoc | Cefepime | Cefepime
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# Overview
Cefepime is a antibiotic (cephalosporin) that is FDA approved for the treatment of pneumonia, febrile neutropenia, uncomplicated UTI, uncomplicated skin infection and complicated intraabdominal infections. Common adverse reactions include rash, hypophosphatemia, diarrhea, Direct Coombs test positive, ALT/SGPT level raised, AST/SGOT level raised.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Cefepime for injection, USP is indicated in the treatment of the following infections caused by susceptible strains of the designated microorganisms:
- Caused by Streptococcus pneumoniae, including cases associated with concurrent bacteremia, Pseudomonas aeruginosa, Klebsiella pneumoniae, or Enterobacter species.
- Cefepime as monotherapy is indicated for empiric treatment of febrile neutropenic patients. In patients at high risk for severe infection (including patients with a history of recent bone marrow transplantation, with hypotension at presentation, with an underlying hematologic malignancy, or with severe or prolonged neutropenia), antimicrobial monotherapy may not be appropriate. Insufficient data exist to support the efficacy of cefepime monotherapy in such patients.
- Caused by Escherichia coli or Klebsiella pneumoniae, when the infection is severe, or caused by Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis, when the infection is mild to moderate, including cases associated with concurrent bacteremia with these microorganisms.
- Caused by Staphylococcus aureus (methicillin-susceptible strains only) or Streptococcus pyogenes.
- Its used in combination with metronidazole. Caused by Escherichia coli, viridans group streptococci, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter species, or Bacteroides fragilis.
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefepime for injection, USP and other antibacterial drugs, cefepime for injection, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Community Acquired Pneumonia - Empiric Therapy for Patients at Risk for Pseudomonas Pneumonia
Dosage: IV beta-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) + IV ciprofloxacin (400 mg q8h-q12h) or IV levofloxacin (750 mg q24h)
- Dosage: IV beta-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) + IV ciprofloxacin (400 mg q8h-q12h) or IV levofloxacin (750 mg q24h)
- Dosage: Multidrug Scheme
Vancomycin hydrochloride 15 mg/kg IV q12h for 6 weeks
Gentamicin sulfate (Can be either IM or IV)
1 mg/kg IV
IM every 8 hours for 2 weeks.
Cefepime 2 g IV q8h for 6 weeks
Rifampin 300 mg IV or orally q8h for 6 weeks
- Vancomycin hydrochloride 15 mg/kg IV q12h for 6 weeks
- Gentamicin sulfate (Can be either IM or IV)
1 mg/kg IV
IM every 8 hours for 2 weeks.
- 1 mg/kg IV
- IM every 8 hours for 2 weeks.
- Cefepime 2 g IV q8h for 6 weeks
- Rifampin 300 mg IV or orally q8h for 6 weeks
### Non–Guideline-Supported Use
- Dosage
Loading dose: Cefepime 2g
Maintenance dose: 1g IP for 9 consecutive days
- Loading dose: Cefepime 2g
- Maintenance dose: 1g IP for 9 consecutive days
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Cefepime for injection, USP is indicated in the treatment of the following infections caused by susceptible strains of the designated microorganisms:
- Caused by Streptococcus pneumoniae, including cases associated with concurrent bacteremia, Pseudomonas aeruginosa, Klebsiella pneumoniae, or Enterobacter species.
- Cefepime as monotherapy is indicated for empiric treatment of febrile neutropenic patients. In patients at high risk for severe infection (including patients with a history of recent bone marrow transplantation, with hypotension at presentation, with an underlying hematologic malignancy, or with severe or prolonged neutropenia), antimicrobial monotherapy may not be appropriate. Insufficient data exist to support the efficacy of cefepime monotherapy in such patients.
- Caused by Escherichia coli or Klebsiella pneumoniae, when the infection is severe, or caused by Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis, when the infection is mild to moderate, including cases associated with concurrent bacteremia with these microorganisms.
- Caused by Staphylococcus aureus (methicillin-susceptible strains only) or Streptococcus pyogenes.
- Its used in combination with metronidazole. Caused by Escherichia coli, viridans group streptococci, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter species, or Bacteroides fragilis.
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefepime for injection, USP and other antibacterial drugs, cefepime for injection, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Community Acquired Pneumonia - Empiric Therapy for Patients at Risk for Pseudomonas Pneumonia
Dosage: IV beta-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) + IV ciprofloxacin (400 mg q8h-q12h) or IV levofloxacin (750 mg q24h)
- Dosage: IV beta-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) + IV ciprofloxacin (400 mg q8h-q12h) or IV levofloxacin (750 mg q24h)
- Dosage: Multidrug Scheme
Vancomycin hydrochloride 15 mg/kg IV q12h for 6 weeks
Gentamicin sulfate (Can be either IM or IV)
1 mg/kg IV
IM every 8 hours for 2 weeks.
Cefepime 2 g IV q8h for 6 weeks
Rifampin 300 mg IV or orally q8h for 6 weeks
- Vancomycin hydrochloride 15 mg/kg IV q12h for 6 weeks
- Gentamicin sulfate (Can be either IM or IV)
1 mg/kg IV
IM every 8 hours for 2 weeks.
- 1 mg/kg IV
- IM every 8 hours for 2 weeks.
- Cefepime 2 g IV q8h for 6 weeks
- Rifampin 300 mg IV or orally q8h for 6 weeks
### Non–Guideline-Supported Use
- Dosage: 50 mg/kg/dose q8h
- Dosage: 2g IV q12h
# Contraindications
- Cefepime for injection is contraindicated in patients who have shown immediate hypersensitivity reactions to cefepime or the cephalosporin class of antibiotics, penicillins or other beta-lactam antibiotics.
# Warnings
### Hypersensitivity
- Before therapy with cefepime for injection is instituted, careful inquiry should be made to determine whether the patient has had previous immediate hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other drugs. If this product is to be given to penicillin-sensitive patients, caution should be exercised because cross-hypersensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to cefepime for injection occurs, discontinue the drug. Serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures including oxygen, corticosteroids, intravenous fluids, intravenous antihistamines, pressor amines, and airway management, as clinically indicated.
### Renal Impairment
- In patients with creatinine clearance less than or equal to 60 mL/min, the dose of cefepime for injection (cefepime hydrochloride) should be adjusted to compensate for the slower rate of renal elimination. Because high and prolonged serum antibiotic concentrations can occur from usual dosages in patients with renal impairment or other conditions that may compromise renal function, the maintenance dosage should be reduced when cefepime is administered to such patients. Continued dosage should be determined by degree of renal impairment, severity of infection, and susceptibility of the causative organisms.
### Clostridium Difficile Associated Diarrhea
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefepime for injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
- C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since ] has been reported to occur over two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
During postmarketing surveillance, serious adverse events have been reported including life-threatening or fatal occurrences of the following: encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, and seizures. Most cases occurred in patients with renal impairment who received doses of cefepime that exceeded the recommended dosage schedules. However, some cases of encephalopathy occurred in patients receiving a dosage adjustment for their renal function. In the majority of cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of cefepime and/or after hemodialysis.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- In clinical trials using multiple doses of cefepime, 4137 patients were treated with the recommended dosages of cefepime (500 mg to 2 g intravenous every 12 hours). There were no deaths or permanent disabilities thought related to drug toxicity. Sixty-four (1.5%) patients discontinued medication due to adverse events thought by the investigators to be possibly, probably, or almost certainly related to drug toxicity. Thirty-three (51%) of these 64 patients who discontinued therapy did so because of rash. The percentage of cefepime-treated patients who discontinued study drug because of drug-related adverse events was very similar at daily doses of 500 mg, 1 g, and 2 g every 12 hours (0.8%, 1.1%, and 2.0%, respectively). However, the incidence of discontinuation due to rash increased with the higher recommended doses. The following adverse events were thought to be probably related to cefepime during evaluation of the drug in clinical trials conducted in North America (n=3125 cefepime-treated patients).
- At the higher dose of 2 g every 8 hours, the incidence of probably-related adverse events was higher among the 795 patients who received this dose of cefepime. They consisted of rash (4%), diarrhea (3%), nausea (2%), vomiting (1%), pruritus (1%), fever (1%), and headache (1%). The following adverse laboratory changes, irrespective of relationship to therapy with Cefepime, were seen during clinical trials conducted in North America.
A similar safety profile was seen in clinical trials of pediatric patients.
## Postmarketing Experience
In addition to the events reported during North American clinical trials with cefepime, the following adverse experiences have been reported during worldwide postmarketing experience.
- As with some other drugs in this class, encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, and seizures have been reported. Although most cases occurred in patients with renal impairment who received doses of cefepime that exceeded the recommended dosage schedules, some cases of encephalopathy occurred in patients receiving a dosage adjustment for their renal function. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated. Precautions should be taken to adjust daily dosage in patients with renal insufficiency or other conditions that may compromise renal function to reduce antibiotic concentrations that can lead or contribute to these and other serious adverse events, including renal failure. As with other cephalosporins, anaphylaxis including anaphylactic shock, transient leukopenia, neutropenia, agranulocytosis and thrombocytopenia have been reported.
- In addition to the adverse reactions listed above that have been observed in patients treated with cefepime, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, renal dysfunction, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, hepatic dysfunction including cholestasis, and pancytopenia.
# Drug Interactions
- Renal function should be monitored carefully if high doses of aminoglycosides are to be administered with cefepime for injection because of the increased potential of nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity has been reported following concomitant administration of other cephalosporins with potent diuretics such as furosemide.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Cefepime was not teratogenic or embryocidal when administered during the period of organogenesis to rats at doses up to 1000 mg/kg/day (1.6 times the recommended maximum human dose calculated on a mg/m2 basis) or to mice at doses up to 1200 mg/kg (approximately equal to the recommended maximum human dose calculated on a mg/m2 basis) or to rabbits at a dose level of 100 mg/kg (0.3 times the recommended maximum human dose calculated on a mg/m2 basis).
- There are, however, no adequate and well-controlled studies of cefepime use in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cefepime in women who are pregnant.
### Labor and Delivery
- Cefepime has not been studied for use during labor and delivery. Treatment should only be given if clearly indicated.
### Nursing Mothers
- Cefepime is excreted in human breast milk in very low concentrations (0.5 mcg/mL). Caution should be exercised when cefepime is administered to a nursing woman.
### Pediatric Use
- The safety and effectiveness of cefepime in the treatment of uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, pneumonia, and as empiric therapy for febrile neutropenic patients have been established in the age groups 2 months up to 16 years. Use of cefepime for injection in these age groups is supported by evidence from adequate and well-controlled studies of cefepime in adults with additional pharmacokinetic and safety data from pediatric trials.
- Safety and effectiveness in pediatric patients below the age of 2 months have not been established. There are insufficient clinical data to support the use of cefepime for injection in pediatric patients under 2 months of age or for the treatment of serious infections in the pediatric population where the suspected or proven pathogen is Haemophilus influenzae type b.
- In those patients in whom meningeal seeding from a distant infection site or in whom meningitis is suspected or documented, an alternate agent with demonstrated clinical efficacy in this setting should be used.
### Geriatic Use
- Of the more than 6400 adults treated with cefepime for injection in clinical studies, 35% were 65 years or older while 16% were 75 years or older. When geriatric patients received the usual recommended adult dose, clinical efficacy and safety were comparable to clinical efficacy and safety in nongeriatric adult patients.
- Serious adverse events have occurred in geriatric patients with renal insufficiency given unadjusted doses of cefepime, including life-threatening or fatal occurrences of the following: encephalopathy, myoclonus, and seizures. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored.
### Gender
There is no FDA guidance on the use of Cefepime with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cefepime with respect to specific racial populations.
### Renal Impairment
- Cefepime pharmacokinetics have been investigated in patients with various degrees of renal impairment (n=30). The average half-life in patients requiring hemodialysis was 13.5 (±2.7) hours and in patients requiring continuous peritoneal dialysis was 19.0 (±2.0) hours. Cefepime total body clearance decreased proportionally with creatinine clearance in patients with abnormal renal function, which serves as the basis for dosage adjustment recommendations in this group of patients.
### Hepatic Impairment
The pharmacokinetics of cefepime were unaltered in patients with hepatic impairment who received a single 1 g dose (n=11).
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cefepime in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cefepime in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Constitute the 500 mg, 1 g, or 2 g vial, and add an appropriate quantity of the resulting solution to an intravenous container with one of the compatible intravenous fluids listed in the compatibility and stability subsection. The resulting solution should be administered over approximately 30 minutes.
- Intermittent intravenous infusion with a Y-type administration set can be accomplished with compatible solutions. However, during infusion of a solution containing cefepime, it is desirable to discontinue the other solution.
- For intramuscular administration, cefepime for injection (cefepime hydrochloride) should be constituted with one of the following diluents: Sterile Water for Injection, 0.9% Sodium Chloride, 5% Dextrose Injection, 0.5% or 1.0% Lidocaine Hydrochloride, or Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol.
### Monitoring
There is limited information regarding Cefepime Monitoring in the drug label.
# IV Compatibility
- Cefepime for injection is compatible at concentrations between 1 mg/mL and 40 mg/mL with the following intravenous infusion fluids: 0.9% Sodium Chloride Injection, 5% and 10% Dextrose Injection, M/6 Sodium Lactate Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, Lactated Ringers and 5% Dextrose Injection, Normosol-R™, and Normosol-M™ in 5% Dextrose Injection. These solutions may be stored up to 24 hours at controlled room temperature 20° to 25° C (68° to 77° F) or 7 days in a refrigerator 2° to 8° C (36° to 46° F).
- Cefepime for injection admixture compatibility information is summarized in the following table:
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- Solutions of cefepime for injection, like those of most beta-lactam antibiotics, should not be added to solutions of ampicillin at a concentration greater than 40 mg/mL, and should not be added to metronidazole, vancomycin, gentamicin, tobramycin, netilmicin sulfate or aminophylline because of potential interaction. However, if concurrent therapy with cefepime for injection is indicated, each of these antibiotics can be administered separately.
- Cefepime for injection (cefepime hydrochloride) constituted as directed is stable for 24 hours at controlled room temperature 20° to 25° C (68° to 77° F) or for 7 days in a refrigerator 2° to 8° C (36° to 46° F) with the following diluents: Sterile Water for Injection, 0.9% Sodium Chloride Injection, 5% Dextrose Injection, Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol, or 0.5% or 1% Lidocaine Hydrochloride.
# Overdosage
- Patients who receive an overdose should be carefully observed and given supportive treatment. In the presence of renal insufficiency, hemodialysis, not peritoneal dialysis, is recommended to aid in the removal of cefepime from the body. Accidental overdosing has occurred when large doses were given to patients with impaired renal function. Symptoms of overdose include encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures, and neuromuscular excitability.
# Pharmacology
## Mechanism of Action
- Cefepime is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Cefepime has a broad spectrum of in vitro activity that encompasses a wide range of Gram-positive and Gram-negative bacteria. Cefepime has a low affinity for chromosomally-encoded beta-lactamases. Cefepime is highly resistant to hydrolysis by most beta-lactamases and exhibits rapid penetration into gram-negative bacterial cells. Within bacterial cells, the molecular targets of cefepime are the penicillin binding proteins (PBP).
## Structure
- Cefepime for injection, USP (cefepime hydrochloride, USP) is a semi-synthetic, broad spectrum, cephalosporin antibiotic for parenteral administration. The chemical name is 1--2-carboxy-8-oxo-5-thia-1-azabicyclo oct-2-en-3-yl]methyl]-1-methylpyrrolidinium chloride, 72-(Z)-(O-methyloxime), monohydrochloride, monohydrate]], which corresponds to the following structural formula:
## Pharmacodynamics
There is limited information regarding Cefepime Pharmacodynamics in the drug label.
## Pharmacokinetics
- The average plasma concentrations of cefepime observed in healthy adult male volunteers (n=9) at various times following single 30-minute infusions (IV) of cefepime 500 mg, 1 g, and 2 g are summarized in Table 1. Elimination of cefepime is principally via renal excretion with an average (±SD) half-life of 2.0 (±0.3) hours and total body clearance of 120.0 (±8.0) mL/min in healthy volunteers. Cefepime pharmacokinetics are linear over the range 250 mg to 2 g. There is no evidence of accumulation in healthy adult male volunteers (n=7) receiving clinically relevant doses for a period of 9 days.
The average plasma concentrations of cefepime and its derived pharmacokinetic parameters after intravenous (IV) administration are portrayed in Table 1.
Following intramuscular (IM) administration, cefepime is completely absorbed. The average plasma concentrations of cefepime at various times following a single intramuscular injection are summarized in Table 2. The pharmacokinetics of cefepime are linear over the range of 500 mg to 2 g intramuscularly and do not vary with respect to treatment duration.
- The average steady-state volume of distribution of cefepime is 18.0 (±2.0) L. The serum protein binding of cefepime is approximately 20% and is independent of its concentration in serum. Cefepime is excreted in human milk. A nursing infant consuming approximately 1000 mL of human milk per day would receive approximately 0.5 mg of cefepime per day. Concentrations of cefepime achieved in specific tissues and body fluids are listed in Table 3.
- Data suggest that cefepime does cross the inflamed blood-brain barrier. The clinical relevance of these data is uncertain at this time.
- Cefepime is metabolized to N-methylpyrrolidine (NMP) which is rapidly converted to the N-oxide (NMP-N-oxide). Urinary recovery of unchanged cefepime accounts for approximately 85% of the administered dose. Less than 1% of the administered dose is recovered from urine as NMP, 6.8% as NMP-N-oxide, and 2.5% as an epimer of Cefepime. Because renal excretion is a significant pathway of elimination, patients with renal dysfunction and patients undergoing hemodialysis require dosage adjustment.
## Nonclinical Toxicology
There is limited information regarding Cefepime Nonclinical Toxicology in the drug label.
# Clinical Studies
- The safety and efficacy of empiric cefepime monotherapy of febrile neutropenic patients have been assessed in two multicenter, randomized trials, comparing cefepime monotherapy (at a dose of 2 g intravenously every 8 hours) to ceftazidime monotherapy (at a dose of 2 g intravenously every 8 hours). These studies comprised 317 evaluable patients. Table 8 describes the characteristics of the evaluable patient population.
Table 9 describes the clinical response rates observed. For all outcome measures, cefepime was therapeutically equivalent to ceftazidime.
- Insufficient data exist to support the efficacy of cefepime monotherapy in patients at high risk for severe infection (including patients with a history of recent bone marrow transplantation, with hypotension at presentation, with an underlying hematologic malignancy, or with severe or prolonged neutropenia). No data are available in patients with septic shock.
- Patients hospitalized with complicated intra-abdominal infections participated in a randomized, double-blind, multicenter trial comparing the combination of cefepime (2 g every 12 hours) plus intravenous metronidazole (500 mg every 6 hours) versus imipenem/cilastatin (500 mg every 6 hours) for a maximum duration of 14 days of therapy. The study was designed to demonstrate equivalence of the two therapies. The primary analyses were conducted on the protocol-valid population, which consisted of those with a surgically confirmed complicated infection, at least one pathogen isolated pretreatment, at least 5 days of treatment, and a 4 to 6 week follow-up assessment for cured patients. Subjects in the imipenem/cilastatin arm had higher APACHE II scores at baseline. The treatment groups were otherwise generally comparable with regard to their pretreatment characteristics. The overall clinical cure rate among the protocol-valid patients was 81% (51 cured/63 evaluable patients) in the cefepime plus metronidazole group and 66% (62/94) in the imipenem/cilastatin group. The observed differences in efficacy may have been due to a greater proportion of patients with high APACHE II scores in the imipenem/cilastatin group.
# How Supplied
- Cefepime for injection, USP (cefepime hydrochloride, USP) for injection is supplied as follows:
## Storage
- Store dry powder between 2° to 25°C (36° to 77°F). Protect from light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Cefepime Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Cefepime interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Maxipime
# Look-Alike Drug Names
There is limited information regarding Cefepime Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Cefepime
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
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# Overview
Cefepime is a antibiotic (cephalosporin) that is FDA approved for the treatment of pneumonia, febrile neutropenia, uncomplicated UTI, uncomplicated skin infection and complicated intraabdominal infections. Common adverse reactions include rash, hypophosphatemia, diarrhea, Direct Coombs test positive, ALT/SGPT level raised, AST/SGOT level raised.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Cefepime for injection, USP is indicated in the treatment of the following infections caused by susceptible strains of the designated microorganisms:
- Caused by Streptococcus pneumoniae, including cases associated with concurrent bacteremia, Pseudomonas aeruginosa, Klebsiella pneumoniae, or Enterobacter species.
- Cefepime as monotherapy is indicated for empiric treatment of febrile neutropenic patients. In patients at high risk for severe infection (including patients with a history of recent bone marrow transplantation, with hypotension at presentation, with an underlying hematologic malignancy, or with severe or prolonged neutropenia), antimicrobial monotherapy may not be appropriate. Insufficient data exist to support the efficacy of cefepime monotherapy in such patients.
- Caused by Escherichia coli or Klebsiella pneumoniae, when the infection is severe, or caused by Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis, when the infection is mild to moderate, including cases associated with concurrent bacteremia with these microorganisms.
- Caused by Staphylococcus aureus (methicillin-susceptible strains only) or Streptococcus pyogenes.
- Its used in combination with metronidazole. Caused by Escherichia coli, viridans group streptococci, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter species, or Bacteroides fragilis.
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefepime for injection, USP and other antibacterial drugs, cefepime for injection, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Community Acquired Pneumonia - Empiric Therapy for Patients at Risk for Pseudomonas Pneumonia
Dosage: IV beta-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) + IV ciprofloxacin (400 mg q8h-q12h) or IV levofloxacin (750 mg q24h)[1]
- Dosage: IV beta-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) + IV ciprofloxacin (400 mg q8h-q12h) or IV levofloxacin (750 mg q24h)[1]
- Dosage: Multidrug Scheme
Vancomycin hydrochloride 15 mg/kg IV q12h for 6 weeks
Gentamicin sulfate (Can be either IM or IV)
1 mg/kg IV
IM every 8 hours for 2 weeks.
Cefepime 2 g IV q8h for 6 weeks[2]
Rifampin 300 mg IV or orally q8h for 6 weeks
- Vancomycin hydrochloride 15 mg/kg IV q12h for 6 weeks
- Gentamicin sulfate (Can be either IM or IV)
1 mg/kg IV
IM every 8 hours for 2 weeks.
- 1 mg/kg IV
- IM every 8 hours for 2 weeks.
- Cefepime 2 g IV q8h for 6 weeks[2]
- Rifampin 300 mg IV or orally q8h for 6 weeks
### Non–Guideline-Supported Use
- Dosage[3]
Loading dose: Cefepime 2g
Maintenance dose: 1g IP for 9 consecutive days
- Loading dose: Cefepime 2g
- Maintenance dose: 1g IP for 9 consecutive days
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Cefepime for injection, USP is indicated in the treatment of the following infections caused by susceptible strains of the designated microorganisms:
- Caused by Streptococcus pneumoniae, including cases associated with concurrent bacteremia, Pseudomonas aeruginosa, Klebsiella pneumoniae, or Enterobacter species.
- Cefepime as monotherapy is indicated for empiric treatment of febrile neutropenic patients. In patients at high risk for severe infection (including patients with a history of recent bone marrow transplantation, with hypotension at presentation, with an underlying hematologic malignancy, or with severe or prolonged neutropenia), antimicrobial monotherapy may not be appropriate. Insufficient data exist to support the efficacy of cefepime monotherapy in such patients.
- Caused by Escherichia coli or Klebsiella pneumoniae, when the infection is severe, or caused by Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis, when the infection is mild to moderate, including cases associated with concurrent bacteremia with these microorganisms.
- Caused by Staphylococcus aureus (methicillin-susceptible strains only) or Streptococcus pyogenes.
- Its used in combination with metronidazole. Caused by Escherichia coli, viridans group streptococci, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter species, or Bacteroides fragilis.
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefepime for injection, USP and other antibacterial drugs, cefepime for injection, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Community Acquired Pneumonia - Empiric Therapy for Patients at Risk for Pseudomonas Pneumonia
Dosage: IV beta-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) + IV ciprofloxacin (400 mg q8h-q12h) or IV levofloxacin (750 mg q24h)[4]
- Dosage: IV beta-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) + IV ciprofloxacin (400 mg q8h-q12h) or IV levofloxacin (750 mg q24h)[4]
- Dosage: Multidrug Scheme
Vancomycin hydrochloride 15 mg/kg IV q12h for 6 weeks
Gentamicin sulfate (Can be either IM or IV)
1 mg/kg IV
IM every 8 hours for 2 weeks.
Cefepime 2 g IV q8h for 6 weeks[5]
Rifampin 300 mg IV or orally q8h for 6 weeks
- Vancomycin hydrochloride 15 mg/kg IV q12h for 6 weeks
- Gentamicin sulfate (Can be either IM or IV)
1 mg/kg IV
IM every 8 hours for 2 weeks.
- 1 mg/kg IV
- IM every 8 hours for 2 weeks.
- Cefepime 2 g IV q8h for 6 weeks[5]
- Rifampin 300 mg IV or orally q8h for 6 weeks
### Non–Guideline-Supported Use
- Dosage: 50 mg/kg/dose q8h[6][7]
- Dosage: 2g IV q12h[8]
# Contraindications
- Cefepime for injection is contraindicated in patients who have shown immediate hypersensitivity reactions to cefepime or the cephalosporin class of antibiotics, penicillins or other beta-lactam antibiotics.
# Warnings
### Hypersensitivity
- Before therapy with cefepime for injection is instituted, careful inquiry should be made to determine whether the patient has had previous immediate hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other drugs. If this product is to be given to penicillin-sensitive patients, caution should be exercised because cross-hypersensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to cefepime for injection occurs, discontinue the drug. Serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures including oxygen, corticosteroids, intravenous fluids, intravenous antihistamines, pressor amines, and airway management, as clinically indicated.
### Renal Impairment
- In patients with creatinine clearance less than or equal to 60 mL/min, the dose of cefepime for injection (cefepime hydrochloride) should be adjusted to compensate for the slower rate of renal elimination. Because high and prolonged serum antibiotic concentrations can occur from usual dosages in patients with renal impairment or other conditions that may compromise renal function, the maintenance dosage should be reduced when cefepime is administered to such patients. Continued dosage should be determined by degree of renal impairment, severity of infection, and susceptibility of the causative organisms.
### Clostridium Difficile Associated Diarrhea
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefepime for injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
- C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since [CDAD]] has been reported to occur over two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
During postmarketing surveillance, serious adverse events have been reported including life-threatening or fatal occurrences of the following: encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, and seizures. Most cases occurred in patients with renal impairment who received doses of cefepime that exceeded the recommended dosage schedules. However, some cases of encephalopathy occurred in patients receiving a dosage adjustment for their renal function. In the majority of cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of cefepime and/or after hemodialysis.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- In clinical trials using multiple doses of cefepime, 4137 patients were treated with the recommended dosages of cefepime (500 mg to 2 g intravenous every 12 hours). There were no deaths or permanent disabilities thought related to drug toxicity. Sixty-four (1.5%) patients discontinued medication due to adverse events thought by the investigators to be possibly, probably, or almost certainly related to drug toxicity. Thirty-three (51%) of these 64 patients who discontinued therapy did so because of rash. The percentage of cefepime-treated patients who discontinued study drug because of drug-related adverse events was very similar at daily doses of 500 mg, 1 g, and 2 g every 12 hours (0.8%, 1.1%, and 2.0%, respectively). However, the incidence of discontinuation due to rash increased with the higher recommended doses. The following adverse events were thought to be probably related to cefepime during evaluation of the drug in clinical trials conducted in North America (n=3125 cefepime-treated patients).
- At the higher dose of 2 g every 8 hours, the incidence of probably-related adverse events was higher among the 795 patients who received this dose of cefepime. They consisted of rash (4%), diarrhea (3%), nausea (2%), vomiting (1%), pruritus (1%), fever (1%), and headache (1%). The following adverse laboratory changes, irrespective of relationship to therapy with Cefepime, were seen during clinical trials conducted in North America.
A similar safety profile was seen in clinical trials of pediatric patients.
## Postmarketing Experience
In addition to the events reported during North American clinical trials with cefepime, the following adverse experiences have been reported during worldwide postmarketing experience.
- As with some other drugs in this class, encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, and seizures have been reported. Although most cases occurred in patients with renal impairment who received doses of cefepime that exceeded the recommended dosage schedules, some cases of encephalopathy occurred in patients receiving a dosage adjustment for their renal function. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated. Precautions should be taken to adjust daily dosage in patients with renal insufficiency or other conditions that may compromise renal function to reduce antibiotic concentrations that can lead or contribute to these and other serious adverse events, including renal failure. As with other cephalosporins, anaphylaxis including anaphylactic shock, transient leukopenia, neutropenia, agranulocytosis and thrombocytopenia have been reported.
- In addition to the adverse reactions listed above that have been observed in patients treated with cefepime, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, renal dysfunction, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, hepatic dysfunction including cholestasis, and pancytopenia.
# Drug Interactions
- Renal function should be monitored carefully if high doses of aminoglycosides are to be administered with cefepime for injection because of the increased potential of nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity has been reported following concomitant administration of other cephalosporins with potent diuretics such as furosemide.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Cefepime was not teratogenic or embryocidal when administered during the period of organogenesis to rats at doses up to 1000 mg/kg/day (1.6 times the recommended maximum human dose calculated on a mg/m2 basis) or to mice at doses up to 1200 mg/kg (approximately equal to the recommended maximum human dose calculated on a mg/m2 basis) or to rabbits at a dose level of 100 mg/kg (0.3 times the recommended maximum human dose calculated on a mg/m2 basis).
- There are, however, no adequate and well-controlled studies of cefepime use in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cefepime in women who are pregnant.
### Labor and Delivery
- Cefepime has not been studied for use during labor and delivery. Treatment should only be given if clearly indicated.
### Nursing Mothers
- Cefepime is excreted in human breast milk in very low concentrations (0.5 mcg/mL). Caution should be exercised when cefepime is administered to a nursing woman.
### Pediatric Use
- The safety and effectiveness of cefepime in the treatment of uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, pneumonia, and as empiric therapy for febrile neutropenic patients have been established in the age groups 2 months up to 16 years. Use of cefepime for injection in these age groups is supported by evidence from adequate and well-controlled studies of cefepime in adults with additional pharmacokinetic and safety data from pediatric trials.
- Safety and effectiveness in pediatric patients below the age of 2 months have not been established. There are insufficient clinical data to support the use of cefepime for injection in pediatric patients under 2 months of age or for the treatment of serious infections in the pediatric population where the suspected or proven pathogen is Haemophilus influenzae type b.
- In those patients in whom meningeal seeding from a distant infection site or in whom meningitis is suspected or documented, an alternate agent with demonstrated clinical efficacy in this setting should be used.
### Geriatic Use
- Of the more than 6400 adults treated with cefepime for injection in clinical studies, 35% were 65 years or older while 16% were 75 years or older. When geriatric patients received the usual recommended adult dose, clinical efficacy and safety were comparable to clinical efficacy and safety in nongeriatric adult patients.
- Serious adverse events have occurred in geriatric patients with renal insufficiency given unadjusted doses of cefepime, including life-threatening or fatal occurrences of the following: encephalopathy, myoclonus, and seizures. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored.
### Gender
There is no FDA guidance on the use of Cefepime with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cefepime with respect to specific racial populations.
### Renal Impairment
- Cefepime pharmacokinetics have been investigated in patients with various degrees of renal impairment (n=30). The average half-life in patients requiring hemodialysis was 13.5 (±2.7) hours and in patients requiring continuous peritoneal dialysis was 19.0 (±2.0) hours. Cefepime total body clearance decreased proportionally with creatinine clearance in patients with abnormal renal function, which serves as the basis for dosage adjustment recommendations in this group of patients.
### Hepatic Impairment
The pharmacokinetics of cefepime were unaltered in patients with hepatic impairment who received a single 1 g dose (n=11).
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cefepime in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cefepime in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Constitute the 500 mg, 1 g, or 2 g vial, and add an appropriate quantity of the resulting solution to an intravenous container with one of the compatible intravenous fluids listed in the compatibility and stability subsection. The resulting solution should be administered over approximately 30 minutes.
- Intermittent intravenous infusion with a Y-type administration set can be accomplished with compatible solutions. However, during infusion of a solution containing cefepime, it is desirable to discontinue the other solution.
- For intramuscular administration, cefepime for injection (cefepime hydrochloride) should be constituted with one of the following diluents: Sterile Water for Injection, 0.9% Sodium Chloride, 5% Dextrose Injection, 0.5% or 1.0% Lidocaine Hydrochloride, or Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol.
### Monitoring
There is limited information regarding Cefepime Monitoring in the drug label.
# IV Compatibility
- Cefepime for injection is compatible at concentrations between 1 mg/mL and 40 mg/mL with the following intravenous infusion fluids: 0.9% Sodium Chloride Injection, 5% and 10% Dextrose Injection, M/6 Sodium Lactate Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, Lactated Ringers and 5% Dextrose Injection, Normosol-R™, and Normosol-M™ in 5% Dextrose Injection. These solutions may be stored up to 24 hours at controlled room temperature 20° to 25° C (68° to 77° F) or 7 days in a refrigerator 2° to 8° C (36° to 46° F).
- Cefepime for injection admixture compatibility information is summarized in the following table:
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- Solutions of cefepime for injection, like those of most beta-lactam antibiotics, should not be added to solutions of ampicillin at a concentration greater than 40 mg/mL, and should not be added to metronidazole, vancomycin, gentamicin, tobramycin, netilmicin sulfate or aminophylline because of potential interaction. However, if concurrent therapy with cefepime for injection is indicated, each of these antibiotics can be administered separately.
- Cefepime for injection (cefepime hydrochloride) constituted as directed is stable for 24 hours at controlled room temperature 20° to 25° C (68° to 77° F) or for 7 days in a refrigerator 2° to 8° C (36° to 46° F) with the following diluents: Sterile Water for Injection, 0.9% Sodium Chloride Injection, 5% Dextrose Injection, Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol, or 0.5% or 1% Lidocaine Hydrochloride.
# Overdosage
- Patients who receive an overdose should be carefully observed and given supportive treatment. In the presence of renal insufficiency, hemodialysis, not peritoneal dialysis, is recommended to aid in the removal of cefepime from the body. Accidental overdosing has occurred when large doses were given to patients with impaired renal function. Symptoms of overdose include encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures, and neuromuscular excitability.
# Pharmacology
## Mechanism of Action
- Cefepime is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Cefepime has a broad spectrum of in vitro activity that encompasses a wide range of Gram-positive and Gram-negative bacteria. Cefepime has a low affinity for chromosomally-encoded beta-lactamases. Cefepime is highly resistant to hydrolysis by most beta-lactamases and exhibits rapid penetration into gram-negative bacterial cells. Within bacterial cells, the molecular targets of cefepime are the penicillin binding proteins (PBP).
## Structure
- Cefepime for injection, USP (cefepime hydrochloride, USP) is a semi-synthetic, broad spectrum, cephalosporin antibiotic for parenteral administration. The chemical name is 1-[[(6R,7R)-7-[2-(2-amino-4-thiazolyl)-glyoxylamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-en-3-yl]methyl]-1-methylpyrrolidinium chloride, 72-(Z)-(O-methyloxime), monohydrochloride, monohydrate]], which corresponds to the following structural formula:
## Pharmacodynamics
There is limited information regarding Cefepime Pharmacodynamics in the drug label.
## Pharmacokinetics
- The average plasma concentrations of cefepime observed in healthy adult male volunteers (n=9) at various times following single 30-minute infusions (IV) of cefepime 500 mg, 1 g, and 2 g are summarized in Table 1. Elimination of cefepime is principally via renal excretion with an average (±SD) half-life of 2.0 (±0.3) hours and total body clearance of 120.0 (±8.0) mL/min in healthy volunteers. Cefepime pharmacokinetics are linear over the range 250 mg to 2 g. There is no evidence of accumulation in healthy adult male volunteers (n=7) receiving clinically relevant doses for a period of 9 days.
The average plasma concentrations of cefepime and its derived pharmacokinetic parameters after intravenous (IV) administration are portrayed in Table 1.
Following intramuscular (IM) administration, cefepime is completely absorbed. The average plasma concentrations of cefepime at various times following a single intramuscular injection are summarized in Table 2. The pharmacokinetics of cefepime are linear over the range of 500 mg to 2 g intramuscularly and do not vary with respect to treatment duration.
- The average steady-state volume of distribution of cefepime is 18.0 (±2.0) L. The serum protein binding of cefepime is approximately 20% and is independent of its concentration in serum. Cefepime is excreted in human milk. A nursing infant consuming approximately 1000 mL of human milk per day would receive approximately 0.5 mg of cefepime per day. Concentrations of cefepime achieved in specific tissues and body fluids are listed in Table 3.
- Data suggest that cefepime does cross the inflamed blood-brain barrier. The clinical relevance of these data is uncertain at this time.
- Cefepime is metabolized to N-methylpyrrolidine (NMP) which is rapidly converted to the N-oxide (NMP-N-oxide). Urinary recovery of unchanged cefepime accounts for approximately 85% of the administered dose. Less than 1% of the administered dose is recovered from urine as NMP, 6.8% as NMP-N-oxide, and 2.5% as an epimer of Cefepime. Because renal excretion is a significant pathway of elimination, patients with renal dysfunction and patients undergoing hemodialysis require dosage adjustment.
## Nonclinical Toxicology
There is limited information regarding Cefepime Nonclinical Toxicology in the drug label.
# Clinical Studies
- The safety and efficacy of empiric cefepime monotherapy of febrile neutropenic patients have been assessed in two multicenter, randomized trials, comparing cefepime monotherapy (at a dose of 2 g intravenously every 8 hours) to ceftazidime monotherapy (at a dose of 2 g intravenously every 8 hours). These studies comprised 317 evaluable patients. Table 8 describes the characteristics of the evaluable patient population.
Table 9 describes the clinical response rates observed. For all outcome measures, cefepime was therapeutically equivalent to ceftazidime.
- Insufficient data exist to support the efficacy of cefepime monotherapy in patients at high risk for severe infection (including patients with a history of recent bone marrow transplantation, with hypotension at presentation, with an underlying hematologic malignancy, or with severe or prolonged neutropenia). No data are available in patients with septic shock.
- Patients hospitalized with complicated intra-abdominal infections participated in a randomized, double-blind, multicenter trial comparing the combination of cefepime (2 g every 12 hours) plus intravenous metronidazole (500 mg every 6 hours) versus imipenem/cilastatin (500 mg every 6 hours) for a maximum duration of 14 days of therapy. The study was designed to demonstrate equivalence of the two therapies. The primary analyses were conducted on the protocol-valid population, which consisted of those with a surgically confirmed complicated infection, at least one pathogen isolated pretreatment, at least 5 days of treatment, and a 4 to 6 week follow-up assessment for cured patients. Subjects in the imipenem/cilastatin arm had higher APACHE II scores at baseline. The treatment groups were otherwise generally comparable with regard to their pretreatment characteristics. The overall clinical cure rate among the protocol-valid patients was 81% (51 cured/63 evaluable patients) in the cefepime plus metronidazole group and 66% (62/94) in the imipenem/cilastatin group. The observed differences in efficacy may have been due to a greater proportion of patients with high APACHE II scores in the imipenem/cilastatin group.
# How Supplied
- Cefepime for injection, USP (cefepime hydrochloride, USP) for injection is supplied as follows:
## Storage
- Store dry powder between 2° to 25°C (36° to 77°F). Protect from light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Cefepime Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Cefepime interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Maxipime
# Look-Alike Drug Names
There is limited information regarding Cefepime Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cefepime | |
480559d8e422ddbf8d820bc73f450e642b7cd3da | wikidoc | Cefixime | Cefixime
# 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
Cefixime is a 3rd generation cephalosporin that is FDA approved for the treatment of uncomplicated urinary tract infections, otitis media, pharyngitis and tonsillitis, acute exacerbations of chronic bronchitis and uncomplicated gonorrhea.. Common adverse reactions include diarrhea, nausea, abdominal pain, dyspepsia and vomiting..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended dose of cefixime is 400 mg daily.
- May be given as a 400 mg tablet or capsule daily or
- 400 mg tablet may be split and given as one half tablet every 12 hours
### Uncomplicated Urinary Tract Infections
- Caused by Escherichia coli and Proteus mirabilis.
### Otitis Media
- Caused by Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pyogenes.
### Pharyngitis and Tonsillitis
- Caused by Streptococcus pyogenes.
- Dosage: A therapeutic dosage of cefixime for at least 10 days
### Acute Exacerbations of Chronic Bronchitis
- Caused by Streptococcus pneumoniae and Haemophilus influenzae.
### Uncomplicated Gonorrhea (cervical/urethral)
- Caused by Neisseria gonorrhoeae.
- Dosage: a single oral dose of 400 mg
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cefixime in adult patients.
### Non–Guideline-Supported Use
- Salmonella infection
- Prophylaxis of sexually transmitted infectious disease for victim of sexual aggression
- Cefixime 400 mg orally in a single dose PLUS metronidazole or azithromycin
- Sinusitis
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Pediatric patients six months of age or older
- The recommended dose is 8 mg/kg/day of the suspension. This may be administered as a single daily dose or may be given in two divided doses, as 4 mg/kg every 12 hours.
- Children weighing more than 45 kg or older than 12 years should be treated with the recommended adult dose. cefixime chewable tablets must be chewed or crushed before swallowing.
### Uncomplicated Urinary Tract Infections
- Caused by Escherichia coli and Proteus mirabilis.
### Otitis Media
- Caused by Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pyogenes
### Pharyngitis and Tonsillitis
- Caused by Streptococcus pyogenes.
- A therapeutic dosage of cefixime for at least 10 days
### Acute Exacerbations of Chronic Bronchitis
- Caused by Streptococcus pneumoniae and Haemophilus influenzae.
### Uncomplicated Gonorrhea (cervical/urethral)
- Caused by Neisseria gonorrhoeae.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cefixime in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cefixime in pediatric patients.
# Contraindications
Cefixime is contraindicated in patients with known allergy to cefixime or other cephalosporins.
# Warnings
### Hypersensitivity Reactions
- Anaphylactic/anaphylactoid reactions (including shock and fatalities) have been reported with the use of cefixime.
- Before therapy with Suprax is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins, or other drugs. If this product is to be given to penicillin-sensitive patients, caution should be exercised because cross hypersensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to Suprax occurs, discontinue the drug.
### Clostridium difficile-Associated Diarrhea
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Suprax, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
- C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
### Dose Adjustment in Renal Impairment
- The dose of cefixime should be adjusted in patients with renal impairment as well as those undergoing continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD). Patients on dialysis should be monitored carefully
### Coagulation Effects
- Cephalosporins may be associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated.
### Development of Drug-Resistant Bacteria
- Prescribing cefixime in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The most commonly seen adverse reactions in U.S. trials of the tablet formulation were gastrointestinal events, which were reported in 30% of adult patients on either the twice daily or the once daily regimen. Five percent (5%) of patients in the U.S. clinical trials discontinued therapy because of drug-related adverse reactions. Individual adverse reactions included diarrhea 16%, loose or frequent stools 6%, abdominal pain 3%, nausea 7%, dyspepsia 3%, and flatulence 4%. The incidence of gastrointestinal adverse reactions, including diarrhea and loose stools, in pediatric patients receiving the suspension was comparable to the incidence seen in adult patients receiving tablets.
## Postmarketing Experience
The following adverse reactions have been reported following the use of cefixime. Incidence rates were less than 1 in 50 (less than 2%).
### Gastrointestinal
- Several cases of documented pseudomembranous colitis were identified in clinical trials. The onset of pseudomembranous colitis symptoms may occur during or after therapy.
### Hypersensitivity Reactions
- Anaphylactic/anaphylactoid reactions (including shock and fatalities), skin rashes, urticaria, drug fever, pruritus, angioedema, and facial edema. Erythema multiforme, Stevens-Johnson syndrome, and serum sickness-like reactions have been reported.
### Hepatic
- Transient elevations in SGPT, SGOT, alkaline phosphatase, hepatitis, jaundice.
### Renal
- Transient elevations in BUN or creatinine, acute renal failure.
### Central Nervous System
- Headaches, dizziness, seizures.
### Hemic and Lymphatic System
- Transient thrombocytopenia, leukopenia, neutropenia, prolongation in prothrombin time, elevated LDH, pancytopenia, agranulocytosis, and eosinophilia.
### Abnormal Laboratory Tests
- Hyperbilirubinemia
### Other Adverse Reactions
- Genital pruritus, vaginitis, candidiasis, toxic epidermal necrolysis.
### Adverse Reactions Reported for Cephalosporin-class Drugs
- Allergic reactions, superinfection, renal dysfunction, toxic nephropathy, hepatic dysfunction including cholestasis, aplastic anemia, hemolytic anemia, hemorrhage, and colitis.
- Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.
# Drug Interactions
### Carbamazepine
- Elevated carbamazepine levels have been reported in postmarketing experience when cefixime is administered concomitantly. Drug monitoring may be of assistance in detecting alterations in carbamazepine plasma concentrations.
### Warfarin and Anticoagulants
- Increased prothrombin time, with or without clinical bleeding, has been reported when cefixime is administered concomitantly.
### Drug/Laboratory Test Interactions
- A false-positive reaction for ketones in the urine may occur with tests using nitroprusside but not with those using nitroferricyanide.
- The administration of cefixime may result in a false-positive reaction for glucose in the urine using Clinitest®, Benedict's solution, or Fehling's solution. It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Clinistix® or TesTape®) be used. A false-positive direct Coombs test has been reported during treatment with other cephalosporins; therefore, it should be recognized that a positive Coombs test may be due to the drug.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and have revealed no evidence of harm to the fetus due to cefixime. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cefixime in women who are pregnant.
### Labor and Delivery
Cefixime has not been studied for use during labor and delivery. Treatment should only be given if clearly needed.
### Nursing Mothers
It is not known whether cefixime is excreted in human milk. Consideration should be given to discontinuing nursing temporarily during treatment with this drug.
### Pediatric Use
Safety and effectiveness of cefixime in children aged less than six months old have not been established. The incidence of gastrointestinal adverse reactions, including diarrhea and loose stools, in the pediatric patients receiving the suspension, was comparable to the incidence seen in adult patients receiving tablets.
### Geriatic Use
Clinical studies did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. A pharmacokinetic study in the elderly detected differences in pharmacokinetic parameters. These differences were small and do not indicate a need for dosage adjustment of the drug in the elderly.
### Gender
There is no FDA guidance on the use of Cefixime with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cefixime with respect to specific racial populations.
### Renal Impairment
The dose of cefixime should be adjusted in patients with renal impairment as well as those undergoing continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD). Patients on dialysis should be monitored carefully.
Cefixime may be administered in the presence of impaired renal function. Normal dose and schedule may be employed in patients with creatinine clearances of 60 mL/min or greater. Refer to Table 2 for dose adjustments for adults with renal impairment. Neither hemodialysis nor peritoneal dialysis removes significant amounts of drug from the body.
### Hepatic Impairment
There is no FDA guidance on the use of Cefixime in patients with hepatic impairment.
### Females of Reproductive Potential and Males
In rats, fertility and reproductive performance were not affected by cefixime at doses up to 25 times the adult therapeutic dose.
### Immunocompromised Patients
There is no FDA guidance one the use of Cefixime in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
Patients on dialysis should be monitored carefully.
# IV Compatibility
There is limited information regarding the compatibility of Cefixime and IV administrations.
# Overdosage
Gastric lavage may be indicated; otherwise, no specific antidote exists. Cefixime is not removed in significant quantities from the circulation by hemodialysis or peritoneal dialysis. Adverse reactions in small numbers of healthy adult volunteers receiving single doses up to 2 g of cefixime did not differ from the profile seen in patients treated at the recommended doses.
# Pharmacology
## Mechanism of Action
Cefixime is a semisynthetic cephalosporin antibacterial drug
## Structure
Chemically, it is (6R,7R)-7--8-oxo-3-vinyl-5-thia-1-azabicyclo oct-2-ene-2-carboxylic acid, 72-(Z)- trihydrate.
Molecular weight = 507.50 as the trihydrate. Chemical Formula is C16H15N5O7S2.3H2O
The structural formula for cefixime is:
## Pharmacodynamics
There is limited information regarding Cefixime Pharmacodynamics in the drug label.
## Pharmacokinetics
Cefixime chewable tablets are bioequivalent to oral suspension.
Cefixime tablets and suspension, given orally, are about 40% to 50% absorbed whether administered with or without food; however, time to maximal absorption is increased approximately 0.8 hours when administered with food. A single 200 mg tablet of cefixime produces an average peak serum concentration of approximately 2 mcg/mL (range 1 to 4 mcg/mL); a single 400 mg tablet produces an average peak concentration of approximately 3.7 mcg/mL (range 1.3 to 7.7 mcg/mL). The oral suspension produces average peak concentrations approximately 25% to 50% higher than the tablets, when tested in normal adult volunteers. Two hundred and 400 mg doses of oral suspension produce average peak concentrations of 3 mcg/mL (range 1 to 4.5 mcg/mL) and 4.6 mcg/mL (range 1.9 to 7.7 mcg/mL), respectively, when tested in normal adult volunteers. The area under the time versus concentration curve (AUC) is greater by approximately 10% to 25% with the oral suspension than with the tablet after doses of 100 to 400 mg, when tested in normal adult volunteers. This increased absorption should be taken into consideration if the oral suspension is to be substituted for the tablet. Because of the lack of bioequivalence, tablets should not be substituted for oral suspension in the treatment of otitis media. Cross-over studies of tablet versus suspension have not been performed in children.
The 400 mg capsule is bioequivalent to the 400 mg tablet under fasting conditions. However, food reduces the absorption following administration of the capsule by approximately 15% based on AUC and 25% based on Cmax.
Peak serum concentrations occur between 2 and 6 hours following oral administration of a single 200 mg tablet, a single 400 mg tablet or 400 mg of cefixime suspension. Peak serum concentrations occur between 2 and 5 hours following a single administration of 200 mg of suspension. Peak serum concentrations occur between 3 and 8 hours following oral administration of a single 400 mg capsule.
### Distribution
Serum protein binding is concentration independent with a bound fraction of approximately 65%. In a multiple dose study conducted with a research formulation which is less bioavailable than the tablet or suspension, there was little accumulation of drug in serum or urine after dosing for 14 days. Adequate data on CSF levels of cefixime are not available.
### Metabolism and Excretion
There is no evidence of metabolism of cefixime in vivo. Approximately 50% of the absorbed dose is excreted unchanged in the urine in 24 hours. In animal studies, it was noted that cefixime is also excreted in the bile in excess of 10% of the administered dose. The serum half-life of cefixime in healthy subjects is independent of dosage form and averages 3 to 4 hours but may range up to 9 hours in some normal volunteers.
### Special Populations
Average AUCs at steady state in elderly patients are approximately 40% higher than average AUCs in other healthy adults. Differences in the pharmacokinetic parameters between 12 young and 12 elderly subjects who received 400 mg of cefixime once daily for 5 days are summarized as follows:
However, these increases were not clinically significant.
In subjects with moderate impairment of renal function (20 to 40 mL/min creatinine clearance), the average serum half-life of cefixime is prolonged to 6.4 hours. In severe renal impairment (5 to 20 mL/min creatinine clearance), the half-life increased to an average of 11.5 hours. The drug is not cleared significantly from the blood by hemodialysis or peritoneal dialysis. However, a study indicated that with doses of 400 mg, patients undergoing hemodialysis have similar blood profiles as subjects with creatinine clearances of 21 to 60 mL/min.
## Nonclinical Toxicology
Lifetime studies in animals to evaluate carcinogenic potential have not been conducted. Cefixime did not cause point mutations in bacteria or mammalian cells, DNA damage, or chromosome damage in vitro and did not exhibit clastogenic potential in vivo in the mouse micronucleus test.
# Clinical Studies
Comparative clinical trials of otitis media were conducted in nearly 400 children between the ages of 6 months to 10 years. Streptococcus pneumoniae was isolated from 47% of the patients, Haemophilus influenzae from 34%, Moraxella catarrhalis from 15% and S. pyogenes from 4%.
The overall response rate of Streptococcus pneumoniae to cefixime was approximately 10% lower and that of Haemophilus influenzae or Moraxella catarrhalis approximately 7% higher (12% when beta-lactamase positive isolates of H. influenzae are included) than the response rates of these organisms to the active control drugs.
In these studies, patients were randomized and treated with either cefixime at dose regimens of 4 mg/kg twice a day or 8 mg/kg once a day, or with a comparator. Sixty-nine to 70% of the patients in each group had resolution of signs and symptoms of otitis media when evaluated 2 to 4 weeks post-treatment, but persistent effusion was found in 15% of the patients. When evaluated at the completion of therapy, 17% of patients receiving cefixime and 14% of patients receiving effective comparative drugs (18% including those patients who had Haemophilus influenzae resistant to the control drug and who received the control antibiotic) were considered to be treatment failures. By the 2 to 4 week follow-up, a total of 30%-31% of patients had evidence of either treatment failure or recurrent disease.
# How Supplied
- Cefixime Tablets 400 mg
- Bottle of 50 tablets, 27437-201-08
- Bottle of 100 tablets, 27437-201-01
- Cefixime Capsules 400 mg
- Bottle of 50 capsules, 27437-208-08
- 1 blister of 10 capsules, 27437-208-11
- Bottles of 10 tablets, 27437-203-10
- Cefixime Capsules 100 mg
- Bottle of 50 tablets, 27437-203-08
- 1 blister of 10 tablets, 27437-203-11
- Bottles of 10 tablets, 27437-204-10
- Cefixime Chewable Tablets 150 mg
- Bottle of 50 tablets, 27437-204-08
- 1 blister of 10 tablets, 27437-204-11
- Bottles of 10 tablets, 27437-205-10
- Cefixime Chewable Tablets 200 mg
- Bottle of 50 tablets, 27437-205-08
- 1 blister of 10 tablets, 27437-205-11
- Cefixime Chewable Tablets 100 mg/5 mL
- Bottle of 75 mL, 68180-202-02
- Bottle of 100 mL, 68180-202-01
- Bottle of 25 mL, 27437-206-05
- Bottle of 37.5 mL, 27437-206-06
- Cefixime for Oral Suspension 200 mg/5 mL
- Bottle of 50 mL, 27437-206-03
- Bottle of 75 mL, 27437-206-02
- Bottle of 100 mL, 27437-206-01
- Cefixime for Oral Suspension 500 mg/5 mL
- Bottle of 10 mL, 27437-207-02
- Bottle of 20 mL, 27437-207-03
## Storage
Store at 20 to 25°C (68 to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients should be counseled that antibacterial drugs, including cefixime, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefixime is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may:
- decrease the effectiveness of the immediate treatment
- increase the likelihood that bacteria will develop resistance and will not be treatable by cefixime for oral suspension or cefixime chewable tablets or other antibacterial drugs in the future.
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
# Precautions with Alcohol
Alcohol-Cefixime interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Suprax
# Look-Alike Drug Names
There is limited information regarding Cefixime Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Cefixime
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Cefixime is a 3rd generation cephalosporin that is FDA approved for the treatment of uncomplicated urinary tract infections, otitis media, pharyngitis and tonsillitis, acute exacerbations of chronic bronchitis and uncomplicated gonorrhea.. Common adverse reactions include diarrhea, nausea, abdominal pain, dyspepsia and vomiting..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended dose of cefixime is 400 mg daily.
- May be given as a 400 mg tablet or capsule daily or
- 400 mg tablet may be split and given as one half tablet every 12 hours
### Uncomplicated Urinary Tract Infections
- Caused by Escherichia coli and Proteus mirabilis.
### Otitis Media
- Caused by Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pyogenes.
### Pharyngitis and Tonsillitis
- Caused by Streptococcus pyogenes.
- Dosage: A therapeutic dosage of cefixime for at least 10 days
### Acute Exacerbations of Chronic Bronchitis
- Caused by Streptococcus pneumoniae and Haemophilus influenzae.
### Uncomplicated Gonorrhea (cervical/urethral)
- Caused by Neisseria gonorrhoeae.
- Dosage: a single oral dose of 400 mg
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cefixime in adult patients.
### Non–Guideline-Supported Use
- Salmonella infection
- Prophylaxis of sexually transmitted infectious disease for victim of sexual aggression
- Cefixime 400 mg orally in a single dose PLUS metronidazole or azithromycin [1]
- Sinusitis
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Pediatric patients six months of age or older
- The recommended dose is 8 mg/kg/day of the suspension. This may be administered as a single daily dose or may be given in two divided doses, as 4 mg/kg every 12 hours.
- Children weighing more than 45 kg or older than 12 years should be treated with the recommended adult dose. cefixime chewable tablets must be chewed or crushed before swallowing.
### Uncomplicated Urinary Tract Infections
- Caused by Escherichia coli and Proteus mirabilis.
### Otitis Media
- Caused by Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pyogenes
### Pharyngitis and Tonsillitis
- Caused by Streptococcus pyogenes.
- A therapeutic dosage of cefixime for at least 10 days
### Acute Exacerbations of Chronic Bronchitis
- Caused by Streptococcus pneumoniae and Haemophilus influenzae.
### Uncomplicated Gonorrhea (cervical/urethral)
- Caused by Neisseria gonorrhoeae.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cefixime in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cefixime in pediatric patients.
# Contraindications
Cefixime is contraindicated in patients with known allergy to cefixime or other cephalosporins.
# Warnings
### Hypersensitivity Reactions
- Anaphylactic/anaphylactoid reactions (including shock and fatalities) have been reported with the use of cefixime.
- Before therapy with Suprax is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins, or other drugs. If this product is to be given to penicillin-sensitive patients, caution should be exercised because cross hypersensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to Suprax occurs, discontinue the drug.
### Clostridium difficile-Associated Diarrhea
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Suprax, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
- C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
### Dose Adjustment in Renal Impairment
- The dose of cefixime should be adjusted in patients with renal impairment as well as those undergoing continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD). Patients on dialysis should be monitored carefully
### Coagulation Effects
- Cephalosporins may be associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated.
### Development of Drug-Resistant Bacteria
- Prescribing cefixime in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The most commonly seen adverse reactions in U.S. trials of the tablet formulation were gastrointestinal events, which were reported in 30% of adult patients on either the twice daily or the once daily regimen. Five percent (5%) of patients in the U.S. clinical trials discontinued therapy because of drug-related adverse reactions. Individual adverse reactions included diarrhea 16%, loose or frequent stools 6%, abdominal pain 3%, nausea 7%, dyspepsia 3%, and flatulence 4%. The incidence of gastrointestinal adverse reactions, including diarrhea and loose stools, in pediatric patients receiving the suspension was comparable to the incidence seen in adult patients receiving tablets.
## Postmarketing Experience
The following adverse reactions have been reported following the use of cefixime. Incidence rates were less than 1 in 50 (less than 2%).
### Gastrointestinal
- Several cases of documented pseudomembranous colitis were identified in clinical trials. The onset of pseudomembranous colitis symptoms may occur during or after therapy.
### Hypersensitivity Reactions
- Anaphylactic/anaphylactoid reactions (including shock and fatalities), skin rashes, urticaria, drug fever, pruritus, angioedema, and facial edema. Erythema multiforme, Stevens-Johnson syndrome, and serum sickness-like reactions have been reported.
### Hepatic
- Transient elevations in SGPT, SGOT, alkaline phosphatase, hepatitis, jaundice.
### Renal
- Transient elevations in BUN or creatinine, acute renal failure.
### Central Nervous System
- Headaches, dizziness, seizures.
### Hemic and Lymphatic System
- Transient thrombocytopenia, leukopenia, neutropenia, prolongation in prothrombin time, elevated LDH, pancytopenia, agranulocytosis, and eosinophilia.
### Abnormal Laboratory Tests
- Hyperbilirubinemia
### Other Adverse Reactions
- Genital pruritus, vaginitis, candidiasis, toxic epidermal necrolysis.
### Adverse Reactions Reported for Cephalosporin-class Drugs
- Allergic reactions, superinfection, renal dysfunction, toxic nephropathy, hepatic dysfunction including cholestasis, aplastic anemia, hemolytic anemia, hemorrhage, and colitis.
- Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.
# Drug Interactions
### Carbamazepine
- Elevated carbamazepine levels have been reported in postmarketing experience when cefixime is administered concomitantly. Drug monitoring may be of assistance in detecting alterations in carbamazepine plasma concentrations.
### Warfarin and Anticoagulants
- Increased prothrombin time, with or without clinical bleeding, has been reported when cefixime is administered concomitantly.
### Drug/Laboratory Test Interactions
- A false-positive reaction for ketones in the urine may occur with tests using nitroprusside but not with those using nitroferricyanide.
- The administration of cefixime may result in a false-positive reaction for glucose in the urine using Clinitest®**, Benedict's solution, or Fehling's solution. It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Clinistix®** or TesTape®**) be used. A false-positive direct Coombs test has been reported during treatment with other cephalosporins; therefore, it should be recognized that a positive Coombs test may be due to the drug.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and have revealed no evidence of harm to the fetus due to cefixime. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cefixime in women who are pregnant.
### Labor and Delivery
Cefixime has not been studied for use during labor and delivery. Treatment should only be given if clearly needed.
### Nursing Mothers
It is not known whether cefixime is excreted in human milk. Consideration should be given to discontinuing nursing temporarily during treatment with this drug.
### Pediatric Use
Safety and effectiveness of cefixime in children aged less than six months old have not been established. The incidence of gastrointestinal adverse reactions, including diarrhea and loose stools, in the pediatric patients receiving the suspension, was comparable to the incidence seen in adult patients receiving tablets.
### Geriatic Use
Clinical studies did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. A pharmacokinetic study in the elderly detected differences in pharmacokinetic parameters. These differences were small and do not indicate a need for dosage adjustment of the drug in the elderly.
### Gender
There is no FDA guidance on the use of Cefixime with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cefixime with respect to specific racial populations.
### Renal Impairment
The dose of cefixime should be adjusted in patients with renal impairment as well as those undergoing continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD). Patients on dialysis should be monitored carefully.
Cefixime may be administered in the presence of impaired renal function. Normal dose and schedule may be employed in patients with creatinine clearances of 60 mL/min or greater. Refer to Table 2 for dose adjustments for adults with renal impairment. Neither hemodialysis nor peritoneal dialysis removes significant amounts of drug from the body.
### Hepatic Impairment
There is no FDA guidance on the use of Cefixime in patients with hepatic impairment.
### Females of Reproductive Potential and Males
In rats, fertility and reproductive performance were not affected by cefixime at doses up to 25 times the adult therapeutic dose.
### Immunocompromised Patients
There is no FDA guidance one the use of Cefixime in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
Patients on dialysis should be monitored carefully.
# IV Compatibility
There is limited information regarding the compatibility of Cefixime and IV administrations.
# Overdosage
Gastric lavage may be indicated; otherwise, no specific antidote exists. Cefixime is not removed in significant quantities from the circulation by hemodialysis or peritoneal dialysis. Adverse reactions in small numbers of healthy adult volunteers receiving single doses up to 2 g of cefixime did not differ from the profile seen in patients treated at the recommended doses.
# Pharmacology
## Mechanism of Action
Cefixime is a semisynthetic cephalosporin antibacterial drug
## Structure
Chemically, it is (6R,7R)-7-[2-(2-Amino-4-thiazolyl)glyoxylamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, 72-(Z)-[O-(carboxy methyl) oxime] trihydrate.
Molecular weight = 507.50 as the trihydrate. Chemical Formula is C16H15N5O7S2.3H2O
The structural formula for cefixime is:
## Pharmacodynamics
There is limited information regarding Cefixime Pharmacodynamics in the drug label.
## Pharmacokinetics
Cefixime chewable tablets are bioequivalent to oral suspension.
Cefixime tablets and suspension, given orally, are about 40% to 50% absorbed whether administered with or without food; however, time to maximal absorption is increased approximately 0.8 hours when administered with food. A single 200 mg tablet of cefixime produces an average peak serum concentration of approximately 2 mcg/mL (range 1 to 4 mcg/mL); a single 400 mg tablet produces an average peak concentration of approximately 3.7 mcg/mL (range 1.3 to 7.7 mcg/mL). The oral suspension produces average peak concentrations approximately 25% to 50% higher than the tablets, when tested in normal adult volunteers. Two hundred and 400 mg doses of oral suspension produce average peak concentrations of 3 mcg/mL (range 1 to 4.5 mcg/mL) and 4.6 mcg/mL (range 1.9 to 7.7 mcg/mL), respectively, when tested in normal adult volunteers. The area under the time versus concentration curve (AUC) is greater by approximately 10% to 25% with the oral suspension than with the tablet after doses of 100 to 400 mg, when tested in normal adult volunteers. This increased absorption should be taken into consideration if the oral suspension is to be substituted for the tablet. Because of the lack of bioequivalence, tablets should not be substituted for oral suspension in the treatment of otitis media. Cross-over studies of tablet versus suspension have not been performed in children.
The 400 mg capsule is bioequivalent to the 400 mg tablet under fasting conditions. However, food reduces the absorption following administration of the capsule by approximately 15% based on AUC and 25% based on Cmax.
Peak serum concentrations occur between 2 and 6 hours following oral administration of a single 200 mg tablet, a single 400 mg tablet or 400 mg of cefixime suspension. Peak serum concentrations occur between 2 and 5 hours following a single administration of 200 mg of suspension. Peak serum concentrations occur between 3 and 8 hours following oral administration of a single 400 mg capsule.
### Distribution
Serum protein binding is concentration independent with a bound fraction of approximately 65%. In a multiple dose study conducted with a research formulation which is less bioavailable than the tablet or suspension, there was little accumulation of drug in serum or urine after dosing for 14 days. Adequate data on CSF levels of cefixime are not available.
### Metabolism and Excretion
There is no evidence of metabolism of cefixime in vivo. Approximately 50% of the absorbed dose is excreted unchanged in the urine in 24 hours. In animal studies, it was noted that cefixime is also excreted in the bile in excess of 10% of the administered dose. The serum half-life of cefixime in healthy subjects is independent of dosage form and averages 3 to 4 hours but may range up to 9 hours in some normal volunteers.
### Special Populations
Average AUCs at steady state in elderly patients are approximately 40% higher than average AUCs in other healthy adults. Differences in the pharmacokinetic parameters between 12 young and 12 elderly subjects who received 400 mg of cefixime once daily for 5 days are summarized as follows:
However, these increases were not clinically significant.
In subjects with moderate impairment of renal function (20 to 40 mL/min creatinine clearance), the average serum half-life of cefixime is prolonged to 6.4 hours. In severe renal impairment (5 to 20 mL/min creatinine clearance), the half-life increased to an average of 11.5 hours. The drug is not cleared significantly from the blood by hemodialysis or peritoneal dialysis. However, a study indicated that with doses of 400 mg, patients undergoing hemodialysis have similar blood profiles as subjects with creatinine clearances of 21 to 60 mL/min.
## Nonclinical Toxicology
Lifetime studies in animals to evaluate carcinogenic potential have not been conducted. Cefixime did not cause point mutations in bacteria or mammalian cells, DNA damage, or chromosome damage in vitro and did not exhibit clastogenic potential in vivo in the mouse micronucleus test.
# Clinical Studies
Comparative clinical trials of otitis media were conducted in nearly 400 children between the ages of 6 months to 10 years. Streptococcus pneumoniae was isolated from 47% of the patients, Haemophilus influenzae from 34%, Moraxella catarrhalis from 15% and S. pyogenes from 4%.
The overall response rate of Streptococcus pneumoniae to cefixime was approximately 10% lower and that of Haemophilus influenzae or Moraxella catarrhalis approximately 7% higher (12% when beta-lactamase positive isolates of H. influenzae are included) than the response rates of these organisms to the active control drugs.
In these studies, patients were randomized and treated with either cefixime at dose regimens of 4 mg/kg twice a day or 8 mg/kg once a day, or with a comparator. Sixty-nine to 70% of the patients in each group had resolution of signs and symptoms of otitis media when evaluated 2 to 4 weeks post-treatment, but persistent effusion was found in 15% of the patients. When evaluated at the completion of therapy, 17% of patients receiving cefixime and 14% of patients receiving effective comparative drugs (18% including those patients who had Haemophilus influenzae resistant to the control drug and who received the control antibiotic) were considered to be treatment failures. By the 2 to 4 week follow-up, a total of 30%-31% of patients had evidence of either treatment failure or recurrent disease.
# How Supplied
- Cefixime Tablets 400 mg
- Bottle of 50 tablets, 27437-201-08
- Bottle of 100 tablets, 27437-201-01
- Cefixime Capsules 400 mg
- Bottle of 50 capsules, 27437-208-08
- 1 blister of 10 capsules, 27437-208-11
- Bottles of 10 tablets, 27437-203-10
- Cefixime Capsules 100 mg
- Bottle of 50 tablets, 27437-203-08
- 1 blister of 10 tablets, 27437-203-11
- Bottles of 10 tablets, 27437-204-10
- Cefixime Chewable Tablets 150 mg
- Bottle of 50 tablets, 27437-204-08
- 1 blister of 10 tablets, 27437-204-11
- Bottles of 10 tablets, 27437-205-10
- Cefixime Chewable Tablets 200 mg
- Bottle of 50 tablets, 27437-205-08
- 1 blister of 10 tablets, 27437-205-11
- Cefixime Chewable Tablets 100 mg/5 mL
- Bottle of 75 mL, 68180-202-02
- Bottle of 100 mL, 68180-202-01
- Bottle of 25 mL, 27437-206-05
- Bottle of 37.5 mL, 27437-206-06
- Cefixime for Oral Suspension 200 mg/5 mL
- Bottle of 50 mL, 27437-206-03
- Bottle of 75 mL, 27437-206-02
- Bottle of 100 mL, 27437-206-01
- Cefixime for Oral Suspension 500 mg/5 mL
- Bottle of 10 mL, 27437-207-02
- Bottle of 20 mL, 27437-207-03
## Storage
Store at 20 to 25°C (68 to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients should be counseled that antibacterial drugs, including cefixime, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefixime is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may:
- decrease the effectiveness of the immediate treatment
- increase the likelihood that bacteria will develop resistance and will not be treatable by cefixime for oral suspension or cefixime chewable tablets or other antibacterial drugs in the future.
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
# Precautions with Alcohol
Alcohol-Cefixime interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Suprax [2]
# Look-Alike Drug Names
There is limited information regarding Cefixime Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cefixime | |
4c2798f62f34e1f29b81417be530bb14281e800a | wikidoc | Cefotiam | Cefotiam
# Overview
Cefotiam is a parenteral second-generation cephalosporin antibiotic. It has broad-spectrum activity against Gram-positive and Gram-negative bacteria. As a beta-lactam, its bactericidal activity results from the inhibition of cell wall synthesis via affinity for penicillin-binding proteins.
Cefotiam was launched as Pansporin in February 1981 by Takeda Pharmaceutical of Japan and has been available as a generic since February 1993.
# Mechanism of action
Cefotiam inhibits final cross-linking stage of peptidoglycan production, thus inhibiting bacterial cell wall synthesis. It has similar or less activity against Gram-positive staphylococci and streptococci, but is resistant to some beta-lactamases produced by Gram-negative bacteria. It is more active against many of the Enterobacteriaceae including Enterobacter, E. coli, Klebsiella, Salmonella and indole-positive Proteus species.
In clinical use, high concentrations of cefotiam are observed in several tissues (kidney, heart, ear, prostate, and genital tract), as well as in fluids and secretions (bile, ascitic fluid).
# Spectrum of bacterial susceptibility
Cefotiam has a broad spectrum of activity and has been used to treat infections caused by a number of enteric bacteria and bacteria responsible for causing skin infections. The following represents MIC susceptibility data for a few medically significant bacteria.
- Bacteroides fragilis: - 16 - >128 μg/ml
- Clostridium difficile: >128 μg/ml
- Staphylococcus aureus: 0.25 - 32 μg/ml
# Indications
This drug is indicated for prophylaxis for surgical infection, postoperative infections, bacterial septicaemia, bone and joint infections, cholangitis, cholecystitis, peritonitis, prostatitis, pyelonephritis, respiratory tract infections, skin and soft tissue infections, cystitis, urethritis, and infections caused by susceptible organisms. It does not have activity against Pseudomonas aeruginosa.
# Dosage
For adults, the dose is up to 6 grams daily by intravenous or intramuscular route in divided doses according to severity of infection. In patients with renal impairment a dose reduction may be needed.
# Adverse effects
Side effects include nausea and vomiting, diarrhoea, hypersensitivity reactions, nephrotoxicity, convulsions, CNS toxicity, hepatic dysfunction, haematologic disorders, pain at injection site, thrombophloebitis, pseudomembranous colitis, and superinfection with prolonged use. | Cefotiam
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Cefotiam is a parenteral second-generation cephalosporin antibiotic. It has broad-spectrum activity against Gram-positive and Gram-negative bacteria. As a beta-lactam, its bactericidal activity results from the inhibition of cell wall synthesis via affinity for penicillin-binding proteins.
Cefotiam was launched as Pansporin in February 1981 by Takeda Pharmaceutical of Japan and has been available as a generic since February 1993.
# Mechanism of action
Cefotiam inhibits final cross-linking stage of peptidoglycan production, thus inhibiting bacterial cell wall synthesis. It has similar or less activity against Gram-positive staphylococci and streptococci, but is resistant to some beta-lactamases produced by Gram-negative bacteria. It is more active against many of the Enterobacteriaceae including Enterobacter, E. coli, Klebsiella, Salmonella and indole-positive Proteus species.
In clinical use, high concentrations of cefotiam are observed in several tissues (kidney, heart, ear, prostate, and genital tract), as well as in fluids and secretions (bile, ascitic fluid).
# Spectrum of bacterial susceptibility
Cefotiam has a broad spectrum of activity and has been used to treat infections caused by a number of enteric bacteria and bacteria responsible for causing skin infections. The following represents MIC susceptibility data for a few medically significant bacteria.
- Bacteroides fragilis: - 16 - >128 μg/ml
- Clostridium difficile: >128 μg/ml
- Staphylococcus aureus: 0.25 - 32 μg/ml
[1]
# Indications
This drug is indicated for prophylaxis for surgical infection, postoperative infections, bacterial septicaemia, bone and joint infections, cholangitis, cholecystitis, peritonitis, prostatitis, pyelonephritis, respiratory tract infections, skin and soft tissue infections, cystitis, urethritis, and infections caused by susceptible organisms. It does not have activity against Pseudomonas aeruginosa.
# Dosage
For adults, the dose is up to 6 grams daily by intravenous or intramuscular route in divided doses according to severity of infection. In patients with renal impairment a dose reduction may be needed.
# Adverse effects
Side effects include nausea and vomiting, diarrhoea, hypersensitivity reactions, nephrotoxicity, convulsions, CNS toxicity, hepatic dysfunction, haematologic disorders, pain at injection site, thrombophloebitis, pseudomembranous colitis, and superinfection with prolonged use.
# External links
- Müller R, Böttger C, Wichmann G (2003). "Suitability of cefotiam and cefuroxime axetil for the perioperative short-term prophylaxis in tonsillectomy patients". Arzneimittelforschung. 53 (2): 126–32. doi:10.1055/s-0031-1297083. PMID 12642969.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Kolben M, Mandoki E, Ulm K, Freitag K (2001). "Randomized trial of cefotiam prophylaxis in the prevention of postoperative infectious morbidity after elective cesarean section". Eur J Clin Microbiol Infect Dis. 20 (1): 40–2. doi:10.1007/s100960000365. PMID 11245321.CS1 maint: Multiple names: authors list (link)
- Shimizu S, Chen K, Miyakawa S (1996). "Cefotiam-induced contact urticaria syndrome: an occupational condition in Japanese nurses". Dermatology. 192 (2): 174–6. doi:10.1159/000246352. PMID 8829507.CS1 maint: Multiple names: authors list (link) | https://www.wikidoc.org/index.php/Cefotiam | |
7f83c3ba101e3ec183235b0b7b9ab71aa1a341f9 | wikidoc | Celacade | Celacade
Celacade is a non-pharmacological treatment also known as Immune Modulation Therapy (IMT), developed by the Canadian based biotherapeutics company Vasogen, for treatment of chronic heart failure and peripheral artery disease.
At the World Congress of Cardiology in September 2006 the Advanced Chronic Heart Failure Clinical Assessment of Immune Modulation Therapy (ACCLAIM) a phase III randomized, double-blind, placebo-controlled clinical trial involving some 2408 patients in 7 countries with left ventricular ejection fraction of 30% or less, reported that patients with a previous cardiovascular event receiving celacade where 39% less likely to die or be hospitalized due to a heart attack or stroke and tended to have improved quality of life.
Celacade is believed to inhibit inflammation, platelet aggregation and progression of arterial lesions by a mechanism independent of cholesterol lowering.
Celcade is a device-based outpatient procedure involving ex vivo exposure of 10ml autologous blood to heat, ultraviolet irradiation, controlled oxidative ozone therapy and subsequent intramuscular administration at monthly intervals.
The results of ACCLAIM support the hypothesis that immune dysfunction plays a role in the pathogenesis of atherosclerosis and Immune Modulation therapy has a broad-spectrum positive effect on a number of immune mediators, including regulation and enhancement of cytokines and the vascular dilator nitric oxide. These cell signaling molecules regulate inflammation and facilitate the healing process.
Vasogen in collaboration with Grupo Ferrer Internacional has regulatory approval to market Celacade as a medical device for the treatment of chronic heart failure in the European Union and Latin America.
In the United States the FDA has recommended that Vasogen conduct a further confirmatory study to support a pre-market approval filing. | Celacade
Celacade is a non-pharmacological treatment also known as Immune Modulation Therapy (IMT), developed by the Canadian based biotherapeutics company Vasogen, for treatment of chronic heart failure and peripheral artery disease. [1][2]
At the World Congress of Cardiology in September 2006 the Advanced Chronic Heart Failure Clinical Assessment of Immune Modulation Therapy (ACCLAIM) a phase III randomized, double-blind, placebo-controlled clinical trial involving some 2408 patients in 7 countries with left ventricular ejection fraction of 30% or less, reported that patients with a previous cardiovascular event receiving celacade where 39% less likely to die or be hospitalized due to a heart attack or stroke and tended to have improved quality of life. [3]
Celacade is believed to inhibit inflammation, platelet aggregation and progression of arterial lesions by a mechanism independent of cholesterol lowering. [4]
Celcade is a device-based outpatient procedure involving ex vivo exposure of 10ml autologous blood to heat, ultraviolet irradiation, controlled oxidative ozone therapy and subsequent intramuscular administration at monthly intervals. [5]
The results of ACCLAIM support the hypothesis that immune dysfunction plays a role in the pathogenesis of atherosclerosis [6] and Immune Modulation therapy has a broad-spectrum positive effect on a number of immune mediators, including regulation and enhancement of cytokines and the vascular dilator nitric oxide. These cell signaling molecules regulate inflammation and facilitate the healing process. [7][8][9][10]
Vasogen in collaboration with Grupo Ferrer Internacional has regulatory approval to market Celacade as a medical device for the treatment of chronic heart failure in the European Union and Latin America.[11]
In the United States the FDA has recommended that Vasogen conduct a further confirmatory study to support a pre-market approval filing. [12] | https://www.wikidoc.org/index.php/Celacade | |
13f692d631805e732e52f3ee017680ece19c280c | wikidoc | Motility | Motility
Motility is a biological term which refers to the ability to move spontaneously and independently. It can apply to either single-celled or multicellular organisms.
In cellular biology or biomedical engineering, motility often refers to directed cell movement down gradients established in biopolymers. Examples are:
- movement along a chemical gradient (see chemotaxis)
- movement along a rigidity gradient (see durotaxis)
- movement along a gradient of cell adhesion sites (see haptotaxis)
de:Motilität
ms:Motiliti
simple:Motile | Motility
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Motility is a biological term which refers to the ability to move spontaneously and independently. It can apply to either single-celled or multicellular organisms.
In cellular biology or biomedical engineering, motility often refers to directed cell movement down gradients established in biopolymers. Examples are:
- movement along a chemical gradient (see chemotaxis)
- movement along a rigidity gradient (see durotaxis)
- movement along a gradient of cell adhesion sites (see haptotaxis)
de:Motilität
ms:Motiliti
simple:Motile
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Cell_motility | |
cf849468bef8ece9aa826c171c5b9199b4ec06fb | wikidoc | Cementum | Cementum
# Overview
Cementum is a specialized calcified substance covering the root of a tooth. Cementum is excreted by cells called cementoblasts within the root of the tooth and is thickest at the root apex. Its coloration is yellowish and it is softer than enamel and dentin due to being less mineralized.
The principle role of cementen within the tooth is to serve as a medium by which the periodontal ligaments can attach to the tooth for stability. Hence, its bottom surface is tangent to the periodontal ligaments running through the jaw (via collagen fibers), and the upper portion of the surface is firmly cemented to the dentin of the tooth. It also meets the enamel lower on the tooth at the cemento-enamel junction. Here the cementum is known as acellular cementum due to its lack of cellular components, and covers approximately 1/3-1/2 of the root. The more permeable form of cementen, cellular cementum, covers 1/3-1/2 of the root apex, where it binds to the dentin. There is also a third type of cementum, afibrillar cementum, which sometimes extends onto the enamel of the tooth.
The chemical makeup of cementum is similar to that of bone, but it lacks vascularization. Volumetrically, it is approximately 65% inorganic material (mainly hydroxyapatite), 23% organic material (mainly collagen type1]) and 12% water. | Cementum
# Overview
Cementum is a specialized calcified substance covering the root of a tooth. Cementum is excreted by cells called cementoblasts within the root of the tooth and is thickest at the root apex. Its coloration is yellowish and it is softer than enamel and dentin due to being less mineralized.
The principle role of cementen within the tooth is to serve as a medium by which the periodontal ligaments can attach to the tooth for stability. Hence, its bottom surface is tangent to the periodontal ligaments running through the jaw (via collagen fibers), and the upper portion of the surface is firmly cemented to the dentin of the tooth. It also meets the enamel lower on the tooth at the cemento-enamel junction. Here the cementum is known as acellular cementum due to its lack of cellular components, and covers approximately 1/3-1/2 of the root. The more permeable form of cementen, cellular cementum, covers 1/3-1/2 of the root apex, where it binds to the dentin. There is also a third type of cementum, afibrillar cementum, which sometimes extends onto the enamel of the tooth.
The chemical makeup of cementum is similar to that of bone, but it lacks vascularization. Volumetrically, it is approximately 65% inorganic material (mainly hydroxyapatite), 23% organic material (mainly collagen type1]) and 12% water. | https://www.wikidoc.org/index.php/Cement | |
c45626f3b94780b0bfe7b75fcdd6c05e9890e680 | wikidoc | Cenozoic | Cenozoic
The Cenozoic (also Cænozoic or Cainozoic) Era (Template:PronEng) (meaning "new life" (Greek Template:Polytonic (kainos), "new", and Template:Polytonic (zoe), "life"), is the most recent of the geologic eras and covers the period from 65.5 million years ago to the present. It is marked by the Cretaceous–Tertiary extinction event at the end of the Cretaceous that saw the demise of the last non-avian dinosaurs and the end of the Mesozoic Era. The Cenozoic era is ongoing.
# Subdivision
The Cenozoic Era is divided into two periods, the Paleogene and Neogene, and they are in turn divided into epochs. The Paleogene consists of the Paleocene, Eocene, and Oligocene epochs, and the Neogene consists of the Miocene, Pliocene, Pleistocene, and Holocene epochs, the last of which is ongoing. Historically, the Cenozoic has been divided into periods (or sub-eras) named the Tertiary (Paleocene through Pliocene) and Quaternary (Pleistocene and Holocene). It is known as the age of mammals.
# Tectonics
Geologically, the Cenozoic is the era when the continents finished forming into their current topographic configuration.
## Australia
Australia-New Guinea split from Gondwana and drifted north and, eventually, adjacent to South-east Asia
## Antarctica
Antarctica moved into its current position over the South Pole.
## Atlantic Ocean
The Atlantic Ocean widened.
## South America
During the Cenozoic South America moved northward toward North America and became attached due to the closure between their plates. From 50 to 25 Ma oceanic plate subduction progressively decreased accompanied by an eastward shift in the loci of magmatic activity in the Andes. At 25 Ma a major reorganization of plate motions to the Chilean Andes was accompanied by subsequent broadening of the locus of magmatic activity into adjacent Bolivia and Argentina.
## India
India collided with Asia between 55 and 45 million years ago. This collision set up a series of reactions of tectonic development in Southeast Asia involving the South China Sea, Burma and Thailand, the Malay peninsula to Sumatra.
## Arabia
The Arabia–Eurasia collision and the closure of the Tethys ocean gateway began in the Late Eocene at ~ 35 Ma, apparently ending the Eocene greenhouse world.
# Climate
The Cenozoic Era has been a period of long-term cooling. After the tectonic creation of Drake Passage, when Australia fully detached from Antarctica during the Oligocene, the climate cooled significantly due to the advent of the Antarctic Circumpolar Current which brought cool deep Antarctic water to the surface. Warm conditions returned in the Miocene due to uncovered gas hydrates releasing carbon dioxide.ref? When South America became attached to North America creating the Isthmus of Panama, the Arctic region cooled due to the strengthening of the Humboldt and Gulf Stream currentsref? , eventually leading to the Glacial Maximum or the last ice age.
# Life
The Cenozoic Era is the age of new life. During the Cenozoic, mammals diverged from a few small, simple, generalized forms into a diverse collection of terrestrial, marine, and flying animals, giving this period its other name, the Age of Mammals, despite the fact that birds still outnumbered mammals two to one. The Cenozoic is just as much the age of savannas, the age of co-dependent flowering plants and insects, or the age of birds. Grass also played a very important role in this epoch, shaping the evolution of the birds and mammals that fed on it. One group that diversified significantly in the Cenozoic as well were the snakes. Evolving in the Cenozic, the snakes evolved into a huge amount of forms, especially colubrids, following the evolution of their current prey source, the rodents.
In the earlier part of the Cenozoic, the world was dominated by the gastornid birds, terrestrial crocodiles like Pristichampsus, and a handful of primitive large mammal groups like uintatheres, mesonychids, and pantodonts. But as the forests began to recede and the climate began to cool, other mammals took over. The cenozoic is full of mammals both strange and familiar, including chalicotheres, oreodonts, whales, primates, entelodonts, saber-toothed cats, mastodons and mammoths, three-toed horses, giant rhinoceross like Indricotherium, and brontotheres. | Cenozoic
The Cenozoic (also Cænozoic or Cainozoic) Era (Template:PronEng) (meaning "new life" (Greek Template:Polytonic (kainos), "new", and Template:Polytonic (zoe), "life"), is the most recent of the geologic eras and covers the period from 65.5 million years ago to the present. It is marked by the Cretaceous–Tertiary extinction event at the end of the Cretaceous that saw the demise of the last non-avian dinosaurs and the end of the Mesozoic Era. The Cenozoic era is ongoing.
# Subdivision
The Cenozoic Era is divided into two periods, the Paleogene and Neogene, and they are in turn divided into epochs. The Paleogene consists of the Paleocene, Eocene, and Oligocene epochs, and the Neogene consists of the Miocene, Pliocene, Pleistocene, and Holocene epochs, the last of which is ongoing. Historically, the Cenozoic has been divided into periods (or sub-eras) named the Tertiary (Paleocene through Pliocene) and Quaternary (Pleistocene and Holocene). It is known as the age of mammals.
# Tectonics
Geologically, the Cenozoic is the era when the continents finished forming into their current topographic configuration.[1]
## Australia
Australia-New Guinea split from Gondwana and drifted north and, eventually, adjacent to South-east Asia
## Antarctica
Antarctica moved into its current position over the South Pole.
## Atlantic Ocean
The Atlantic Ocean widened.
## South America
During the Cenozoic South America moved northward toward North America and became attached due to the closure between their plates.[2] From 50 to 25 Ma oceanic plate subduction progressively decreased accompanied by an eastward shift in the loci of magmatic activity in the Andes.[3] At 25 Ma a major reorganization of plate motions to the Chilean Andes was accompanied by subsequent broadening of the locus of magmatic activity into adjacent Bolivia and Argentina.[3]
## India
India collided with Asia between 55 and 45 million years ago.[4] This collision set up a series of reactions of tectonic development in Southeast Asia involving the South China Sea, Burma and Thailand, the Malay peninsula to Sumatra.[5]
## Arabia
The Arabia–Eurasia collision and the closure of the Tethys ocean gateway began in the Late Eocene at ~ 35 Ma, apparently ending the Eocene greenhouse world.[6]
# Climate
The Cenozoic Era has been a period of long-term cooling. After the tectonic creation of Drake Passage, when Australia fully detached from Antarctica during the Oligocene, the climate cooled significantly due to the advent of the Antarctic Circumpolar Current which brought cool deep Antarctic water to the surface. Warm conditions returned in the Miocene due to uncovered gas hydrates releasing carbon dioxide.ref? When South America became attached to North America creating the Isthmus of Panama, the Arctic region cooled due to the strengthening of the Humboldt and Gulf Stream currentsref? , eventually leading to the Glacial Maximum or the last ice age.
# Life
The Cenozoic Era is the age of new life. During the Cenozoic, mammals diverged from a few small, simple, generalized forms into a diverse collection of terrestrial, marine, and flying animals, giving this period its other name, the Age of Mammals, despite the fact that birds still outnumbered mammals two to one. The Cenozoic is just as much the age of savannas, the age of co-dependent flowering plants and insects, or the age of birds. Grass also played a very important role in this epoch, shaping the evolution of the birds and mammals that fed on it. One group that diversified significantly in the Cenozoic as well were the snakes. Evolving in the Cenozic, the snakes evolved into a huge amount of forms, especially colubrids, following the evolution of their current prey source, the rodents.
In the earlier part of the Cenozoic, the world was dominated by the gastornid birds, terrestrial crocodiles like Pristichampsus, and a handful of primitive large mammal groups like uintatheres, mesonychids, and pantodonts. But as the forests began to recede and the climate began to cool, other mammals took over. The cenozoic is full of mammals both strange and familiar, including chalicotheres, oreodonts, whales, primates, entelodonts, saber-toothed cats, mastodons and mammoths, three-toed horses, giant rhinoceross like Indricotherium, and brontotheres.
Template:Wikisource1911Enc | https://www.wikidoc.org/index.php/Cenozoic | |
21cb70c3e62913c2ff22ddc2755ab9133430884c | wikidoc | Cercozoa | Cercozoa
The Cercozoa are a group of protists, including most amoeboids and flagellates that feed by means of filose pseudopods. These may be restricted to part of the cell surface, but there is never a true cytostome or mouth as found in many other protozoa. They show a variety of forms and have proven difficult to define in terms of structural characteristics, although their unity is strongly supported by genetic studies. Cercozoa are closely related to Foraminifera and Radiolaria, amoeboids that usually have complex shells, and together with them form a supergroup called the Rhizaria.
The best-known Cercozoa are the euglyphids, filose amoebae with shells of siliceous scales or plates, which are commonly found in soils, nutrient-rich waters, and on aquatic plants. Some other filose amoebae produce organic shells, including the tectofilosids and Gromia. They were formerly classified with the euglyphids as the Testaceafilosia. This group is not monophyletic, but nearly all studied members fall in or near the Cercozoa, related to similarly shelled flagellates.
Another important group placed here are the chlorarachniophytes, strange amoebae that form a reticulating net. They are set apart by the presence of chloroplasts, which apparently developed from an ingested green alga. They are bound by four membranes and still possess a vestigial nucleus, called a nucleomorph. As such, they have been of great interest to researchers studying the endosymbiotic origins of organelles.
Other notable cercozoans include the cercomonads, which are common soil flagellates, and the Phaeodarea, marine protozoa that were previously considered radiolarians. In addition, three groups that are traditionally considered heliozoans belong here: the dimorphids, desmothoracids, and gymnosphaerids. The exact composition and classification of the Cercozoa are still being worked out. A general scheme is:
In addition two groups of parasites, the Phytomyxea and Ascetosporea, and the shelled amoeba Gromia may be basal Cercozoa, although some trees place them closer to the Foraminifera. The spongomonads have been included here, but more recently have been considered Amoebozoa. Some other small groups of protozoans are considered Cercozoa but are of uncertain placement, and it is likely many obscure genera will turn out to be cercozoans with further study. | Cercozoa
The Cercozoa are a group of protists, including most amoeboids and flagellates that feed by means of filose pseudopods. These may be restricted to part of the cell surface, but there is never a true cytostome or mouth as found in many other protozoa. They show a variety of forms and have proven difficult to define in terms of structural characteristics, although their unity is strongly supported by genetic studies. Cercozoa are closely related to Foraminifera and Radiolaria, amoeboids that usually have complex shells, and together with them form a supergroup called the Rhizaria.
The best-known Cercozoa are the euglyphids, filose amoebae with shells of siliceous scales or plates, which are commonly found in soils, nutrient-rich waters, and on aquatic plants. Some other filose amoebae produce organic shells, including the tectofilosids and Gromia. They were formerly classified with the euglyphids as the Testaceafilosia. This group is not monophyletic, but nearly all studied members fall in or near the Cercozoa, related to similarly shelled flagellates.
Another important group placed here are the chlorarachniophytes, strange amoebae that form a reticulating net. They are set apart by the presence of chloroplasts, which apparently developed from an ingested green alga. They are bound by four membranes and still possess a vestigial nucleus, called a nucleomorph. As such, they have been of great interest to researchers studying the endosymbiotic origins of organelles.
Other notable cercozoans include the cercomonads, which are common soil flagellates, and the Phaeodarea, marine protozoa that were previously considered radiolarians. In addition, three groups that are traditionally considered heliozoans belong here: the dimorphids, desmothoracids, and gymnosphaerids. The exact composition and classification of the Cercozoa are still being worked out. A general scheme is:
In addition two groups of parasites, the Phytomyxea and Ascetosporea, and the shelled amoeba Gromia may be basal Cercozoa, although some trees place them closer to the Foraminifera. The spongomonads have been included here, but more recently have been considered Amoebozoa. Some other small groups of protozoans are considered Cercozoa but are of uncertain placement, and it is likely many obscure genera will turn out to be cercozoans with further study. | https://www.wikidoc.org/index.php/Cercozoa | |
b3e3a04f7b0afcdfff130ac77b8b007be7502c77 | wikidoc | Cereblon | Cereblon
Cereblon is a protein that in humans is encoded by the CRBN gene. The gene that encodes the cereblon protein is found on the human chromosome 3, on the short arm at position p26.3 from base pair 3,190,676 to base pair 3,221,394. CRBN orthologs are highly conserved from plants to humans.
# Clinical significance
## Birth defects
It was believed that the drug thalidomide binds and inactivates cereblon, which leads to an antiproliferative effect on myeloma cells and a teratogenic effect on fetal development. Thalidomide was used as a treatment for morning sickness from 1957 until 1961 but was withdrawn from the market after it was discovered that it caused birth defects. It is estimated that 10,000 to 20,000 children were affected. However, the finding that cereblon inhibition is responsible for the teratogenic activity of thalidomide in the chick and zebrafish was cast into doubt due to a 2013 report that pomalidomide (a more potent thalidomide analog) does not cause teratogenic effects in these same model systems even though it is a stronger cereblon inhibitor than thalidomide is.
## Intellectual disability
Mutations in the CRBN gene are associated with autosomal recessive nonsyndromic intellectual disability, possibly as a result of dysregulation of calcium-activated potassium channels in the brain (see below) during development.
# Function
## Ubiquitinization and role in development
Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). This complex ubiquitinates a number of other proteins. Through a mechanism which has not been completely elucidated, this ubiquitination results in reduced levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 in turn regulates a number of developmental processes, such as limb and auditory vesicle formation. The net result is that this ubiquitin ligase complex is important for limb outgrowth in embryos.
In the absence of cereblon, DDB1 forms a complex with DDB2 that functions as a DNA damage-binding protein. Furthermore, cereblon and DDB2 bind to DDB1 in a competitive manner.
## Regulation of potassium channels
Cereblon binds to the large-conductance calcium-activated potassium channel (KCNMA1) and regulates its activity. Moreover, mice lacking this channel develop neurological disorders. | Cereblon
Cereblon is a protein that in humans is encoded by the CRBN gene.[1] The gene that encodes the cereblon protein is found on the human chromosome 3, on the short arm at position p26.3 from base pair 3,190,676 to base pair 3,221,394. CRBN orthologs are highly conserved from plants to humans.[1]
# Clinical significance
## Birth defects
It was believed that the drug thalidomide binds and inactivates cereblon, which leads to an antiproliferative effect on myeloma cells and a teratogenic effect on fetal development.[2][3][4][5] Thalidomide was used as a treatment for morning sickness from 1957 until 1961 but was withdrawn from the market after it was discovered that it caused birth defects.[6] It is estimated that 10,000 to 20,000 children were affected.[7] However, the finding that cereblon inhibition is responsible for the teratogenic activity of thalidomide in the chick and zebrafish was cast into doubt due to a 2013 report that pomalidomide (a more potent thalidomide analog) does not cause teratogenic effects in these same model systems even though it is a stronger cereblon inhibitor than thalidomide is.[8][9]
## Intellectual disability
Mutations in the CRBN gene are associated with autosomal recessive nonsyndromic intellectual disability,[1] possibly as a result of dysregulation of calcium-activated potassium channels in the brain (see below) during development.[2]
# Function
## Ubiquitinization and role in development
Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1).[10] This complex ubiquitinates a number of other proteins. Through a mechanism which has not been completely elucidated, this ubiquitination results in reduced levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 in turn regulates a number of developmental processes, such as limb and auditory vesicle formation. The net result is that this ubiquitin ligase complex is important for limb outgrowth in embryos.[2]
In the absence of cereblon, DDB1 forms a complex with DDB2 that functions as a DNA damage-binding protein. Furthermore, cereblon and DDB2 bind to DDB1 in a competitive manner.[2]
## Regulation of potassium channels
Cereblon binds to the large-conductance calcium-activated potassium channel (KCNMA1) and regulates its activity.[11][12] Moreover, mice lacking this channel develop neurological disorders.[13] | https://www.wikidoc.org/index.php/Cereblon | |
35d4253780bef4a97a4eb8cca29e6471927fbe60 | wikidoc | Meninges | Meninges
# Overview
The meninges (singular meninx) is the system of membranes which envelop the central nervous system. The meninges consist of three layers: the dura mater, the arachnoid mater, and the pia mater. The primary function of the meninges and of the cerebrospinal fluid is to protect the central nervous system.
# Anatomy
## Pia mater
The pia or pia mater is a very delicate membrane. It is attached to (nearest) the brain or the spinal cord. As such it follows all the minor contours of the brain (gyri and sulci). The pia mater is the meningeal envelope which firmly adheres to the surface of the brain and spinal cord. It is a very thin membrane composed of fibrous tissue covered on its outer surface by a sheet of flat cells thought to be impermeable to fluid. The pia mater is pierced by blood vessels which travel to the brain and spinal cord, and its capillaries are responsible for nourishing the brain.
## Arachnoid mater
The middle element of the meninges is the arachnoid mater, so named because of its spider web-like appearance. It provides a cushioning effect for the central nervous system. The arachnoid mater exists as a thin, transparent membrane. It is composed of fibrous tissue and, like the pia mater, is covered by flat cells also thought to be impermeable to fluid. The arachnoid does not follow the convolutions of the surface of the brain and so looks like a loosely fitting sac. In the region of the brain, particularly, a large number of fine filaments called arachnoid trabeculae pass from the arachnoid through the subarachnoid space to blend with the tissue of the pia mater.
The arachnoid and pia mater are sometimes together called the leptomeninges.
## Dura mater
The dura mater (also rarely called meninx fibrosa, or pachymeninx) is a thick, durable membrane, closest to the skull. It contains larger blood vessels which split into the capilliaries in the pia mater. It is composed of dense fibrous tissue, and its inner surface is covered by flattened cells like those present on the surfaces of the pia mater and arachnoid. The dura mater is a sac which envelops the arachnoid and has been modified to serve several functions. The dura mater surrounds and supports the large venous channels (dural sinuses) carrying blood from the brain toward the heart.
## Spaces
The subarachnoid space is the space which normally exists between the arachnoid and the pia mater, which is filled with cerebrospinal fluid.
Normally, the dura mater is attached to the skull in the head, or to the bones of the vertebral canal in the spinal cord. The arachnoid is attached to the dura mater, and the pia mater is attached to the central nervous system tissue. When the dura mater and the arachnoid separate through injury or illness, the space between them is the subdural space.
# Pathology
There are three types of hemorrhage involving the meninges:
- A subarachnoid hemorrhage is acute bleeding under the arachnoid; it may occur spontaneously or as a result of trauma.
- A subdural hematoma is a hematoma (collection of blood) located in a separation of the arachnoid from the dura mater. The small veins which connect the dura mater and the arachnoid are torn, usually during an accident, and blood can leak into this area.
- An epidural hematoma similarly may arise after an accident or spontaneously.
Other medical conditions which affect the meninges include meningitis (usually from fungal, bacterial, or viral infection) and meningiomas arising from the meninges or from tumors formed elsewhere in the body which metastasize to the meninges.
# Additional images
- Diagrammatic representation of a section across the top of the skull
- Diagrammatic section of scalp. | Meninges
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The meninges (singular meninx) is the system of membranes which envelop the central nervous system. The meninges consist of three layers: the dura mater, the arachnoid mater, and the pia mater. The primary function of the meninges and of the cerebrospinal fluid is to protect the central nervous system.
# Anatomy
## Pia mater
The pia or pia mater is a very delicate membrane. It is attached to (nearest) the brain or the spinal cord. As such it follows all the minor contours of the brain (gyri and sulci). The pia mater is the meningeal envelope which firmly adheres to the surface of the brain and spinal cord. It is a very thin membrane composed of fibrous tissue covered on its outer surface by a sheet of flat cells thought to be impermeable to fluid. The pia mater is pierced by blood vessels which travel to the brain and spinal cord, and its capillaries are responsible for nourishing the brain.
## Arachnoid mater
The middle element of the meninges is the arachnoid mater, so named because of its spider web-like appearance. It provides a cushioning effect for the central nervous system. The arachnoid mater exists as a thin, transparent membrane. It is composed of fibrous tissue and, like the pia mater, is covered by flat cells also thought to be impermeable to fluid. The arachnoid does not follow the convolutions of the surface of the brain and so looks like a loosely fitting sac. In the region of the brain, particularly, a large number of fine filaments called arachnoid trabeculae pass from the arachnoid through the subarachnoid space to blend with the tissue of the pia mater.
The arachnoid and pia mater are sometimes together called the leptomeninges.
## Dura mater
The dura mater (also rarely called meninx fibrosa, or pachymeninx) is a thick, durable membrane, closest to the skull. It contains larger blood vessels which split into the capilliaries in the pia mater. It is composed of dense fibrous tissue, and its inner surface is covered by flattened cells like those present on the surfaces of the pia mater and arachnoid. The dura mater is a sac which envelops the arachnoid and has been modified to serve several functions. The dura mater surrounds and supports the large venous channels (dural sinuses) carrying blood from the brain toward the heart.
## Spaces
The subarachnoid space is the space which normally exists between the arachnoid and the pia mater, which is filled with cerebrospinal fluid.
Normally, the dura mater is attached to the skull in the head, or to the bones of the vertebral canal in the spinal cord. The arachnoid is attached to the dura mater, and the pia mater is attached to the central nervous system tissue. When the dura mater and the arachnoid separate through injury or illness, the space between them is the subdural space.
# Pathology
There are three types of hemorrhage involving the meninges:[1]
- A subarachnoid hemorrhage is acute bleeding under the arachnoid; it may occur spontaneously or as a result of trauma.
- A subdural hematoma is a hematoma (collection of blood) located in a separation of the arachnoid from the dura mater. The small veins which connect the dura mater and the arachnoid are torn, usually during an accident, and blood can leak into this area.
- An epidural hematoma similarly may arise after an accident or spontaneously.
Other medical conditions which affect the meninges include meningitis (usually from fungal, bacterial, or viral infection) and meningiomas arising from the meninges or from tumors formed elsewhere in the body which metastasize to the meninges.
# Additional images
- Diagrammatic representation of a section across the top of the skull
- Diagrammatic section of scalp.
- | https://www.wikidoc.org/index.php/Cerebral_meninges | |
7cd48ab8256f8154799360034be111be38f53255 | wikidoc | Cerebrum | Cerebrum
The telencephalon (Template:PronEng) is the name for the forebrain, a large region within the brain to which many functions are attributed. Many people refer to it as the cerebrum; however, it is technically referred to as the telencephalon.
As a more technical definition, the telencephalon refers to the cerebral hemispheres and other, smaller structures within the brain, although the telencephalon is one of the larger divisions (in terms of number). It is the anterior-most embryological division of the brain that develops from the prosencephalon.
# Structure
The telencephalon is composed of the following sub-regions;
- Limbic system
- Cerebral cortex or cortices of the cerebral hemispheres.
- Basal ganglia
- Olfactory bulb
# Composition
The telencephalon comprises what most people think of as the "brain." It lies on top of the brainstem and is the largest and most well-developed of the five major divisions of the brain. The telencephalon is the newest structure in the phylogenetic sense, with mammals having the largest and most well-developed among all species. It emerges from the prosencephalon, the first of three vesicles that form from the embryonic neural tube.
The traditional division first sectioned the telencephalon into four parts. More recent research describes further sub-divisions.
In humans, the telencephalon surrounds older parts of the brain. Limbic, olfactory, and motor systems project fibers from subcortical (deeper) areas of the cerebrum to parts of the brainstem. Cognitive and volitive systems project fibers from cortical areas of the cerebrum to thalamus and to other regions of the brainstem. The neural networks of the telencephalon facilitate complex learned behaviors, such as language, and contains white matter and grey matter. Grey matter is highly folded; with respect to function, this is thought to allow a greater number of cells in the same volume due to the increase in its surface area. The telencephalon includes regions of archipalliar, paleopalliar, and neopalliar origin. Profound development of the neopallium, which comprises the cerebral cortex, is unique among humans and primates.
# Functions
Note: As the telencephalon is a gross division with many subdivisions and sub-regions, it is important to state that this section lists the functions that the telencephalon as a whole serves.
## Language and communication
Speech and language are mainly attributed to parts of the cerebral cortex, which is one portion of the telencephalon. Motor portions of language are attributed to Broca's area within the frontal lobe. Speech comprehension is attributed to Wernicke's area, at the temporal-parietal lobe junction. These two regions are interconnected by a large white matter tract, the arcuate fasciculus. Damage to the Broca's area results in expressive aphasia (non-fluent aphasia) while damage to Wernicke's area results in receptive aphasia (also called fluent aphasia).
## Movement
The telencephalon attributes motor function to the body. These functions originate within the primary motor cortex and other frontal lobe motor areas. In many cases, when this part of the brain is damaged, the brain is unable to send signals to nerves that innervate muscles' motorneurons, and can lead to diseases such as Motor Neurone Disease. This kind of damage results in loss of muscular power and precision rather than total paralysis.
## Olfaction
The olfactory bulb is on the underside of the anterior-most portion of the brain. This is a rather large portion of the telencephalon in most mammals. However, in humans, this part of the brain is relatively smaller. Damage to the olfactory bulb results in a loss of the sense of smell.
## Memory
Memory formation is associated with the hippocampus. This association was originally described after a patient (HM) had both his hippocampuses (left and right) surgically removed to treat severe epilepsy. After surgery, HM had anterograde amnesia, or the inability to form new memories. This problem is also addressed slightly in the film Memento, in which the protagonist has to take pictures of people he has met in order to be able to remember what to do in the days following his accident.
# Programmed cell death
## Purpose
Programmed Cell Death (PCD) is not uncommon in the telencephalon. It is thought to be one of the processes by which growth and differentiation occurs, and is a universal feature of the embryonic and postnatal central nervous system , and has been noted in the telencephalons of rats and mice. In some animals, such as the monkey, over 50% of neurons in the cerebral cortex are affected by PCD during early stages of life. This is thought to solicit growth of the brain due to increase in the size of the cranium and other parts of the body expected to grow throughout the life cycle of a monkey.
The main reason for PCD is to create space for new cells. If a neuron does not establish correct synaptic connections, it will die. This is seen as a form of "competition" within the space of the telencephalon and is a form of "survival of the fittest" (see Neural Darwinism). However, there are exceptions to the rule; in rats some cells are even programmed to die during proliferation within the ventricular zones of the telencephalon. It is thought that this is at a stage during which axons are not yet formed or synaptically connected.
## Effects
PCD in the brain affects glial cells and neurons through apoptosis (4). According to research on rodents, this period is usually during developmental or adolescent stages. During this time, the regeneration process can take place because the "materials" and environment are a perfect breeding ground for cell regeneration.
## Stages
During the stages of apoptosis, which seems to constitute most PCD in the brain, various morphological changes occur, such as:
- Cell enlargement
- Membrane blebbage, or inconsistency within the structure of the membrane
- Pyknosis, or a condensation of chromatin within the nucleus
- Karyorrhexis, or fragmentation of the nuclei
- Lack of inflammation
- Removal by microphages or adjacent glial cells, as organelles and plasma membrane remain intact throughout the process.
Of course, there are some differences to these stages, but they are relatively similar in practice. The apoptosis in the telencephalon can also be characterised distinctly by its DNA pattern, which becomes fragmented into oligonucleosomal fragments of around 180-200 pairs. These give a typical "ladder" pattern when viewed on or in agarose gel electrophoresis.
# Cell regeneration
## Xenopus laevis
### Larval stage
In a study of the telencephalon conducted in Hokkaido University on African clawed frogs (xenopus laevis), it was discovered that, during larval stages, the telencephalon was able to regenerate around half of the anterior portion (otherwise known as partially truncated), after a reconstruction of a would-be accident, or malformation of features.
The regeneration and active proliferation of cells within the clawed frog is quite remarkable, regenerated cells being almost functionally identical to the ones originally found in the brain after birth, despite the lack of brain matter for a sustained period of time.
This kind of regeneration depends on ependymal layer cells covering the cerebral lateral ventricles, within a short period before, or within the initial stage of wound-healing. This is observed within the stages of healing within larvae of the clawed frog.
### Developed stage
The regeneration within the developed stage of the clawed frog is different from that in the larval stage. Because the cells adhere to one another, they are unable to form an entity that can cover the cerebral lateral ventricles. Thus, the telencephalon remains truncated and the loss of function becomes permanent.
### Effects of abnormality
After removing over half of the telencephalon in the developed stage of the clawed frog, the lack of functions within the animal was apparent, manifesting with obvious difficulties in movement, nonverbal communication between other species, as well as other difficulties thought to be similar to those seen in humans.
This kind of regeneration is still relatively unknown in regard to regeneration within larval stages, similar to the human fetal stage. | Cerebrum
Template:Infobox Brain
The telencephalon (Template:PronEng) is the name for the forebrain, a large region within the brain to which many functions are attributed. Many people refer to it as the cerebrum; however, it is technically referred to as the telencephalon.
As a more technical definition, the telencephalon refers to the cerebral hemispheres and other, smaller structures within the brain, although the telencephalon is one of the larger divisions (in terms of number). It is the anterior-most embryological division of the brain that develops from the prosencephalon.
# Structure
The telencephalon is composed of the following sub-regions;
- Limbic system
- Cerebral cortex or cortices of the cerebral hemispheres.
- Basal ganglia
- Olfactory bulb
# Composition
The telencephalon comprises what most people think of as the "brain." It lies on top of the brainstem and is the largest and most well-developed of the five major divisions of the brain. The telencephalon is the newest structure in the phylogenetic sense, with mammals having the largest and most well-developed among all species. It emerges from the prosencephalon, the first of three vesicles that form from the embryonic neural tube.
The traditional division first sectioned the telencephalon into four parts. More recent research describes further sub-divisions.
In humans, the telencephalon surrounds older parts of the brain. Limbic, olfactory, and motor systems project fibers from subcortical (deeper) areas of the cerebrum to parts of the brainstem. Cognitive and volitive systems project fibers from cortical areas of the cerebrum to thalamus and to other regions of the brainstem. The neural networks of the telencephalon facilitate complex learned behaviors, such as language, and contains white matter and grey matter. Grey matter is highly folded; with respect to function, this is thought to allow a greater number of cells in the same volume due to the increase in its surface area. The telencephalon includes regions of archipalliar, paleopalliar, and neopalliar origin. Profound development of the neopallium, which comprises the cerebral cortex, is unique among humans and primates.
# Functions
Note: As the telencephalon is a gross division with many subdivisions and sub-regions, it is important to state that this section lists the functions that the telencephalon as a whole serves.
## Language and communication
Speech and language are mainly attributed to parts of the cerebral cortex, which is one portion of the telencephalon. Motor portions of language are attributed to Broca's area within the frontal lobe. Speech comprehension is attributed to Wernicke's area, at the temporal-parietal lobe junction. These two regions are interconnected by a large white matter tract, the arcuate fasciculus. Damage to the Broca's area results in expressive aphasia (non-fluent aphasia) while damage to Wernicke's area results in receptive aphasia (also called fluent aphasia).
## Movement
The telencephalon attributes motor function to the body. These functions originate within the primary motor cortex and other frontal lobe motor areas. In many cases, when this part of the brain is damaged, the brain is unable to send signals to nerves that innervate muscles' motorneurons, and can lead to diseases such as Motor Neurone Disease. This kind of damage results in loss of muscular power and precision rather than total paralysis.
## Olfaction
The olfactory bulb is on the underside of the anterior-most portion of the brain. This is a rather large portion of the telencephalon in most mammals. However, in humans, this part of the brain is relatively smaller. Damage to the olfactory bulb results in a loss of the sense of smell.
## Memory
Memory formation is associated with the hippocampus. This association was originally described after a patient (HM) had both his hippocampuses (left and right) surgically removed to treat severe epilepsy. After surgery, HM had anterograde amnesia, or the inability to form new memories. This problem is also addressed slightly in the film Memento, in which the protagonist has to take pictures of people he has met in order to be able to remember what to do in the days following his accident.
# Programmed cell death
## Purpose
Programmed Cell Death (PCD) is not uncommon in the telencephalon. It is thought to be one of the processes by which growth and differentiation occurs, and is a universal feature of the embryonic and postnatal central nervous system [1], and has been noted in the telencephalons of rats and mice. In some animals, such as the monkey, over 50% of neurons in the cerebral cortex are affected by PCD during early stages of life. This is thought to solicit growth of the brain due to increase in the size of the cranium and other parts of the body expected to grow throughout the life cycle of a monkey.
The main reason for PCD is to create space for new cells. If a neuron does not establish correct synaptic connections, it will die. This is seen as a form of "competition" within the space of the telencephalon and is a form of "survival of the fittest" (see Neural Darwinism). However, there are exceptions to the rule; in rats some cells are even programmed to die during proliferation within the ventricular zones of the telencephalon. It is thought that this is at a stage during which axons are not yet formed or synaptically connected.
## Effects
PCD in the brain affects glial cells and neurons through apoptosis (4). According to research on rodents, this period is usually during developmental or adolescent stages. During this time, the regeneration process can take place because the "materials" and environment are a perfect breeding ground for cell regeneration.
## Stages
During the stages of apoptosis, which seems to constitute most PCD in the brain, various morphological changes occur, such as:
- Cell enlargement
- Membrane blebbage, or inconsistency within the structure of the membrane
- Pyknosis, or a condensation of chromatin within the nucleus
- Karyorrhexis, or fragmentation of the nuclei
- Lack of inflammation
- Removal by microphages or adjacent glial cells, as organelles and plasma membrane remain intact throughout the process.
Of course, there are some differences to these stages, but they are relatively similar in practice. The apoptosis in the telencephalon can also be characterised distinctly by its DNA pattern, which becomes fragmented into oligonucleosomal fragments of around 180-200 pairs. These give a typical "ladder" pattern when viewed on or in agarose gel electrophoresis.
# Cell regeneration
## Xenopus laevis
### Larval stage
In a study of the telencephalon conducted in Hokkaido University on African clawed frogs (xenopus laevis)[2], it was discovered that, during larval stages, the telencephalon was able to regenerate around half of the anterior portion (otherwise known as partially truncated), after a reconstruction of a would-be accident, or malformation of features.
The regeneration and active proliferation of cells within the clawed frog is quite remarkable, regenerated cells being almost functionally identical to the ones originally found in the brain after birth, despite the lack of brain matter for a sustained period of time.
This kind of regeneration depends on ependymal layer cells covering the cerebral lateral ventricles, within a short period before, or within the initial stage of wound-healing. This is observed within the stages of healing within larvae of the clawed frog.
### Developed stage
The regeneration within the developed stage of the clawed frog is different from that in the larval stage. Because the cells adhere to one another, they are unable to form an entity that can cover the cerebral lateral ventricles. Thus, the telencephalon remains truncated and the loss of function becomes permanent.
### Effects of abnormality
After removing over half of the telencephalon in the developed stage of the clawed frog, the lack of functions within the animal was apparent, manifesting with obvious difficulties in movement, nonverbal communication between other species, as well as other difficulties thought to be similar to those seen in humans.
This kind of regeneration is still relatively unknown in regard to regeneration within larval stages, similar to the human fetal stage. | https://www.wikidoc.org/index.php/Cerebrum | |
f3c54c1dbaf9bbdfa0536a9fcf49846b88191d0f | wikidoc | Cervarix | Cervarix
Cervarix is a vaccine against certain types of the human papillomavirus (HPV) that cause cervical cancer. It received approval in May 2007 in Australia for women ages 10 to 45.. If approved in the United States, will be marketed by GlaxoSmithKline. It is designed to prevent infection from HPV types 16 and 18, which currently cause about 70% of HPV-related cervical cancer cases. Type 16 has also been found to be associated with oropharyngeal squamous-cell carcinoma, a form of throat cancer. Additionally, "substantial" protection against virus strains 45 and 31 were shown in clinical trials. Cervarix is also formulated with AS04, a proprietary adjuvant that has been found to boost the immune system response for a longer period of time.
# Biotechnology
Cervarix is created using the L1 protein of the viral capsid. Recombinant activity in a baculovirus vector produces L1 protein spheres, which are very immunogenic. The viral proteins induce the formation of neutralizing antibodies. The vaccine contains no live virus and no DNA, so it cannot infect the patient. The vaccine was developed, in parallel, by researchers at Georgetown University Medical Center, the University of Rochester, the University of Queensland in Australia, and the U.S. National Cancer Institute .
# Indications
Cervarix is a preventative cervical cancer vaccine, not therapeutic. HPV immunity is type-specific, so a successful series of Cervarix shots will not block infection from cervical cancer-causing HPV strains other than HPV 16, 18, 31 and 45, so experts continue to recommend routine cervical Pap smears even for women who have been vaccinated.
# Administration
Phase II trials demonstrated 100% protection of the vaccine against types 16 and 18 HPV, including among 1100 women from North America and Brazil. Phase III trials included over 660 women from Germany and Poland. Company officials are now conducting a clinical trial to determine whether Cervarix is more effective than rival Merck's HPV vaccine Gardasil.
Longevity of the vaccination has proven so far to be at least 5.5 years. In the clinical trials, women were given three doses over a six-month span -- at 0 month, 1 month, and 6 months. The technology used in this vaccine was licensed from the University of Rochester.
On March 29, 2007 GlaxoSmithKline submitted a Biologics License Application (BLA) for Cervarix (human papillomavirus vaccine, AS04 adjuvant-adsorbed), to the FDA which included data from clinical trials in almost 30,000 females 10 to 55 years of age and contains data from the largest Phase III cervical cancer vaccine efficacy trial to date.
# Cervarix in Manila
On august 25, 2007 GlaxoSmithKline (GSK) launched its Cervarix anti-cervical cancer vaccine in the Philippines after approval by the local Bureau of Food and Drugs which also approved a similar vaccine Gardasil (15,000 pesos or US$320; euro235 for 3 doses, produced by U.S.-based drug company Merck & Co. (MRK) on 2006). Cervarix fights types 16 and 18 of the human papillomavirus which cause 70% of cervical cancer worldwide.
Professor Cecilia Llave, University of the Philippines' Cancer Institute head reported that yearly, 6,000 women develop cervical cancer in Philippines and about 4,300 of them die from the disease. In Asia Pacific, it is the 2nd most common female cancer (266,000 women affected yearly, killing 140,000). | Cervarix
Template:Seealso
Cervarix is a vaccine against certain types of the human papillomavirus (HPV) that cause cervical cancer. It received approval in May 2007 in Australia for women ages 10 to 45.[1]. If approved in the United States, will be marketed by GlaxoSmithKline. It is designed to prevent infection from HPV types 16 and 18, which currently cause about 70% of HPV-related cervical cancer cases. Type 16 has also been found to be associated with oropharyngeal squamous-cell carcinoma, a form of throat cancer.[2] Additionally, "substantial" protection against virus strains 45 and 31 were shown in clinical trials.[3] Cervarix is also formulated with AS04, a proprietary adjuvant that has been found to boost the immune system response for a longer period of time.[4]
# Biotechnology
Cervarix is created using the L1 protein of the viral capsid. Recombinant activity in a baculovirus vector produces L1 protein spheres, which are very immunogenic. The viral proteins induce the formation of neutralizing antibodies. The vaccine contains no live virus and no DNA, so it cannot infect the patient. The vaccine was developed, in parallel, by researchers at Georgetown University Medical Center, the University of Rochester, the University of Queensland in Australia, and the U.S. National Cancer Institute [5] .
# Indications
Cervarix is a preventative cervical cancer vaccine, not therapeutic. HPV immunity is type-specific, so a successful series of Cervarix shots will not block infection from cervical cancer-causing HPV strains other than HPV 16, 18, 31 and 45, so experts continue to recommend routine cervical Pap smears even for women who have been vaccinated.
# Administration
Phase II trials demonstrated 100% protection of the vaccine against types 16 and 18 HPV, including among 1100 women from North America and Brazil.[6] Phase III trials included over 660 women from Germany and Poland. Company officials are now conducting a clinical trial to determine whether Cervarix is more effective than rival Merck's HPV vaccine Gardasil.[7]
Longevity of the vaccination has proven so far to be at least 5.5 years.[8] In the clinical trials, women were given three doses over a six-month span -- at 0 month, 1 month, and 6 months. The technology used in this vaccine was licensed from the University of Rochester.[9]
On March 29, 2007 GlaxoSmithKline submitted a Biologics License Application (BLA) for Cervarix (human papillomavirus vaccine, AS04 adjuvant-adsorbed), to the FDA which included data from clinical trials in almost 30,000 females 10 to 55 years of age and contains data from the largest Phase III cervical cancer vaccine efficacy trial to date.[10]
# Cervarix in Manila
On august 25, 2007 GlaxoSmithKline (GSK) launched its Cervarix anti-cervical cancer vaccine in the Philippines after approval by the local Bureau of Food and Drugs which also approved a similar vaccine Gardasil (15,000 pesos or US$320; euro235 for 3 doses, produced by U.S.-based drug company Merck & Co. (MRK) on 2006). Cervarix fights types 16 and 18 of the human papillomavirus which cause 70% of cervical cancer worldwide.[11]
Professor Cecilia Llave, University of the Philippines' Cancer Institute head reported that yearly, 6,000 women develop cervical cancer in Philippines and about 4,300 of them die from the disease. In Asia Pacific, it is the 2nd most common female cancer (266,000 women affected yearly, killing 140,000).[12] | https://www.wikidoc.org/index.php/Cervarix | |
64fb92491b2223cded1b88824263e5128aae6019 | wikidoc | Nabilone | Nabilone
# 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
Nabilone is a Cannabinoid and antihemetic that is FDA approved for the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. Common adverse reactions include hypotension, xerostomia, asthenia, ataxia, dyssomnia, headache, poor concentration, somnolence, vertigo, visual disturbance, dysphoric mood and euphoria.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The usual adult dosage is 1 or 2 mg 2 times a day. On the day of chemotherapy, the initial dose should be given 1 to 3 hours before the chemotherapeutic agent is administered. To minimize side effects, it is recommended that the lower starting dose be used and that the dose be increased as necessary. A dose of 1 or 2 mg the night before may be useful. The maximum recommended daily dose is 6 mg given in divided doses 3 times a day.
- Nabilone may be administered 2 or 3 times a day during the entire course of each cycle of chemotherapy and, if needed, for 48 hours after the last dose of each cycle of chemotherapy.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nabilone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nabilone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Nabilone 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 Nabilone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nabilone in pediatric patients.
# Contraindications
Nabilone is contraindicated in any patient who has a history of hypersensitivity to any cannabinoid.
# Warnings
- The effects of Nabilone may persist for a variable and unpredictable period of time following its oral administration. *Adverse psychiatric reactions can persist for 48 to 72 hours following cessation of treatment.
- Nabilone has the potential to affect the CNS, which might manifest itself in dizziness, drowsiness, euphoria “high”, ataxia, anxiety, disorientation, depression, hallucinations and psychosis.
- Nabilone can cause tachycardia and orthostatic hypotension.
- Because of individual variation in response and tolerance to the effects of Nabilone patients should remain under supervision of a responsible adult especially during initial use of Nabilone and during dose adjustments.
- Patients receiving treatment with Nabilone should be specifically warned not to drive, operate machinery, or engage in any hazardous activity while receiving Nabilone.
- Nabilone should not be taken with alcohol, sedatives, hypnotics, or other psychoactive substances because these substances can potentiate the central nervous system effects of nabilone.
# Adverse Reactions
## Clinical Trials Experience
- During controlled clinical trials of Nabilone, virtually all patients experienced at least one adverse reaction. The most commonly encountered events were drowsiness, vertigo, dry mouth, euphoria (feeling “high”), ataxia, headache, and concentration difficulties.
- Accurate estimates of the incidence of adverse events associated with the use of any drug are difficult to obtain. Estimates are influenced by factors such as drug dose, detection technique, setting, and physician judgments, among others. Consequently, the tables presented below are presented solely to indicate the relative frequency of adverse events reported in representative controlled clinical studies conducted to evaluate the safety and efficacy of Nabilone under relatively similar conditions of use. The figures cited cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice, in which patient characteristics and other factors may differ from those that prevailed in the clinical trials. These incidence figures also cannot be compared with those obtained from other clinical studies involving related drug products because each group of drug trials is conducted under a different set of conditions. Finally, it is important to emphasize that these tabulations do not reflect the relative severity and/or clinical importance of the adverse events.
The following tables list in order of decreasing frequency the adverse reactions encountered by a substantial proportion of patients treated with Nabilone participating in representative controlled clinical trials.
- Anemia
- Orthostatic hypotension
- Hypotension
- Tachycardia
- Syncope
- Palpitation
- Flushing
- Hypertension
- Arrhythmia
- Cerebral vascular accident
- Vision disturbance
- Ear tightness
- Eye irritation
- Eye dryness
- Equilibrium dysfunction
- Tinnitus
- Eye disorder
- Amblyopia
- Eye swelling
- Eyelid diseases
- Pupil dilation
- Photophobia
- Visual field defect
- Dry mouth
- Nausea
- Anorexia
- Vomiting
- Diarrhea
- Abdominal pain
- Constipation
- Aphthous ulcer
- Mouth irritation
- Gastritis
- Dyspepsia
- Increased urination
- Decreased urination
- Hot flashes
- Urinary retention
- Frequency of micturition
- Bacterial infection
- Thirst
- Muscle pain
- Back pain
- Neck pain
- Joint pain
- Unspecified pain
- Drowsiness
- Vertigo
- Ataxia
- Decreased concentration
- Sedation
- Hallucinations
- Paresthesia
- Tremor
- Memory disturbance
- Perception disturbance
- Convulsions
- Dystonia
- Numbness
- Akathisia
- Euphoria (feeling “high”)
- Sleep disturbance
- Depression
- Confusion
- Disorientation
- Anxiety
- Depersonalization syndrome
- Speech disorder
- Abnormal dreams
- Insomnia
- Mood swings
- Inebriated feeling
- Toxic psychosis
- Paranoia
- Apathy
- Thought disorder
- Withdrawal
- Panic disorder
- Phobic neurosis
- Emotional disorder
- Hyperactivity
- Dyspnea
- Pharyngitis
- Nasal congestion
- Sinus headache
- Thick tongue
- Dry throat
- Dry nose
- Wheezing
- Nosebleed
- Cough
- Voice change
- Chest pain
- Anhidrosis
- Photosensitivity
- Pruritus
- Rash
- Allergic reactions
- Headache
- Fatigue
- Lightheadedness
- Coordination disturbance
- Asthenia
- Dysphoria
- Dizziness
- Taste change
- Excessive appetite
- Chills
- Excessive sweating
- Nervousness
- Malaise
- Postural dizziness
- Twitch
- Irritability
- Fever
- Inhibited walking
- Unconsciousness
- Hypotonia
- Impaired urination
## Postmarketing Experience
Nabilone has been marketed internationally since 1982. The following adverse reactions listed in order of decreasing frequency by body system have been reported since Nabilone has been marketed. All events are listed regardless of causality assessment.
- Leukopenia
- Hypotension
- Tachycardia
- Visual disturbances
- Dry mouth
- Nausea
- Vomiting
- Constipation
- Hallucinations
- CNS depression
- CNS stimulation
- Ataxia
- Stupor
- Vertigo
- Convulsion
- Circumoral paresthesia
- Somnolence
- Confusion
- Euphoria
- Depression
- Dysphoria
- Depersonalization
- Anxiety
- Psychosis
- Emotional lability
- Dizziness
- Headache
- Insomnia
- Abnormal thinking
- Chest pain
- Lack of effect
- Face edema
# Drug Interactions
- Potential interactions between Nabilone 2 mg, and diazepam 5 mg; sodium secobarbital 100 mg; alcohol 45 mL (absolute laboratory alcohol); or codeine 65 mg, were evaluated in 15 subjects. Only a single combination was utilized at any one time. The subjects were evaluated according to physiologic (i.e., heart rate and blood pressure), psychometric, psychomotor, and subjective parameters. In this study, as expected, the depressant effects of the combinations were additive. Psychomotor function was particularly impaired with concurrent use of diazepam. Caution must thus be used when administering nabilone in combination with any CNS depressant.
- Nabilone is purportedly highly bound to plasma proteins, and therefore, might displace other protein-bound drugs. Therefore, practitioners should monitor patients for a change in dosage requirements when administering nabilone to patients receiving other highly protein-bound drugs. Published reports of drug-drug interactions involving cannabinoids are summarized in the following table.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Teratology studies conducted in pregnant rats at doses up to 12 mg/kg/day (about 16 times the human dose on a body surface area basis) and in pregnant rabbits at doses up to 3.3 mg/kg/day (about 9 times the human dose on a body surface area basis) did not disclose any evidence for a teratogenic potential of nabilone. However, there was dose related developmental toxicity in both species as evidenced by increases in embryo lethality, fetal resorptions, decreased fetal weights and pregnancy disruptions. In rats, postnatal developmental toxicity was also observed. There are no adequate and well-controlled studies in pregnant women. Because animal studies cannot rule out the possibility of harm, Nabilone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nabilone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nabilone during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in breast milk. Because many drugs including some cannabinoids are excreted in breast milk it is not recommended that Nabilone be given to nursing mothers.
### Pediatric Use
- Safety and effectiveness have not been established in patients younger than 18 years of age. Caution is recommended in prescribing Nabilone to children because of psychoactive effects.
### Geriatic Use
- Clinical studies of Nabilone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Nabilone should be used with caution in elderly patients aged 65 and over because they are generally more sensitive to the psychoactive effects of drugs and Nabilone can elevate supine and standing heart rates and cause postural hypotension.
### Gender
There is no FDA guidance on the use of Nabilone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nabilone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Nabilone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Nabilone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nabilone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nabilone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Nabilone Administration in the drug label.
### Monitoring
There is limited information regarding Nabilone Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Nabilone and IV administrations.
# Overdosage
- Signs and symptoms of overdosage are an extension of the psychotomimetic and physiologic effects of Nabilone.
- To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians' Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.
- Overdosage may be considered to have occurred, even at prescribed dosages, if disturbing psychiatric symptoms are present. In these cases, the patient should be observed in a quiet environment and supportive measures, including reassurance, should be used. Subsequent doses should be withheld until patients have returned to their baseline mental status; routine dosing may then be resumed if clinically indicated. In such instances, a lower initiating dose is suggested. In controlled clinical trials, alterations in mental status related to the use of Nabilone resolved within 72 hours without specific medical therapy. In overdose settings, attention should be paid to vital signs, since both hypertension and hypotension have been known to occur; tachycardia and orthostatic hypotension were most commonly reported.
- No cases of overdosage with more than 10 mg/day of nabilone were reported during clinical trials. Signs and symptoms that would be expected to occur in large overdose situations are psychotic episodes, including hallucinations, anxiety reactions, respiratory depression, and coma. If psychotic episodes occur, the patient should be managed conservatively, if possible. For moderate psychotic episodes and anxiety reactions, verbal support and comforting may be sufficient. In more severe cases, antipsychotic drugs may be useful; however, the utility of antipsychotic drugs in cannabinoid psychosis has not been systematically evaluated. Support for their use is drawn from limited experience using antipsychotic agents to manage cannabis overdoses. Because of the potential for drug-drug interactions (e.g., additive CNS depressant effects due to nabilone and chlorpromazine), such patients should be closely monitored.
- Protect the patient's airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient's vital signs, blood gases, serum electrolytes, as well as other laboratory values and physical assessments. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient's airway when employing gastric emptying or charcoal.
- The use of forced diuresis, peritoneal dialysis, hemodialysis, charcoal hemoperfusion, or cholestyramine has not been reported. In the presence of normal renal function, most of a dose of nabilone is eliminated through the biliary system. Treatment for respiratory depression and comatose state consists in symptomatic and supportive therapy. Particular attention should be paid to the occurrence of hypothermia. If the patient becomes hypotensive, consider fluids, inotropes, and/or vasopressors. The estimated oral median lethal dose in female mice is between 1,000 and 2,000 mg/kg; in the female rat, it is greater than 2,000 mg/kg,
# Pharmacology
## Mechanism of Action
- Chemically, nabilone is similar to the active ingredient found in naturally occurring Cannabis sativa L. . Nabilone is (±)-trans-3-(1,1-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6-6-dimethyl-9H-dibenzopyran-9-one and has the empirical formula C24H36O3. It has a molecular weight of 372.55. The structural formula is as follows:
## Structure
There is limited information regarding Nabilone Structure in the drug label.
## Pharmacodynamics
Nabilone (nabilone) is an orally active synthetic cannabinoid which, like other cannabinoids, has complex effects on the central nervous system (CNS). It has been suggested that the antiemetic effect of nabilone is caused by interaction with the cannabinoid receptor system, i.e., the CB (1) receptor, which has been discovered in neural tissues.
- Nabilone, a synthetic cannabinoid, has the potential to be abused and to produce psychological dependence. Nabilone has complex effects on the central nervous system. Its effects on the mental state (i.e., "inner mental life") are similar to those of cannabis. Subjects given Nabilone may experience changes in mood (euphoria, detachment, depression, anxiety, panic, paranoia), decrements in cognitive performance and memory, a decreased ability to control drives and impulses, and alterations in the experience of reality (e.g., distortions in the perception of objects and the sense of time, hallucinations). These phenomena appear to be more common when larger doses of Nabilone are administered; however, a full-blown picture of psychosis (psychotic organic brain syndrome) may occur in patients receiving doses within the lower portion of the therapeutic range.
- Data on the chronic use of Nabilone are not available; experience with cannabis suggests that chronic use of cannabinoids may be associated with a variety of untoward effects on motivation, cognition, judgment, as well as other mental status changes. Whether these phenomena reflect the underlying character of individuals chronically abusing cannabis or are a result of the use of cannabis is not known.
- The simultaneous use of Nabilone and alcohol or barbiturates may produce additive depressive effects on central nervous system function. Possible changes in mood and other adverse behavioral effects may occur in patients receiving Nabilone. Patients should remain under supervision of a responsible adult while using Nabilone. Nabilone has central nervous system activity. It produces relaxation, drowsiness, and euphoria in the recommended dosage range. Tolerance to these effects develops rapidly and is readily reversible.
- In addition to effects on the mental state, Nabilone has several systemic actions; most prominent are dry mouth and hypotension. Nabilone has been observed to elevate supine and standing heart rates and to cause supine and orthostatic hypotension. In clinical studies, oral administration of 2 mg of Nabilone did produce some decrease in airway resistance in normal controls but had no effect in patients with asthma. No other nontherapeutic effects of clinical significance due to Nabilone have been reported.
## Pharmacokinetics
- Nabilone (nabilone) appears to be completely absorbed from the human gastrointestinal tract when administered orally. Following oral administration of a 2 mg dose of radiolabeled nabilone, peak plasma concentrations of approximately 2 ng/mL nabilone and 10 ng equivalents/mL total radioactivity are achieved within 2.0 hours. The plasma half-life (T1/2) values for nabilone and total radioactivity of identified and unidentified metabolites are about 2 and 35 hours, respectively. The initial rapid disappearance of radioactivity represents uptake and distribution of nabilone into tissue and the slower phase elimination by metabolism and excretion. The apparent volume of distribution of nabilone is about 12.5 L/kg. Nabilone exhibits dose linearity within its therapeutic range. Clinical data suggests that the intake of food does not significantly affect either the rate or extent of absorption.
- Metabolism of nabilone is extensive and several metabolites have been identified. Precise information concerning the metabolites that may accumulate is not available. The relative activities of the metabolites and the parent drug have not been established. There are at least two metabolic pathways involved in the biotransformation of nabilone. A minor pathway is initiated by the stereospecific enzymatic reduction of the 9-keto moiety of nabilone to produce the isomeric carbinol metabolite. The peak concentrations of nabilone and its carbinol metabolites are comparable, but their combined exposures in plasma do not account for more than 20% of that of total radioactivity. Secondly, a metabolite of nabilone in feces has been identified as a diol formed by reduction of the 9-keto group plus oxidation at the penultimate carbon of the dimethylheptyl side chain. In addition, there is evidence of extensive metabolism of Nabilone by multiple P450 enzyme isoforms. In vitro P450 inhibition studies using human liver microsomes showed that nabilone did not significantly inhibit CYP1A2, CYP2A6, CYP2C19, CYP2D6, and CYP3A4 (using midazolam and nifedipine as substrates). Nabilone had a weak inhibitory effect on CYP2E1 and CYP3A4 (testosterone IC50 > 50 µM) and had a moderate inhibitory effect on CYP2C8 and CYP2C9 (IC50 > 10 µM). However, in clinical use, the very low nabilone plasma concentration is unlikely to interfere with the P450-mediated degradation of co-administered drugs. Chronic oral administration of 1 mg t.i.d. for 14 days to 3 subjects gave no indication there was any significant accumulation of nabilone. Available evidence suggests that one or more of the metabolites has a terminal elimination half-life that exceeds that of nabilone. Consequently, in repeated use, the metabolites may accumulate at concentrations in excess of the parent drug.
- The route and rate of the elimination of nabilone and its metabolites are similar to those observed with other cannabinoids, including delta-9-THC (dronabinol). When nabilone is administered intravenously, the drug and its metabolites are eliminated mainly in the feces (approximately 67%) and to a lesser extent in the urine (approximately 22%) within 7 days. Of the 67% recovered from the feces, 5% corresponded to the parent compound and 16% to its carbinol metabolite. Following oral administration about 60% of nabilone and its metabolites were recovered in the feces and about 24% in urine. Therefore, it appears that the major excretory pathway is the biliary system. The effects of age, gender, hepatic dysfunction, and renal insufficiency on the metabolism and elimination of nabilone have not been determined.
## Nonclinical Toxicology
There is limited information regarding Nabilone Nonclinical Toxicology in the drug label.
# Clinical Studies
- Nabilone was evaluated for its effectiveness and safety in the treatment of nausea and vomiting induced by cancer chemotherapy in patients receiving a wide variety of chemotherapy regimens, including low-dose cisplatin (20 mg/m2) in both placebo-controlled and active controlled (prochlorperazine) trials. During Nabilone treatment patients reported a higher incidence of adverse effects. The most frequent were drowsiness, vertigo, dry mouth and euphoria. However, most of the adverse effects occurring with Nabilone were of mild to moderate severity.
# How Supplied
- Nabilone® capsules (blue and white): 1 mg (bottles of 50 capsules) NDC 0037-1221-50. Capsules are imprinted with MEDA on the blue cap and a four-digit code (1221) on the white body.
## Storage
- Store at controlled room temperature, 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Nabilone Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Nabilone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Cesamet
# Look-Alike Drug Names
There is limited information regarding Nabilone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Nabilone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Nabilone is a Cannabinoid and antihemetic that is FDA approved for the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. Common adverse reactions include hypotension, xerostomia, asthenia, ataxia, dyssomnia, headache, poor concentration, somnolence, vertigo, visual disturbance, dysphoric mood and euphoria.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The usual adult dosage is 1 or 2 mg 2 times a day. On the day of chemotherapy, the initial dose should be given 1 to 3 hours before the chemotherapeutic agent is administered. To minimize side effects, it is recommended that the lower starting dose be used and that the dose be increased as necessary. A dose of 1 or 2 mg the night before may be useful. The maximum recommended daily dose is 6 mg given in divided doses 3 times a day.
- Nabilone may be administered 2 or 3 times a day during the entire course of each cycle of chemotherapy and, if needed, for 48 hours after the last dose of each cycle of chemotherapy.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nabilone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nabilone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Nabilone 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 Nabilone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nabilone in pediatric patients.
# Contraindications
Nabilone is contraindicated in any patient who has a history of hypersensitivity to any cannabinoid.
# Warnings
- The effects of Nabilone may persist for a variable and unpredictable period of time following its oral administration. *Adverse psychiatric reactions can persist for 48 to 72 hours following cessation of treatment.
- Nabilone has the potential to affect the CNS, which might manifest itself in dizziness, drowsiness, euphoria “high”, ataxia, anxiety, disorientation, depression, hallucinations and psychosis.
- Nabilone can cause tachycardia and orthostatic hypotension.
- Because of individual variation in response and tolerance to the effects of Nabilone patients should remain under supervision of a responsible adult especially during initial use of Nabilone and during dose adjustments.
- Patients receiving treatment with Nabilone should be specifically warned not to drive, operate machinery, or engage in any hazardous activity while receiving Nabilone.
- Nabilone should not be taken with alcohol, sedatives, hypnotics, or other psychoactive substances because these substances can potentiate the central nervous system effects of nabilone.
# Adverse Reactions
## Clinical Trials Experience
- During controlled clinical trials of Nabilone, virtually all patients experienced at least one adverse reaction. The most commonly encountered events were drowsiness, vertigo, dry mouth, euphoria (feeling “high”), ataxia, headache, and concentration difficulties.
- Accurate estimates of the incidence of adverse events associated with the use of any drug are difficult to obtain. Estimates are influenced by factors such as drug dose, detection technique, setting, and physician judgments, among others. Consequently, the tables presented below are presented solely to indicate the relative frequency of adverse events reported in representative controlled clinical studies conducted to evaluate the safety and efficacy of Nabilone under relatively similar conditions of use. The figures cited cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice, in which patient characteristics and other factors may differ from those that prevailed in the clinical trials. These incidence figures also cannot be compared with those obtained from other clinical studies involving related drug products because each group of drug trials is conducted under a different set of conditions. Finally, it is important to emphasize that these tabulations do not reflect the relative severity and/or clinical importance of the adverse events.
The following tables list in order of decreasing frequency the adverse reactions encountered by a substantial proportion of patients treated with Nabilone participating in representative controlled clinical trials.
- Anemia
- Orthostatic hypotension
- Hypotension
- Tachycardia
- Syncope
- Palpitation
- Flushing
- Hypertension
- Arrhythmia
- Cerebral vascular accident
- Vision disturbance
- Ear tightness
- Eye irritation
- Eye dryness
- Equilibrium dysfunction
- Tinnitus
- Eye disorder
- Amblyopia
- Eye swelling
- Eyelid diseases
- Pupil dilation
- Photophobia
- Visual field defect
- Dry mouth
- Nausea
- Anorexia
- Vomiting
- Diarrhea
- Abdominal pain
- Constipation
- Aphthous ulcer
- Mouth irritation
- Gastritis
- Dyspepsia
- Increased urination
- Decreased urination
- Hot flashes
- Urinary retention
- Frequency of micturition
- Bacterial infection
- Thirst
- Muscle pain
- Back pain
- Neck pain
- Joint pain
- Unspecified pain
- Drowsiness
- Vertigo
- Ataxia
- Decreased concentration
- Sedation
- Hallucinations
- Paresthesia
- Tremor
- Memory disturbance
- Perception disturbance
- Convulsions
- Dystonia
- Numbness
- Akathisia
- Euphoria (feeling “high”)
- Sleep disturbance
- Depression
- Confusion
- Disorientation
- Anxiety
- Depersonalization syndrome
- Speech disorder
- Abnormal dreams
- Insomnia
- Mood swings
- Inebriated feeling
- Toxic psychosis
- Paranoia
- Apathy
- Thought disorder
- Withdrawal
- Panic disorder
- Phobic neurosis
- Emotional disorder
- Hyperactivity
- Dyspnea
- Pharyngitis
- Nasal congestion
- Sinus headache
- Thick tongue
- Dry throat
- Dry nose
- Wheezing
- Nosebleed
- Cough
- Voice change
- Chest pain
- Anhidrosis
- Photosensitivity
- Pruritus
- Rash
- Allergic reactions
- Headache
- Fatigue
- Lightheadedness
- Coordination disturbance
- Asthenia
- Dysphoria
- Dizziness
- Taste change
- Excessive appetite
- Chills
- Excessive sweating
- Nervousness
- Malaise
- Postural dizziness
- Twitch
- Irritability
- Fever
- Inhibited walking
- Unconsciousness
- Hypotonia
- Impaired urination
## Postmarketing Experience
Nabilone has been marketed internationally since 1982. The following adverse reactions listed in order of decreasing frequency by body system have been reported since Nabilone has been marketed. All events are listed regardless of causality assessment.
- Leukopenia
- Hypotension
- Tachycardia
- Visual disturbances
- Dry mouth
- Nausea
- Vomiting
- Constipation
- Hallucinations
- CNS depression
- CNS stimulation
- Ataxia
- Stupor
- Vertigo
- Convulsion
- Circumoral paresthesia
- Somnolence
- Confusion
- Euphoria
- Depression
- Dysphoria
- Depersonalization
- Anxiety
- Psychosis
- Emotional lability
- Dizziness
- Headache
- Insomnia
- Abnormal thinking
- Chest pain
- Lack of effect
- Face edema
# Drug Interactions
- Potential interactions between Nabilone 2 mg, and diazepam 5 mg; sodium secobarbital 100 mg; alcohol 45 mL (absolute laboratory alcohol); or codeine 65 mg, were evaluated in 15 subjects. Only a single combination was utilized at any one time. The subjects were evaluated according to physiologic (i.e., heart rate and blood pressure), psychometric, psychomotor, and subjective parameters. In this study, as expected, the depressant effects of the combinations were additive. Psychomotor function was particularly impaired with concurrent use of diazepam. Caution must thus be used when administering nabilone in combination with any CNS depressant.
- Nabilone is purportedly highly bound to plasma proteins, and therefore, might displace other protein-bound drugs. Therefore, practitioners should monitor patients for a change in dosage requirements when administering nabilone to patients receiving other highly protein-bound drugs. Published reports of drug-drug interactions involving cannabinoids are summarized in the following table.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Teratology studies conducted in pregnant rats at doses up to 12 mg/kg/day (about 16 times the human dose on a body surface area basis) and in pregnant rabbits at doses up to 3.3 mg/kg/day (about 9 times the human dose on a body surface area basis) did not disclose any evidence for a teratogenic potential of nabilone. However, there was dose related developmental toxicity in both species as evidenced by increases in embryo lethality, fetal resorptions, decreased fetal weights and pregnancy disruptions. In rats, postnatal developmental toxicity was also observed. There are no adequate and well-controlled studies in pregnant women. Because animal studies cannot rule out the possibility of harm, Nabilone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nabilone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nabilone during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in breast milk. Because many drugs including some cannabinoids are excreted in breast milk it is not recommended that Nabilone be given to nursing mothers.
### Pediatric Use
- Safety and effectiveness have not been established in patients younger than 18 years of age. Caution is recommended in prescribing Nabilone to children because of psychoactive effects.
### Geriatic Use
- Clinical studies of Nabilone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Nabilone should be used with caution in elderly patients aged 65 and over because they are generally more sensitive to the psychoactive effects of drugs and Nabilone can elevate supine and standing heart rates and cause postural hypotension.
### Gender
There is no FDA guidance on the use of Nabilone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nabilone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Nabilone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Nabilone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nabilone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nabilone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Nabilone Administration in the drug label.
### Monitoring
There is limited information regarding Nabilone Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Nabilone and IV administrations.
# Overdosage
- Signs and symptoms of overdosage are an extension of the psychotomimetic and physiologic effects of Nabilone.
- To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians' Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.
- Overdosage may be considered to have occurred, even at prescribed dosages, if disturbing psychiatric symptoms are present. In these cases, the patient should be observed in a quiet environment and supportive measures, including reassurance, should be used. Subsequent doses should be withheld until patients have returned to their baseline mental status; routine dosing may then be resumed if clinically indicated. In such instances, a lower initiating dose is suggested. In controlled clinical trials, alterations in mental status related to the use of Nabilone resolved within 72 hours without specific medical therapy. In overdose settings, attention should be paid to vital signs, since both hypertension and hypotension have been known to occur; tachycardia and orthostatic hypotension were most commonly reported.
- No cases of overdosage with more than 10 mg/day of nabilone were reported during clinical trials. Signs and symptoms that would be expected to occur in large overdose situations are psychotic episodes, including hallucinations, anxiety reactions, respiratory depression, and coma. If psychotic episodes occur, the patient should be managed conservatively, if possible. For moderate psychotic episodes and anxiety reactions, verbal support and comforting may be sufficient. In more severe cases, antipsychotic drugs may be useful; however, the utility of antipsychotic drugs in cannabinoid psychosis has not been systematically evaluated. Support for their use is drawn from limited experience using antipsychotic agents to manage cannabis overdoses. Because of the potential for drug-drug interactions (e.g., additive CNS depressant effects due to nabilone and chlorpromazine), such patients should be closely monitored.
- Protect the patient's airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient's vital signs, blood gases, serum electrolytes, as well as other laboratory values and physical assessments. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient's airway when employing gastric emptying or charcoal.
- The use of forced diuresis, peritoneal dialysis, hemodialysis, charcoal hemoperfusion, or cholestyramine has not been reported. In the presence of normal renal function, most of a dose of nabilone is eliminated through the biliary system. Treatment for respiratory depression and comatose state consists in symptomatic and supportive therapy. Particular attention should be paid to the occurrence of hypothermia. If the patient becomes hypotensive, consider fluids, inotropes, and/or vasopressors. The estimated oral median lethal dose in female mice is between 1,000 and 2,000 mg/kg; in the female rat, it is greater than 2,000 mg/kg,
# Pharmacology
## Mechanism of Action
- Chemically, nabilone is similar to the active ingredient found in naturally occurring Cannabis sativa L. [Marijuana; delta-9-tetrahydrocannabinol (delta-9-THC)]. Nabilone is (±)-trans-3-(1,1-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6-6-dimethyl-9H-dibenzo[b,d]pyran-9-one and has the empirical formula C24H36O3. It has a molecular weight of 372.55. The structural formula is as follows:
## Structure
There is limited information regarding Nabilone Structure in the drug label.
## Pharmacodynamics
Nabilone (nabilone) is an orally active synthetic cannabinoid which, like other cannabinoids, has complex effects on the central nervous system (CNS). It has been suggested that the antiemetic effect of nabilone is caused by interaction with the cannabinoid receptor system, i.e., the CB (1) receptor, which has been discovered in neural tissues.
- Nabilone, a synthetic cannabinoid, has the potential to be abused and to produce psychological dependence. Nabilone has complex effects on the central nervous system. Its effects on the mental state (i.e., "inner mental life") are similar to those of cannabis. Subjects given Nabilone may experience changes in mood (euphoria, detachment, depression, anxiety, panic, paranoia), decrements in cognitive performance and memory, a decreased ability to control drives and impulses, and alterations in the experience of reality (e.g., distortions in the perception of objects and the sense of time, hallucinations). These phenomena appear to be more common when larger doses of Nabilone are administered; however, a full-blown picture of psychosis (psychotic organic brain syndrome) may occur in patients receiving doses within the lower portion of the therapeutic range.
- Data on the chronic use of Nabilone are not available; experience with cannabis suggests that chronic use of cannabinoids may be associated with a variety of untoward effects on motivation, cognition, judgment, as well as other mental status changes. Whether these phenomena reflect the underlying character of individuals chronically abusing cannabis or are a result of the use of cannabis is not known.
- The simultaneous use of Nabilone and alcohol or barbiturates may produce additive depressive effects on central nervous system function. Possible changes in mood and other adverse behavioral effects may occur in patients receiving Nabilone. Patients should remain under supervision of a responsible adult while using Nabilone. Nabilone has central nervous system activity. It produces relaxation, drowsiness, and euphoria in the recommended dosage range. Tolerance to these effects develops rapidly and is readily reversible.
- In addition to effects on the mental state, Nabilone has several systemic actions; most prominent are dry mouth and hypotension. Nabilone has been observed to elevate supine and standing heart rates and to cause supine and orthostatic hypotension. In clinical studies, oral administration of 2 mg of Nabilone did produce some decrease in airway resistance in normal controls but had no effect in patients with asthma. No other nontherapeutic effects of clinical significance due to Nabilone have been reported.
## Pharmacokinetics
- Nabilone (nabilone) appears to be completely absorbed from the human gastrointestinal tract when administered orally. Following oral administration of a 2 mg dose of radiolabeled nabilone, peak plasma concentrations of approximately 2 ng/mL nabilone and 10 ng equivalents/mL total radioactivity are achieved within 2.0 hours. The plasma half-life (T1/2) values for nabilone and total radioactivity of identified and unidentified metabolites are about 2 and 35 hours, respectively. The initial rapid disappearance of radioactivity represents uptake and distribution of nabilone into tissue and the slower phase elimination by metabolism and excretion. The apparent volume of distribution of nabilone is about 12.5 L/kg. Nabilone exhibits dose linearity within its therapeutic range. Clinical data suggests that the intake of food does not significantly affect either the rate or extent of absorption.
- Metabolism of nabilone is extensive and several metabolites have been identified. Precise information concerning the metabolites that may accumulate is not available. The relative activities of the metabolites and the parent drug have not been established. There are at least two metabolic pathways involved in the biotransformation of nabilone. A minor pathway is initiated by the stereospecific enzymatic reduction of the 9-keto moiety of nabilone to produce the isomeric carbinol metabolite. The peak concentrations of nabilone and its carbinol metabolites are comparable, but their combined exposures in plasma do not account for more than 20% of that of total radioactivity. Secondly, a metabolite of nabilone in feces has been identified as a diol formed by reduction of the 9-keto group plus oxidation at the penultimate carbon of the dimethylheptyl side chain. In addition, there is evidence of extensive metabolism of Nabilone by multiple P450 enzyme isoforms. In vitro P450 inhibition studies using human liver microsomes showed that nabilone did not significantly inhibit CYP1A2, CYP2A6, CYP2C19, CYP2D6, and CYP3A4 (using midazolam and nifedipine as substrates). Nabilone had a weak inhibitory effect on CYP2E1 and CYP3A4 (testosterone IC50 > 50 µM) and had a moderate inhibitory effect on CYP2C8 and CYP2C9 (IC50 > 10 µM). However, in clinical use, the very low nabilone plasma concentration is unlikely to interfere with the P450-mediated degradation of co-administered drugs. Chronic oral administration of 1 mg t.i.d. for 14 days to 3 subjects gave no indication there was any significant accumulation of nabilone. Available evidence suggests that one or more of the metabolites has a terminal elimination half-life that exceeds that of nabilone. Consequently, in repeated use, the metabolites may accumulate at concentrations in excess of the parent drug.
- The route and rate of the elimination of nabilone and its metabolites are similar to those observed with other cannabinoids, including delta-9-THC (dronabinol). When nabilone is administered intravenously, the drug and its metabolites are eliminated mainly in the feces (approximately 67%) and to a lesser extent in the urine (approximately 22%) within 7 days. Of the 67% recovered from the feces, 5% corresponded to the parent compound and 16% to its carbinol metabolite. Following oral administration about 60% of nabilone and its metabolites were recovered in the feces and about 24% in urine. Therefore, it appears that the major excretory pathway is the biliary system. The effects of age, gender, hepatic dysfunction, and renal insufficiency on the metabolism and elimination of nabilone have not been determined.
## Nonclinical Toxicology
There is limited information regarding Nabilone Nonclinical Toxicology in the drug label.
# Clinical Studies
- Nabilone was evaluated for its effectiveness and safety in the treatment of nausea and vomiting induced by cancer chemotherapy in patients receiving a wide variety of chemotherapy regimens, including low-dose cisplatin (20 mg/m2) in both placebo-controlled and active controlled (prochlorperazine) trials. During Nabilone treatment patients reported a higher incidence of adverse effects. The most frequent were drowsiness, vertigo, dry mouth and euphoria. However, most of the adverse effects occurring with Nabilone were of mild to moderate severity.
# How Supplied
- Nabilone® capsules (blue and white): 1 mg (bottles of 50 capsules) NDC 0037-1221-50. Capsules are imprinted with MEDA on the blue cap and a four-digit code (1221) on the white body.
## Storage
- Store at controlled room temperature, 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Nabilone Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Nabilone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Cesamet
# Look-Alike Drug Names
There is limited information regarding Nabilone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cesamet | |
ddd2211b7f6bf4b6dcce4ab95c6fcd4064fffffb | wikidoc | Chaining | Chaining
Chaining is an instructional procedure used in Behavioral psychology, experimental analysis of behavior and applied behavior analysis. It involves reinforcing individual responses occurring in a sequence to form a complex behavior. It is frequently used for training behavioral sequences (or "chains") that are beyond the current repertoire of the learner.
# Procedure
The chain of responses is broken down into small steps using task analysis. Parts of a chain are referred to as links. The learner's skill level is assessed by an appropriate professional and is then either taught one step at a time while being assisted through the other steps forward or backwards or if the learner already can complete a certain percentage of the steps independently, the remaining steps are all worked on during each trial total task. A verbal stimulus or prompt is used at the beginning of the teaching trial. The stimulus change that occurs between each response becomes the reinforcer for that response as well as the prompt/stimulus for the next response without requiring assistance from the teacher. For example, in purchasing a soda you pull the money out of your pocket and see the money in your hand and then put the money in the machine. Seeing the money in your hand both was the reinforcer for the first response (getting money out of pocket) and was what prompted you to do the next response (putting money in machine).
As small chains become mastered, i.e. are performed consistently following the initial discriminative stimulus prompt, they may be used as links in larger chains. . Chaining requires that the teachers present the training skill in the same order each time and is most effective when teachers are delivering the same prompts to the learner. The most common forms of chaining are backward chaining, forward chaining, and total task presentation. | Chaining
Chaining is an instructional procedure used in Behavioral psychology, experimental analysis of behavior and applied behavior analysis. It involves reinforcing individual responses occurring in a sequence to form a complex behavior. It is frequently used for training behavioral sequences (or "chains") that are beyond the current repertoire of the learner.
# Procedure
The chain of responses is broken down into small steps using task analysis. Parts of a chain are referred to as links. The learner's skill level is assessed by an appropriate professional and is then either taught one step at a time while being assisted through the other steps forward or backwards or if the learner already can complete a certain percentage of the steps independently, the remaining steps are all worked on during each trial total task. A verbal stimulus or prompt is used at the beginning of the teaching trial. The stimulus change that occurs between each response becomes the reinforcer for that response as well as the prompt/stimulus for the next response without requiring assistance from the teacher. For example, in purchasing a soda you pull the money out of your pocket and see the money in your hand and then put the money in the machine. Seeing the money in your hand both was the reinforcer for the first response (getting money out of pocket) and was what prompted you to do the next response (putting money in machine).
As small chains become mastered, i.e. are performed consistently following the initial discriminative stimulus prompt, they may be used as links in larger chains. [Ex. teach hand washing, tooth brushing, and showering until mastered and then teach morning hygiene routine which includes the mastered skills]. Chaining requires that the teachers present the training skill in the same order each time and is most effective when teachers are delivering the same prompts to the learner. The most common forms of chaining are backward chaining, forward chaining, and total task presentation. | https://www.wikidoc.org/index.php/Chaining | |
0c8f5f0c7059ced716f638a5d3dd54946d5aa8ac | wikidoc | Tramadol | Tramadol
# Disclaimer
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# Overview
Tramadol is an opioid analgesic that is FDA approved for the treatment of management of moderate to moderately severe chronic pain in adults who require around-the-clock treatment of their pain for an extended period of time. Common adverse reactions include seizure risk, suicide risk, serotonin syndrome, anaphylactoid and allergic reactions, respiratory depression, withdrawal symptoms.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- It is indicated for the management of moderate to moderately severe chronic pain in adults who require around-the-clock treatment of their pain for an extended period of time.
- 100 mg Capsules: White capsule imprinted with blue ink “G 252” on cap and “100” between lines on the body
- 200 mg Capsules: White capsule imprinted with violet ink “G 253” on cap and “200” between lines on the body
- 300 mg Capsules: White capsule imprinted with red ink “G 254” on cap and “300” between lines on the body
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tramadol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tramadol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Tramadol in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tramadol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tramadol in pediatric patients.
# Contraindications
- Tramadol is contraindicated in patients who have previously demonstrated hypersensitivity to tramadol, any other component of ConZip™, or opioids. Reactions range from pruritis to fatal anaphylactoid reactions.
- ConZip™ is contraindicated in patients with significant respiratory depression in unmonitored settings or the absence of resuscitative equipment.
- ConZip™ is contraindicated in patients with acute or severe bronchial asthma or hypercapnia in unmonitored settings or the absence of resuscitative equipment.
# Warnings
- Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. - Concomitant use of tramadol increases the seizure risk in patients taking:
- Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors (SNRIs) antidepressants or anorectics,
Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), other opioids, MAO inhibitors, neuroleptics, or other drugs that reduce the seizure threshold.
- Risk of seizures may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections).
- In tramadol overdose, naloxone administration may increase the risk of seizure.
- Do not prescribe ConZip™ for patients who are suicidal or addiction-prone. Consideration should be given to the use of non-narcotic analgesics in patients who are suicidal or depressed.
- Prescribe ConZip™ with caution for patients with a history of misuse and/or are taking CNS-active drugs including tranquilizers or antidepressant drugs, or alcohol in excess, and patients who suffer from emotional disturbance or depression.
- Tell your patients not to exceed the recommended dose and to limit their intake of alcohol.
- The development of a potentially life-threatening serotonin syndrome may occur with use of tramadol products, including ConZip™ , particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs and triptans, with drugs which impair metabolism of serotonin (including MAOIs) and with drugs which impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors).
- This may occur within the recommended dose.
- Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
- Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol. When these events do occur it is often following the first dose.
- Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive ConZip™.
- Administer ConZip™ cautiously in patients at risk for respiratory depression.
- In these patients alternative non-opioid analgesics should be considered. If large doses of tramadol are administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose.
- If naloxone is to be administered, use cautiously because it may precipitate seizures.
- Tramadol may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. Use ConZip™ with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics.
- ConZip™ increases the risk of CNS and respiratory depression in these patients. Alcohol-containing beverages should not be consumed by patients using ConZip™.
- Use ConZip™ with caution in patients with increased intracranial pressure or head injury.
- The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in these patients.
- Additionally, pupillary changes (miosis) from tramadol may obscure the existence, extent, or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving ConZip™.
- ConZip™ may impair the mental and or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.
- Caution patients initiating therapy with ConZip™ or those whose dose has been increased to refrain from potentially hazardous activities until it is established that their mental and physical abilities are not significantly impaired.
- Use ConZip™ with great caution in patients taking monoamine oxidase inhibitors.
- Animal studies have shown increased deaths with combined administration. Concomitant use of ConZip™ with MAO inhibitors or SSRI's increases the risk of adverse reactions, including seizure and serotonin syndrome.
- Withdrawal symptoms may occur if ConZip™ is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations.
- Clinical experience with other formulations of tramadol suggests that withdrawal symptoms may be reduced by tapering ConZip™ when discontinuing tramadol therapy.
- ConZip™ contains tramadol, an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.
- Tramadol can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing ConZip™ in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.
- ConZip™ could be abused by crushing, chewing, snorting, or injecting the dissolved product. These practices will result in the uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death.
- Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients.
- Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.
- Serious potential consequences of overdosage with ConZip™ are central nervous system depression, respiratory depression and death. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment.
- The administration of ConZip™ may complicate the clinical assessment of patients with acute abdominal conditions.
# Adverse Reactions
## Clinical Trials Experience
- The serious or otherwise important adverse reactions are following.
- Seizure risk
- Suicide risk
- Serotonin syndrome
- Anaphylactoid and allergic reactions
- Respiratory depression
- Withdrawal symptoms
- 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.
- ConZip™ capsules were administered to a total of 1987 patients in clinical trials. These included four double-blind and one long-term, open-label study in patients with osteoarthritis of the hip and knee. A total of 812 patients were 65 years or older.
- Adverse reactions with doses from 100 mg to 300 mg in the four pooled, randomized, double-blind, placebo-controlled studies in patients with chronic non-malignant pain are presented in the following table.
- Cardiac disorders: hypertension
- Gastrointestinal disorders: dyspepsia, flatulence
- General disorders: abdominal pain, accidental injury, chills, fever, flu syndrome, neck pain, pelvic pain
- Investigations: hyperglycemia, urine abnormality
- Metabolism and nutrition disorders: peripheral edema, weight loss
- Musculoskeletal, connective tissue and bone disorders: myalgia
- Nervous system disorders: paresthesia, tremor, withdrawal syndrome
- Psychiatric disorders: agitation, anxiety, apathy, confusion, depersonalization, depression, euphoria, nervousness
- Respiratory, thoracic and mediastinal disorders: bronchitis, pharyngitis, rhinitis, sinusitis
- Skin and subcutaneous tissue disorders: rash
- Urogenital disorders: prostatic disorder, urinary tract infection
- Vascular disorders: vasodilatation
- Cardiac disorders: EKG abnormal, hypotension, tachycardia
- Gastrointestinal disorders: gastroenteritis
- General disorders: neck rigidity, viral infection
- Hematologic/Lymphatic disorders; anemia, ecchymoses
- Metabolism and nutrition disorders: blood urea nitrogen increased, GGT increased, gout, SGPT increased
- Musculoskeletal disorders: arthritis, arthrosis, joint disorder, leg cramps
- Nervous system disorders: emotional lability, hyperkinesia, hypertonia, thinking abnormal, twitching, vertigo
- Respiratory disorders: pneumonia
- Skin and subcutaneous tissue disorders: hair disorder, skin disorder, urticaria
- Special Senses: eye disorder, lacrimation disorder
- Urogenital disorders: cystitis, dysuria, sexual function abnormality, urinary retention
## Postmarketing Experience
There is limited information regarding Tramadol Postmarketing Experience in the drug label.
# Drug Interactions
- Concomitant use of tramadol increases the seizure risk in patients taking SSRI/SNRI antidepressants or anorectics, TCA antidepressants and other tricyclic compounds, other opioids, MAOIs, neuroleptics or other drugs that lower the seizure threshold.
- Tramadol is metabolized by CYP2D6 to form the active metabolite, O-desmethyl tramadol (M1). In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol.
- Tramadol is also metabolized by CYP3A4. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin with ConZip™ may affect the metabolism of tramadol leading to altered tramadol exposure.
- Concomitant administration of CYP2D6 and/or CYP3A4 inhibitors, such as quinidine, fluoxetine, paroxetine and amitriptyline (CYP2D6 inhibitors), and ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of tramadol increasing the risk for serious adverse events including seizures and serotonin syndrome.
- There have been post-marketing reports of serotonin syndrome with use of tramadol and SSRIs/SNRIs or MAOIs and α2-adrenergic blockers. Caution is advised when ConZip™ is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, or St. John's Wort. If concomitant treatment of ConZip™ with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
- Based on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is advised when ConZip™ is co-administered with a triptan.
- If concomitant treatment of ConZip™ with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
- ConZip™ should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. ConZip™ increases the risk of CNS and respiratory depression in these patients.
- Quinidine is a strong inhibitor of CYP2D6. Coadministration of quinidine with an extended-release tramadol product resulted in a 50-60% increase in tramadol exposure and a 50-60% decrease in M1 exposure. The clinical consequences of these findings are unknown.
- In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism.
- Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times.
- Administration of CYP3A4 inducers, such as carbamazepine, rifampin and St. John's Wort, with ConZip™ may affect the metabolism of tramadol leading to reduced tramadol exposure.
- Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of ConZip™ and carbamazepine is not recommended.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies in pregnant women. Use ConZip™ during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during post-marketing reports with tramadol HCl immediate-release products. ConZip™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Tramadol was not teratogenic at oral dose levels up to 50 mg/kg/day (1.6-fold the maximum daily human dose (MDHD)) in rats and 100 mg/kg (approximately 6.5-fold MDHD) in rabbits during organogenesis. However, embryo-fetal lethality, reductions in fetal weight and skeletal ossification, and increased supernumerary ribs were observed at a maternal toxic dose of 140 mg/kg in mice (approximately 2.3-fold MDHD), 80 mg/kg in rats (2.6-fold MDHD) or 300 mg/kg in rabbits (approximately 19-fold MDHD).
- Tramadol caused a reduction in neonatal body weight at a dose of 50 mg/kg (1.6-fold the MDHD) and reduced pup survival at an oral dose of 80 mg/kg (approximately 2.6-fold MDHD) when rats were treated during late gestation throughout lactation period.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tramadol in women who are pregnant.
### Labor and Delivery
- ConZip™ should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks.
- Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and post-partum withdrawal symptoms in the newborn.
- Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor.
- The effect of ConZip™, if any, on the later growth, development, and functional maturation of the child is unknown.
### Nursing Mothers
- ConZip™ is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied.
- Following a single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours post-dose was 100 μg of tramadol (0.1% of the maternal dose) and 27 μg of M1. It is not known whether this drug is excreted in human milk following an oral dose.
### Pediatric Use
- The safety and efficacy of ConZip™ in patients under 18 years of age have not been established. The use of ConZip™ in the pediatric population is not recommended.
### Geriatic Use
- In general, caution should be used when selecting the dose for an elderly patient. Usually, dose administration should start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.
- Eight hundred and twelve elderly (65 years of age or older) subjects were exposed to ConZip™ in clinical trials. Of those subjects, two hundred and forty were 75 years of age and older. In general, higher incidence rates of adverse events were observed for patients older than 65 years of age compared with patients 65 years and younger, particularly for the following adverse events: nausea, constipation, somnolence, dizziness, dry mouth, vomiting, asthenia, pruritus, anorexia sweating, fatigue, weakness, postural hypotension and dyspepsia.
- For this reason, ConZip™ should be used with great caution in patients older than 75 years of age.
### Gender
There is no FDA guidance on the use of Tramadol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tramadol with respect to specific racial populations.
### Renal Impairment
- ConZip™ has not been studied in patients with renal impairment. Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1.
- The limited availability of dose strengths of ConZip™ does not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, ConZip™ should not be used in patients with severe renal impairment.
### Hepatic Impairment
- ConZip™ has not been studied in patients with hepatic impairment. The limited availability of dose strengths of ConZip™ does not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, ConZip™ should not be used in patients with severe hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tramadol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tramadol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
- ConZip™ is an extended-release formulation intended for once a day dosing in adults aged 18 years and older. The tablets must be swallowed whole with liquid and must not be split, chewed, dissolved or crushed.
- Chewing, crushing or splitting the tablet could result in the uncontrolled delivery of tramadol, in overdose and death.
- Do not administer ConZip™ at a dose exceeding 300 mg per day. Do not use ConZip™ more than once daily or concomitantly with other tramadol products.
- Initiate treatment with ConZip™ at a dose of 100 mg once daily and titrated up as necessary by 100 mg increments every five days to achieve a balance between relief of pain and tolerability.
- Calculate the 24-hour tramadol IR dose and initiate a total daily dose of ConZip™ rounded down to the next lowest 100 mg increment. The dose may subsequently be individualized according to patient need. Due to limitations in flexibility of dose selection with ConZip™, some patients maintained on tramadol IR products may not be able to convert to ConZip™.
- Initiate dosing of an elderly patient (over 65 years of age) should be initiated cautiously, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.
- ConZip™ should be administered with even greater caution in patients over 75 years, due to the greater frequency of adverse events seen in this population.
- The limited availability of dose strengths and once daily dosing of ConZip™ do not permit the dosing flexibility required for safe use in patients with severe renal impairment. Do not use ConZip™ in patients with creatinine clearance less than 30 mL/min.
- The limited availability of dose strengths and once daily dosing of tramadol hydrochloride extended-release capsules do not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. - Do not use ConZip™ in patients with severe hepatic impairment (Child-Pugh Class C).
- Withdrawal symptoms may occur if ConZip™ is discontinued abruptly. Clinical experience with tramadol suggests that withdrawal symptoms may be reduced by tapering ConZip™.
- ConZip™ may be taken without regard to food.
# IV Compatibility
There is limited information regarding IV Compatibility of Tramadol in the drug label.
# Overdosage
- Acute overdosage with tramadol can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, bradycardia, hypotension, and death.
- Deaths due to overdose have been reported with abuse and misuse of tramadol, by ingesting, inhaling, or injecting the crushed tablets. Review of case reports has indicated that the risk of fatal overdose is further increased when tramadol is abused concurrently with alcohol or other CNS depressants, including other opioids.
- In the treatment of tramadol overdosage, primary attention should be given to the reestablishment of a patent airway and institution of assisted or controlled ventilation. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated.
- Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
- While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration.
- In animals, convulsions following the administration of toxic doses of ConZip™ could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice.
- Hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period.
# Pharmacology
## Mechanism of Action
- ConZip™ contains tramadol, a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to μ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin.
- Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to μ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests.
- The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound.
## Structure
## Pharmacodynamics
- Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramadol.
- The relationship between exposure of tramadol and M1 and efficacy has not been evaluated in clinical studies.
- Apart from analgesia, tramadol administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids.
- In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left ventricular function or cardiac index.
- Orthostatic hypotension has been observed.
## Pharmacokinetics
- The analgesic activity of tramadol is due to both parent drug and the M1 metabolite. ConZip™ is administered as a racemate and both tramadol and M1 are detected in the circulation.
- The Cmax and AUC of ConZip™ capsules have been observed to be dose-proportional over an oral dose range of 100 to 300 mg in healthy subjects.
- After a single dose administration of ConZip™, Tmax occurs around 10-12 hours.
- The mean Cmax and AUC of ConZip™ capsules after a 300 mg single dose was 308 ng/mL and 6777 ng*hr/mL, respectively under fasting conditions. ConZip™ is bioequivalent to a reference extended-release tramadol product following a single 300 mg dose under fasting conditions.
- At steady-state, ConZip™ at 200 mg has been observed to be bioequivalent to a reference extended-release tramadol product at 200 mg under fasting conditions.
- Following administration of ConZip™ 200 mg capsules, steady-state plasma concentrations of both tramadol and M1 are achieved within four days of once daily dosing.
- The rate and extent of absorption of ConZip™ capsules (300 mg) are similar following oral administration with or without food. Therefore, ConZip™ capsules can be administered without regard to meals.
- The volume of distribution of tramadol was 2.6 and 2.9 liters/kg in male and female subjects, respectively, following a 100 mg intravenous tramadol dose.
- The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 μg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.
- Tramadol is extensively metabolized after oral administration. The major metabolic pathways appear to be N – (mediated by CYP3A4 and CYP2B6) and O – (mediated by CYP2D6) demethylation and glucuronidation or sulfation in the liver.
- One metabolite (O-desmethyl tramadol, denoted M1) is pharmacologically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition and polymorphism, which may affect the therapeutic response.
- Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys.
- Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites.
- The mean plasma elimination half-lives of racemic tramadol and racemic M1 after administration of ConZip™ capsules are approximately 10 and 11 hours, respectively.
- Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. The pharmacokinetics of tramadol was studied in patients with mild or moderate renal impairment after receiving multiple doses of an extended-release tramadol product at 100 mg.
- There is no consistent trend observed for tramadol exposure related to renal function in patients with mild (CLcr: 50-80 mL/min) or moderate (CLcr: 30-50 mL/min) renal impairment in comparison to patients with normal renal function (CLcr > 80 mL/min).
- However, exposure of M1 increased 20-40% with increased severity of the renal impairment (from normal to mild and moderate). The pharmacokinetics of tramadol has not been studied in patients with severe renal impairment (CLcr < 30 mL/min).
- The limited availability of dose strengths of ConZip™ does not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, ConZip™ should not be used in patients with severe renal impairment.
- The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose.
- Pharmacokinetics of tramadol was studied in patients with mild or moderate hepatic impairment after receiving multiple doses of an extended-release tramadol product at 100 mg.
- The exposure of (+)- and (-)-tramadol was similar in mild and moderate hepatic impairment patients in comparison to patients with normal hepatic function. However, exposure of (+)- and (-)-M1 decreased ~50% with increased severity of the hepatic impairment (from normal to mild and moderate).
- The pharmacokinetics of tramadol has not been studied in patients with severe hepatic impairment. After the administration of tramadol immediate-release tablets to patients with advanced cirrhosis of the liver, tramadol area under the plasma concentration time curve was larger and the tramadol and M1 half-lives were longer than subjects with normal hepatic function.
- The limited availability of dose strengths of ConZip™ does not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, ConZip™ should not be used in patients with severe hepatic impairment.
- Based on pooled multiple-dose pharmacokinetics studies for an extended-release tramadol product in 166 healthy subjects (111 males and 55 females), the dose-normalized AUC values for tramadol were somewhat higher in females than in males.
- There was a considerable degree of overlap in values between male and female groups. Dosage adjustment based on gender is not recommended.
- The effect of age on pharmacokinetics of ConZip™ has not been studied. Healthy elderly subjects aged 65 to 75 years administered an immediate-release formulation of tramadol, have plasma concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age.
- In subjects over 75 years, mean maximum plasma concentrations are elevated (208 vs. 162 ng/mL) and the mean elimination half-life is prolonged (7 vs. 6 hours) compared to subjects 65 to 75 years of age.
- Adjustment of the daily dose is recommended for patients older than 75 years.
- The formation of the active metabolite, M1, is mediated by CYP2D6, a polymorphic enzyme. Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P-450 metabolizing enzyme system. These individuals are “poor metabolizers” of debrisoquine, dextromethorphan and tricyclic antidepressants, among other drugs. Based on a population PK analysis of Phase 1 studies with IR tablets in healthy subjects, concentrations of tramadol were approximately 20% higher in "poor metabolizers" versus "extensive metabolizers," while M1 concentrations were 40% lower.
- In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol.
- Tramadol is metabolized to active metabolite M1 by CYP2D6. Coadministration of quinidine, a selective inhibitor of CYP2D6, with tramadol ER resulted in a 50-60% increase in tramadol exposure and a 50-60% decrease in M1 exposure. The clinical consequences of these findings are unknown.
- To evaluate the effect of tramadol, a CYP2D6 substrate on quinidine, an in vitro drug interaction study in human liver microsomes was conducted. The results from this study indicate that tramadol has no effect on quinidine metabolism.
- Since tramadol is also metabolized by CYP3A4, administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or CYP3A4 inducers, such as rifampin and St. John's Wort, with ConZip™ may affect the metabolism of tramadol leading to altered tramadol exposure
- Concomitant administration of tramadol immediate-release tablets with cimetidine, a weak CPY3A4 inhibitor, does not result in clinically significant changes in tramadol pharmacokinetics. No alteration of the ConZip™ dosage regimen with cimetidine is recommended.
- Carbamazepine, a CYP3A4 inducer, increases tramadol metabolism. Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Concomitant administration of ConZip™ and carbamazepine is not recommended.
## Nonclinical Toxicology
- Carcinogenicity assessment has been conducted in mice, rats and p53(+/-) heterozygous mice. A slight, but statistically significant, increase in two common murine tumors, pulmonary and hepatic, was observed in a mouse carcinogenicity study, particularly in aged mice. Mice were dosed orally up to 30 mg/kg (90 mg/m2 or 0.5 times the maximum daily human dosage of 185 mg/m2) for approximately two years, although the study was not done with the Maximum Tolerated Dose. This finding is not believed to suggest risk in humans.
- No treatment-related tumors were noted in a rat carcinogenicity study (dosing orally up to 30 mg/kg, 180 mg/m2, or equivalent to the maximum daily human dosage) or in a second study where rats were treated with up to 75 mg/kg/day for males and 100 mg/kg/day for females (approximately 2.4 and 3.2-fold MDHD, respectively) for two years. However, the excessive decrease in body weight gain observed in the rat study might have reduced their sensitivity to any potential carcinogenic effect of the drug.
- No carcinogenic effect of tramadol was observed in p53(+/–)-heterozygous mice at oral doses up to 150 mg/kg/day (approximately 2.4-fold maximum daily human dose of 300 mg/day for a 60 kg adult based on body surface conversion) for 26 weeks.
- Tramadol was not mutagenic in the following assays: a bacterial reverse mutation assay using Salmonella and E. coli, a mouse lymphoma assay (in the absence of metabolic activation), chromosomal aberration test in Chinese hamsters, a bone marrow micronucleus test in mice and Chinese hamsters, and a dominant lethal mutation test in mice. Mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats. Overall, the weight of evidence from these tests indicates that tramadol does not pose a genotoxic risk to humans.
- No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg/day in male and female rats (1.6-fold the MDHD).
# Clinical Studies
- ConZip™ is bioequivalent under fasting conditions to another extended-release tramadol product which did demonstrate efficacy in two of four clinical trials of patients with chronic pain.
- To qualify for inclusion into these studies, patients were required to have moderate to moderately severe pain as defined by a pain intensity score of ≥40 mm, off previous medications, on a 0 – 100 mm visual analog scale (VAS).
- In one 12-week randomized, double-blind, placebo-controlled study, patients with moderate to moderately severe pain due to osteoarthritis of the knee and/or hip were administered doses from 100 mg to 400 mg daily. Treatment with the extended-release tramadol product was initiated at 100 mg once daily for four days then increased by 100 mg per day increments every five days to the randomized fixed dose. Between 51% and 59% of patients in active treatment groups completed the study and 56% of patients in the placebo group completed the study.
- Discontinuations due to adverse events were more common in the extended-release tramadol product 200 mg, 300 mg and 400 mg treatment groups (20%, 27%, and 30% of discontinuations, respectively) compared to 14% of the patients treated with the extended-release tramadol product 100 mg and 10% of patients treated with placebo.
- Pain, as assessed by the WOMAC Pain subscale, was measured at 1, 2, 3, 6, 9, and 12 weeks and change from baseline assessed. A responder analysis based on the percent change in WOMAC Pain subscale demonstrated a statistically significant improvement in pain for the 100 mg and 200 mg treatment groups compared to placebo.
- In one 12-week randomized, double-blind, placebo-controlled flexible-dosing trial of the extended-release tramadol product in patients with osteoarthritis of the knee, patients titrated to an average daily dose of approximately 270 mg/day.
- Forty-nine percent of patients randomized to the active treatment group completed the study, while 52% of patients randomized to placebo completed the study. Most of the early discontinuations in the active treatment group were due to adverse events, accounting for 27% of the early discontinuations in contrast to 7% of the discontinuations from the placebo group.
- Thirty-seven percent of the placebo-treated patients discontinued the study due to lack of efficacy compared to 15% of active-treated patients. The active treatment group demonstrated a statistically significant decrease in the mean Visual Analog Scale (VAS) score, and a statistically significant difference in the responder rate, based on the percent change from baseline in the VAS score, measured at 1, 2, 4, 8, and 12 weeks, between patients receiving the extended-release tramadol product and placebo
- Four randomized, placebo-controlled clinical trials of ConZip™ were conducted, none of which demonstrated efficacy but which differed in design from the preceding clinical studies described.
- Two trials were 12-week randomized placebo-controlled trials of ConZip™ 100 mg/day, 200 mg/day, and 300 mg/day versus placebo in patients with moderate to moderately severe osteoarthritis pain of the hip and knee. The other two 12 week trials were similar in design, but only studied ConZip™ 300 mg/day.
- In this fixed-dose design, subjects were required to titrate to a fixed dose, even if their pain responded to a lower titration dose
# How Supplied
- ConZip™ capsules (tramadol hydrochloride) are supplied as opaque white hard gelatin capsules, imprinted as follows.
- 100 mg Capsules: White capsule imprinted with blue ink “G 252” on cap and “100” between lines on the body
- Bottle of 30 capsules: NDC 68025-053-30
- 200 mg Capsules: White capsule imprinted with violet ink “G 253” on cap and “200” between lines on the body
- Bottle of 30 capsules: NDC 68025-055-30
- 300 mg Capsules: White capsule imprinted with red ink “G 254” on cap and “300” between lines on the body
- Bottle of 30 capsules: NDC 68025-056-30
## Storage
- Dispense in a tight container. Store at 25°C; excursions permitted to 15°C to 30°C (59°F to 86°F). Keep out of reach of children.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Inform patients that:
- ConZip™ is for oral use only and should be swallowed whole. The capsule should not be chewed, dissolved, crushed or split.
- ConZip™ may cause seizures and/or serotonin syndrome with concomitant use of serotonergic agents (including SRIs, NRIs, and triptans) or drugs that significantly reduce the metabolic clearance of tramadol.
- Not to change the prescribed single-dose or 24-hour dosing regimen of ConZip™, and that exceeding the prescribed dose can result in respiratory depression, seizures or death.
- ConZip™ may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.
- ConZip™ should not be taken with alcohol containing beverages.
ConZip™ should be used with caution when taking medications such as tranquilizers, hypnotics or other opiate containing analgesics.
- Instruct female patients to inform the prescriber if they are pregnant, think they might become pregnant, or are trying to become pregnant.
- ConZip™ is to be taken once-a-day and at approximately the same time every day. Also, exceeding these recommendations and the maximum recommended daily dose can result in respiratory depression, seizures or death.
- Elderly patients, especially those over 75 years of age, and other patients who have renal or hepatic impairments may need to be cautioned about reduced dosages.
- Not to abruptly withdraw or discontinue tramadol therapy, as clinical experience with tramadol suggests the possible onset of signs and symptoms of withdrawal. These affects may be reduced by tapering tramadol therapy.
- ConZip™ must be kept out of reach of children.
# Precautions with Alcohol
- Alcohol-Tramadol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- TRAMADOL HCL®
# Look-Alike Drug Names
There is limited information regarding Tramadol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Tramadol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
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# Overview
Tramadol is an opioid analgesic that is FDA approved for the treatment of management of moderate to moderately severe chronic pain in adults who require around-the-clock treatment of their pain for an extended period of time. Common adverse reactions include seizure risk, suicide risk, serotonin syndrome, anaphylactoid and allergic reactions, respiratory depression, withdrawal symptoms.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- It is indicated for the management of moderate to moderately severe chronic pain in adults who require around-the-clock treatment of their pain for an extended period of time.
- 100 mg Capsules: White capsule imprinted with blue ink “G 252” on cap and “100” between lines on the body
- 200 mg Capsules: White capsule imprinted with violet ink “G 253” on cap and “200” between lines on the body
- 300 mg Capsules: White capsule imprinted with red ink “G 254” on cap and “300” between lines on the body
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
]
There is limited information regarding Off-Label Guideline-Supported Use of Tramadol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tramadol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Tramadol in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tramadol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tramadol in pediatric patients.
# Contraindications
- Tramadol is contraindicated in patients who have previously demonstrated hypersensitivity to tramadol, any other component of ConZip™, or opioids. Reactions range from pruritis to fatal anaphylactoid reactions.
- ConZip™ is contraindicated in patients with significant respiratory depression in unmonitored settings or the absence of resuscitative equipment.
- ConZip™ is contraindicated in patients with acute or severe bronchial asthma or hypercapnia in unmonitored settings or the absence of resuscitative equipment.
# Warnings
- Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. * Concomitant use of tramadol increases the seizure risk in patients taking:
- Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors (SNRIs) antidepressants or anorectics,
Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), other opioids, MAO inhibitors, neuroleptics, or other drugs that reduce the seizure threshold.
- Risk of seizures may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections).
- In tramadol overdose, naloxone administration may increase the risk of seizure.
- Do not prescribe ConZip™ for patients who are suicidal or addiction-prone. Consideration should be given to the use of non-narcotic analgesics in patients who are suicidal or depressed.
- Prescribe ConZip™ with caution for patients with a history of misuse and/or are taking CNS-active drugs including tranquilizers or antidepressant drugs, or alcohol in excess, and patients who suffer from emotional disturbance or depression.
- Tell your patients not to exceed the recommended dose and to limit their intake of alcohol.
- The development of a potentially life-threatening serotonin syndrome may occur with use of tramadol products, including ConZip™ , particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs and triptans, with drugs which impair metabolism of serotonin (including MAOIs) and with drugs which impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors).
- This may occur within the recommended dose.
- Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
- Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol. When these events do occur it is often following the first dose.
- Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive ConZip™.
- Administer ConZip™ cautiously in patients at risk for respiratory depression.
- In these patients alternative non-opioid analgesics should be considered. If large doses of tramadol are administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose.
- If naloxone is to be administered, use cautiously because it may precipitate seizures.
- Tramadol may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. Use ConZip™ with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics.
- ConZip™ increases the risk of CNS and respiratory depression in these patients. Alcohol-containing beverages should not be consumed by patients using ConZip™.
- Use ConZip™ with caution in patients with increased intracranial pressure or head injury.
- The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in these patients.
- Additionally, pupillary changes (miosis) from tramadol may obscure the existence, extent, or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving ConZip™.
- ConZip™ may impair the mental and or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.
- Caution patients initiating therapy with ConZip™ or those whose dose has been increased to refrain from potentially hazardous activities until it is established that their mental and physical abilities are not significantly impaired.
- Use ConZip™ with great caution in patients taking monoamine oxidase inhibitors.
- Animal studies have shown increased deaths with combined administration. Concomitant use of ConZip™ with MAO inhibitors or SSRI's increases the risk of adverse reactions, including seizure and serotonin syndrome.
- Withdrawal symptoms may occur if ConZip™ is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations.
- Clinical experience with other formulations of tramadol suggests that withdrawal symptoms may be reduced by tapering ConZip™ when discontinuing tramadol therapy.
- ConZip™ contains tramadol, an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.
- Tramadol can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing ConZip™ in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.
- ConZip™ could be abused by crushing, chewing, snorting, or injecting the dissolved product. These practices will result in the uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death.
- Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients.
- Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.
- Serious potential consequences of overdosage with ConZip™ are central nervous system depression, respiratory depression and death. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment.
- The administration of ConZip™ may complicate the clinical assessment of patients with acute abdominal conditions.
# Adverse Reactions
## Clinical Trials Experience
- The serious or otherwise important adverse reactions are following.
- Seizure risk
- Suicide risk
- Serotonin syndrome
- Anaphylactoid and allergic reactions
- Respiratory depression
- Withdrawal symptoms
- 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.
- ConZip™ capsules were administered to a total of 1987 patients in clinical trials. These included four double-blind and one long-term, open-label study in patients with osteoarthritis of the hip and knee. A total of 812 patients were 65 years or older.
- Adverse reactions with doses from 100 mg to 300 mg in the four pooled, randomized, double-blind, placebo-controlled studies in patients with chronic non-malignant pain are presented in the following table.
- Cardiac disorders: hypertension
- Gastrointestinal disorders: dyspepsia, flatulence
- General disorders: abdominal pain, accidental injury, chills, fever, flu syndrome, neck pain, pelvic pain
- Investigations: hyperglycemia, urine abnormality
- Metabolism and nutrition disorders: peripheral edema, weight loss
- Musculoskeletal, connective tissue and bone disorders: myalgia
- Nervous system disorders: paresthesia, tremor, withdrawal syndrome
- Psychiatric disorders: agitation, anxiety, apathy, confusion, depersonalization, depression, euphoria, nervousness
- Respiratory, thoracic and mediastinal disorders: bronchitis, pharyngitis, rhinitis, sinusitis
- Skin and subcutaneous tissue disorders: rash
- Urogenital disorders: prostatic disorder, urinary tract infection
- Vascular disorders: vasodilatation
- Cardiac disorders: EKG abnormal, hypotension, tachycardia
- Gastrointestinal disorders: gastroenteritis
- General disorders: neck rigidity, viral infection
- Hematologic/Lymphatic disorders; anemia, ecchymoses
- Metabolism and nutrition disorders: blood urea nitrogen increased, GGT increased, gout, SGPT increased
- Musculoskeletal disorders: arthritis, arthrosis, joint disorder, leg cramps
- Nervous system disorders: emotional lability, hyperkinesia, hypertonia, thinking abnormal, twitching, vertigo
- Respiratory disorders: pneumonia
- Skin and subcutaneous tissue disorders: hair disorder, skin disorder, urticaria
- Special Senses: eye disorder, lacrimation disorder
- Urogenital disorders: cystitis, dysuria, sexual function abnormality, urinary retention
## Postmarketing Experience
There is limited information regarding Tramadol Postmarketing Experience in the drug label.
# Drug Interactions
- Concomitant use of tramadol increases the seizure risk in patients taking SSRI/SNRI antidepressants or anorectics, TCA antidepressants and other tricyclic compounds, other opioids, MAOIs, neuroleptics or other drugs that lower the seizure threshold.
- Tramadol is metabolized by CYP2D6 to form the active metabolite, O-desmethyl tramadol (M1). In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol.
- Tramadol is also metabolized by CYP3A4. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin with ConZip™ may affect the metabolism of tramadol leading to altered tramadol exposure.
- Concomitant administration of CYP2D6 and/or CYP3A4 inhibitors, such as quinidine, fluoxetine, paroxetine and amitriptyline (CYP2D6 inhibitors), and ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of tramadol increasing the risk for serious adverse events including seizures and serotonin syndrome.
- There have been post-marketing reports of serotonin syndrome with use of tramadol and SSRIs/SNRIs or MAOIs and α2-adrenergic blockers. Caution is advised when ConZip™ is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, or St. John's Wort. If concomitant treatment of ConZip™ with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
- Based on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is advised when ConZip™ is co-administered with a triptan.
- If concomitant treatment of ConZip™ with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
- ConZip™ should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. ConZip™ increases the risk of CNS and respiratory depression in these patients.
- Quinidine is a strong inhibitor of CYP2D6. Coadministration of quinidine with an extended-release tramadol product resulted in a 50-60% increase in tramadol exposure and a 50-60% decrease in M1 exposure. The clinical consequences of these findings are unknown.
- In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism.
- Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times.
- Administration of CYP3A4 inducers, such as carbamazepine, rifampin and St. John's Wort, with ConZip™ may affect the metabolism of tramadol leading to reduced tramadol exposure.
- Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of ConZip™ and carbamazepine is not recommended.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies in pregnant women. Use ConZip™ during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during post-marketing reports with tramadol HCl immediate-release products. ConZip™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Tramadol was not teratogenic at oral dose levels up to 50 mg/kg/day (1.6-fold the maximum daily human dose (MDHD)) in rats and 100 mg/kg (approximately 6.5-fold MDHD) in rabbits during organogenesis. However, embryo-fetal lethality, reductions in fetal weight and skeletal ossification, and increased supernumerary ribs were observed at a maternal toxic dose of 140 mg/kg in mice (approximately 2.3-fold MDHD), 80 mg/kg in rats (2.6-fold MDHD) or 300 mg/kg in rabbits (approximately 19-fold MDHD).
- Tramadol caused a reduction in neonatal body weight at a dose of 50 mg/kg (1.6-fold the MDHD) and reduced pup survival at an oral dose of 80 mg/kg (approximately 2.6-fold MDHD) when rats were treated during late gestation throughout lactation period.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tramadol in women who are pregnant.
### Labor and Delivery
- ConZip™ should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks.
- Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and post-partum withdrawal symptoms in the newborn.
- Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor.
- The effect of ConZip™, if any, on the later growth, development, and functional maturation of the child is unknown.
### Nursing Mothers
- ConZip™ is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied.
- Following a single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours post-dose was 100 μg of tramadol (0.1% of the maternal dose) and 27 μg of M1. It is not known whether this drug is excreted in human milk following an oral dose.
### Pediatric Use
- The safety and efficacy of ConZip™ in patients under 18 years of age have not been established. The use of ConZip™ in the pediatric population is not recommended.
### Geriatic Use
- In general, caution should be used when selecting the dose for an elderly patient. Usually, dose administration should start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.
- Eight hundred and twelve elderly (65 years of age or older) subjects were exposed to ConZip™ in clinical trials. Of those subjects, two hundred and forty were 75 years of age and older. In general, higher incidence rates of adverse events were observed for patients older than 65 years of age compared with patients 65 years and younger, particularly for the following adverse events: nausea, constipation, somnolence, dizziness, dry mouth, vomiting, asthenia, pruritus, anorexia sweating, fatigue, weakness, postural hypotension and dyspepsia.
- For this reason, ConZip™ should be used with great caution in patients older than 75 years of age.
### Gender
There is no FDA guidance on the use of Tramadol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tramadol with respect to specific racial populations.
### Renal Impairment
- ConZip™ has not been studied in patients with renal impairment. Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1.
- The limited availability of dose strengths of ConZip™ does not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, ConZip™ should not be used in patients with severe renal impairment.
### Hepatic Impairment
- ConZip™ has not been studied in patients with hepatic impairment. The limited availability of dose strengths of ConZip™ does not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, ConZip™ should not be used in patients with severe hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tramadol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tramadol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
- ConZip™ is an extended-release formulation intended for once a day dosing in adults aged 18 years and older. The tablets must be swallowed whole with liquid and must not be split, chewed, dissolved or crushed.
- Chewing, crushing or splitting the tablet could result in the uncontrolled delivery of tramadol, in overdose and death.
- Do not administer ConZip™ at a dose exceeding 300 mg per day. Do not use ConZip™ more than once daily or concomitantly with other tramadol products.
- Initiate treatment with ConZip™ at a dose of 100 mg once daily and titrated up as necessary by 100 mg increments every five days to achieve a balance between relief of pain and tolerability.
- Calculate the 24-hour tramadol IR dose and initiate a total daily dose of ConZip™ rounded down to the next lowest 100 mg increment. The dose may subsequently be individualized according to patient need. Due to limitations in flexibility of dose selection with ConZip™, some patients maintained on tramadol IR products may not be able to convert to ConZip™.
- Initiate dosing of an elderly patient (over 65 years of age) should be initiated cautiously, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.
- ConZip™ should be administered with even greater caution in patients over 75 years, due to the greater frequency of adverse events seen in this population.
- The limited availability of dose strengths and once daily dosing of ConZip™ do not permit the dosing flexibility required for safe use in patients with severe renal impairment. Do not use ConZip™ in patients with creatinine clearance less than 30 mL/min.
- The limited availability of dose strengths and once daily dosing of tramadol hydrochloride extended-release capsules do not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. * Do not use ConZip™ in patients with severe hepatic impairment (Child-Pugh Class C).
- Withdrawal symptoms may occur if ConZip™ is discontinued abruptly. Clinical experience with tramadol suggests that withdrawal symptoms may be reduced by tapering ConZip™.
- ConZip™ may be taken without regard to food.
# IV Compatibility
There is limited information regarding IV Compatibility of Tramadol in the drug label.
# Overdosage
- Acute overdosage with tramadol can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, bradycardia, hypotension, and death.
- Deaths due to overdose have been reported with abuse and misuse of tramadol, by ingesting, inhaling, or injecting the crushed tablets. Review of case reports has indicated that the risk of fatal overdose is further increased when tramadol is abused concurrently with alcohol or other CNS depressants, including other opioids.
- In the treatment of tramadol overdosage, primary attention should be given to the reestablishment of a patent airway and institution of assisted or controlled ventilation. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated.
- Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
- While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration.
- In animals, convulsions following the administration of toxic doses of ConZip™ could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice.
- Hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period.
# Pharmacology
## Mechanism of Action
- ConZip™ contains tramadol, a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to μ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin.
- Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to μ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests.
- The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound.
## Structure
## Pharmacodynamics
- Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramadol.
- The relationship between exposure of tramadol and M1 and efficacy has not been evaluated in clinical studies.
- Apart from analgesia, tramadol administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids.
- In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left ventricular function or cardiac index.
- Orthostatic hypotension has been observed.
## Pharmacokinetics
- The analgesic activity of tramadol is due to both parent drug and the M1 metabolite. ConZip™ is administered as a racemate and both tramadol and M1 are detected in the circulation.
- The Cmax and AUC of ConZip™ capsules have been observed to be dose-proportional over an oral dose range of 100 to 300 mg in healthy subjects.
- After a single dose administration of ConZip™, Tmax occurs around 10-12 hours.
- The mean Cmax and AUC of ConZip™ capsules after a 300 mg single dose was 308 ng/mL and 6777 ng*hr/mL, respectively under fasting conditions. ConZip™ is bioequivalent to a reference extended-release tramadol product following a single 300 mg dose under fasting conditions.
- At steady-state, ConZip™ at 200 mg has been observed to be bioequivalent to a reference extended-release tramadol product at 200 mg under fasting conditions.
- Following administration of ConZip™ 200 mg capsules, steady-state plasma concentrations of both tramadol and M1 are achieved within four days of once daily dosing.
- The rate and extent of absorption of ConZip™ capsules (300 mg) are similar following oral administration with or without food. Therefore, ConZip™ capsules can be administered without regard to meals.
- The volume of distribution of tramadol was 2.6 and 2.9 liters/kg in male and female subjects, respectively, following a 100 mg intravenous tramadol dose.
- The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 μg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.
- Tramadol is extensively metabolized after oral administration. The major metabolic pathways appear to be N – (mediated by CYP3A4 and CYP2B6) and O – (mediated by CYP2D6) demethylation and glucuronidation or sulfation in the liver.
- One metabolite (O-desmethyl tramadol, denoted M1) is pharmacologically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition and polymorphism, which may affect the therapeutic response.
- Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys.
- Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites.
- The mean plasma elimination half-lives of racemic tramadol and racemic M1 after administration of ConZip™ capsules are approximately 10 and 11 hours, respectively.
- Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. The pharmacokinetics of tramadol was studied in patients with mild or moderate renal impairment after receiving multiple doses of an extended-release tramadol product at 100 mg.
- There is no consistent trend observed for tramadol exposure related to renal function in patients with mild (CLcr: 50-80 mL/min) or moderate (CLcr: 30-50 mL/min) renal impairment in comparison to patients with normal renal function (CLcr > 80 mL/min).
- However, exposure of M1 increased 20-40% with increased severity of the renal impairment (from normal to mild and moderate). The pharmacokinetics of tramadol has not been studied in patients with severe renal impairment (CLcr < 30 mL/min).
- The limited availability of dose strengths of ConZip™ does not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, ConZip™ should not be used in patients with severe renal impairment.
- The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose.
- Pharmacokinetics of tramadol was studied in patients with mild or moderate hepatic impairment after receiving multiple doses of an extended-release tramadol product at 100 mg.
- The exposure of (+)- and (-)-tramadol was similar in mild and moderate hepatic impairment patients in comparison to patients with normal hepatic function. However, exposure of (+)- and (-)-M1 decreased ~50% with increased severity of the hepatic impairment (from normal to mild and moderate).
- The pharmacokinetics of tramadol has not been studied in patients with severe hepatic impairment. After the administration of tramadol immediate-release tablets to patients with advanced cirrhosis of the liver, tramadol area under the plasma concentration time curve was larger and the tramadol and M1 half-lives were longer than subjects with normal hepatic function.
- The limited availability of dose strengths of ConZip™ does not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, ConZip™ should not be used in patients with severe hepatic impairment.
- Based on pooled multiple-dose pharmacokinetics studies for an extended-release tramadol product in 166 healthy subjects (111 males and 55 females), the dose-normalized AUC values for tramadol were somewhat higher in females than in males.
- There was a considerable degree of overlap in values between male and female groups. Dosage adjustment based on gender is not recommended.
- The effect of age on pharmacokinetics of ConZip™ has not been studied. Healthy elderly subjects aged 65 to 75 years administered an immediate-release formulation of tramadol, have plasma concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age.
- In subjects over 75 years, mean maximum plasma concentrations are elevated (208 vs. 162 ng/mL) and the mean elimination half-life is prolonged (7 vs. 6 hours) compared to subjects 65 to 75 years of age.
- Adjustment of the daily dose is recommended for patients older than 75 years.
- The formation of the active metabolite, M1, is mediated by CYP2D6, a polymorphic enzyme. Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P-450 metabolizing enzyme system. These individuals are “poor metabolizers” of debrisoquine, dextromethorphan and tricyclic antidepressants, among other drugs. Based on a population PK analysis of Phase 1 studies with IR tablets in healthy subjects, concentrations of tramadol were approximately 20% higher in "poor metabolizers" versus "extensive metabolizers," while M1 concentrations were 40% lower.
- In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol.
- Tramadol is metabolized to active metabolite M1 by CYP2D6. Coadministration of quinidine, a selective inhibitor of CYP2D6, with tramadol ER resulted in a 50-60% increase in tramadol exposure and a 50-60% decrease in M1 exposure. The clinical consequences of these findings are unknown.
- To evaluate the effect of tramadol, a CYP2D6 substrate on quinidine, an in vitro drug interaction study in human liver microsomes was conducted. The results from this study indicate that tramadol has no effect on quinidine metabolism.
- Since tramadol is also metabolized by CYP3A4, administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or CYP3A4 inducers, such as rifampin and St. John's Wort, with ConZip™ may affect the metabolism of tramadol leading to altered tramadol exposure
- Concomitant administration of tramadol immediate-release tablets with cimetidine, a weak CPY3A4 inhibitor, does not result in clinically significant changes in tramadol pharmacokinetics. No alteration of the ConZip™ dosage regimen with cimetidine is recommended.
- Carbamazepine, a CYP3A4 inducer, increases tramadol metabolism. Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Concomitant administration of ConZip™ and carbamazepine is not recommended.
## Nonclinical Toxicology
- Carcinogenicity assessment has been conducted in mice, rats and p53(+/-) heterozygous mice. A slight, but statistically significant, increase in two common murine tumors, pulmonary and hepatic, was observed in a mouse carcinogenicity study, particularly in aged mice. Mice were dosed orally up to 30 mg/kg (90 mg/m2 or 0.5 times the maximum daily human dosage of 185 mg/m2) for approximately two years, although the study was not done with the Maximum Tolerated Dose. This finding is not believed to suggest risk in humans.
- No treatment-related tumors were noted in a rat carcinogenicity study (dosing orally up to 30 mg/kg, 180 mg/m2, or equivalent to the maximum daily human dosage) or in a second study where rats were treated with up to 75 mg/kg/day for males and 100 mg/kg/day for females (approximately 2.4 and 3.2-fold MDHD, respectively) for two years. However, the excessive decrease in body weight gain observed in the rat study might have reduced their sensitivity to any potential carcinogenic effect of the drug.
- No carcinogenic effect of tramadol was observed in p53(+/–)-heterozygous mice at oral doses up to 150 mg/kg/day (approximately 2.4-fold maximum daily human dose [MDHD] of 300 mg/day for a 60 kg adult based on body surface conversion) for 26 weeks.
- Tramadol was not mutagenic in the following assays: a bacterial reverse mutation assay using Salmonella and E. coli, a mouse lymphoma assay (in the absence of metabolic activation), chromosomal aberration test in Chinese hamsters, a bone marrow micronucleus test in mice and Chinese hamsters, and a dominant lethal mutation test in mice. Mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats. Overall, the weight of evidence from these tests indicates that tramadol does not pose a genotoxic risk to humans.
- No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg/day in male and female rats (1.6-fold the MDHD).
# Clinical Studies
- ConZip™ is bioequivalent under fasting conditions to another extended-release tramadol product which did demonstrate efficacy in two of four clinical trials of patients with chronic pain.
- To qualify for inclusion into these studies, patients were required to have moderate to moderately severe pain as defined by a pain intensity score of ≥40 mm, off previous medications, on a 0 – 100 mm visual analog scale (VAS).
- In one 12-week randomized, double-blind, placebo-controlled study, patients with moderate to moderately severe pain due to osteoarthritis of the knee and/or hip were administered doses from 100 mg to 400 mg daily. Treatment with the extended-release tramadol product was initiated at 100 mg once daily for four days then increased by 100 mg per day increments every five days to the randomized fixed dose. Between 51% and 59% of patients in active treatment groups completed the study and 56% of patients in the placebo group completed the study.
- Discontinuations due to adverse events were more common in the extended-release tramadol product 200 mg, 300 mg and 400 mg treatment groups (20%, 27%, and 30% of discontinuations, respectively) compared to 14% of the patients treated with the extended-release tramadol product 100 mg and 10% of patients treated with placebo.
- Pain, as assessed by the WOMAC Pain subscale, was measured at 1, 2, 3, 6, 9, and 12 weeks and change from baseline assessed. A responder analysis based on the percent change in WOMAC Pain subscale demonstrated a statistically significant improvement in pain for the 100 mg and 200 mg treatment groups compared to placebo.
- In one 12-week randomized, double-blind, placebo-controlled flexible-dosing trial of the extended-release tramadol product in patients with osteoarthritis of the knee, patients titrated to an average daily dose of approximately 270 mg/day.
- Forty-nine percent of patients randomized to the active treatment group completed the study, while 52% of patients randomized to placebo completed the study. Most of the early discontinuations in the active treatment group were due to adverse events, accounting for 27% of the early discontinuations in contrast to 7% of the discontinuations from the placebo group.
- Thirty-seven percent of the placebo-treated patients discontinued the study due to lack of efficacy compared to 15% of active-treated patients. The active treatment group demonstrated a statistically significant decrease in the mean Visual Analog Scale (VAS) score, and a statistically significant difference in the responder rate, based on the percent change from baseline in the VAS score, measured at 1, 2, 4, 8, and 12 weeks, between patients receiving the extended-release tramadol product and placebo
- Four randomized, placebo-controlled clinical trials of ConZip™ were conducted, none of which demonstrated efficacy but which differed in design from the preceding clinical studies described.
- Two trials were 12-week randomized placebo-controlled trials of ConZip™ 100 mg/day, 200 mg/day, and 300 mg/day versus placebo in patients with moderate to moderately severe osteoarthritis pain of the hip and knee. The other two 12 week trials were similar in design, but only studied ConZip™ 300 mg/day.
- In this fixed-dose design, subjects were required to titrate to a fixed dose, even if their pain responded to a lower titration dose
# How Supplied
- ConZip™ capsules (tramadol hydrochloride) are supplied as opaque white hard gelatin capsules, imprinted as follows.
- 100 mg Capsules: White capsule imprinted with blue ink “G 252” on cap and “100” between lines on the body
- Bottle of 30 capsules: NDC 68025-053-30
- 200 mg Capsules: White capsule imprinted with violet ink “G 253” on cap and “200” between lines on the body
- Bottle of 30 capsules: NDC 68025-055-30
- 300 mg Capsules: White capsule imprinted with red ink “G 254” on cap and “300” between lines on the body
- Bottle of 30 capsules: NDC 68025-056-30
## Storage
- Dispense in a tight container. Store at 25°C; excursions permitted to 15°C to 30°C (59°F to 86°F). Keep out of reach of children.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Inform patients that:
- ConZip™ is for oral use only and should be swallowed whole. The capsule should not be chewed, dissolved, crushed or split.
- ConZip™ may cause seizures and/or serotonin syndrome with concomitant use of serotonergic agents (including SRIs, NRIs, and triptans) or drugs that significantly reduce the metabolic clearance of tramadol.
- Not to change the prescribed single-dose or 24-hour dosing regimen of ConZip™, and that exceeding the prescribed dose can result in respiratory depression, seizures or death.
- ConZip™ may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.
- ConZip™ should not be taken with alcohol containing beverages.
ConZip™ should be used with caution when taking medications such as tranquilizers, hypnotics or other opiate containing analgesics.
- Instruct female patients to inform the prescriber if they are pregnant, think they might become pregnant, or are trying to become pregnant.
- ConZip™ is to be taken once-a-day and at approximately the same time every day. Also, exceeding these recommendations and the maximum recommended daily dose can result in respiratory depression, seizures or death.
- Elderly patients, especially those over 75 years of age, and other patients who have renal or hepatic impairments may need to be cautioned about reduced dosages.
- Not to abruptly withdraw or discontinue tramadol therapy, as clinical experience with tramadol suggests the possible onset of signs and symptoms of withdrawal. These affects may be reduced by tapering tramadol therapy.
- ConZip™ must be kept out of reach of children.
# Precautions with Alcohol
- Alcohol-Tramadol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- TRAMADOL HCL®[1]
# Look-Alike Drug Names
There is limited information regarding Tramadol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Chem_Mart_Tramadol | |
2813ad935a558afd2ba287aa0110fab899dad392 | wikidoc | Chemerin | Chemerin
Chemerin, also known as retinoic acid receptor responder protein 2 (RARRES2), tazarotene-induced gene 2 protein (TIG2), or RAR-responsive protein TIG2 is a protein that in humans is encoded by the RARRES2 gene.
# Function
Retinoids exert biologic effects such as potent growth inhibitory and cell differentiation activities and are used in the treatment of hyperproliferative dermatological diseases. These effects are mediated by specific nuclear receptor proteins that are members of the steroid and thyroid hormone receptor superfamily of transcriptional regulators. RARRES1, RARRES2 (this gene), and RARRES3 are genes whose expression is upregulated by the synthetic retinoid tazarotene. RARRES2 is thought to act as a cell surface receptor.
Chemerin is a chemoattractant protein that acts as a ligand for the G protein-coupled receptor CMKLR1 (also known as ChemR23). Chemerin is a 14 kDa protein secreted in an inactive form as prochemerin and is activated through cleavage of the C-terminus by inflammatory and coagulation serine proteases.
Chemerin was found to stimulate chemotaxis of dendritic cells and macrophages to the site of inflammation.
In humans, chemerin mRNA is highly expressed in white adipose tissue, liver and lung while its receptor, CMKLR1 is predominantly expressed in immune cells as well as adipose tissue. Because of its role in adipocyte differentiation and glucose uptake, chemerin is classified as an adipokine.
# Role as an adipokine
Chemerin has been implicated in autocrine / paracrine signaling for adipocyte differentiation and also stimulation of lipolysis. Studies with 3T3-L1 cells have shown chemerin expression is low in pre-differentiated adipocytes but its expression and secretion increases both during and after differentiation in vitro. Genetic knockdown of chemerin or its receptor, CMKLR1 impairs differentiation into adipocytes, and reduces the expression of GLUT4 and adiponectin, while increasing expression of IL-6 and insulin receptor. Furthermore, post-differentiation knockdown of chemerin reduced GLUT4, leptin, adiponectin, perilipin, and reduced lipolysis, suggesting chemerin plays a role in metabolic function of mature adipocytes. Studies using mature human adipocytes, 3T3-L1 cells, and in vivo studies in mice showed chemerin stimulates the phosphorylation of the MAPKs, ERK1, and ERK2, which are involved in mediating lipolysis.
Studies in mice have shown neither chemerin nor CMKLR1 are highly expressed in brown adipose tissue, indicating that chemerin plays a role in energy storage rather than thermogenesis.2
# Role in obesity and diabetes
Given chemerin’s role as a chemoattractant and a recent finding macrophages have been implicated in chronic inflammation of adipose tissue in obesity. This suggests chemerin may play an important role in the pathogenesis of obesity and insulin resistance.
Studies in mice found that feeding mice a high-fat diet, resulted in increased expression of both chemerin and CMKLR1. In humans, chemerin levels are significantly different between individuals with normal glucose tolerance and individuals with type II diabetes and first degree relatives. Moreover, chemerin levels show a significant correlation with body mass index, plasma triglyceride levels and blood pressure.
It was found incubation of 3T3-L1 cells with recombinant human chemerin protein facilitated insulin-stimulated glucose uptake. This suggests chemerin plays a role in insulin sensitivity and may be a potential therapeutic target for treating type II diabetes. | Chemerin
Chemerin, also known as retinoic acid receptor responder protein 2 (RARRES2), tazarotene-induced gene 2 protein (TIG2), or RAR-responsive protein TIG2 is a protein that in humans is encoded by the RARRES2 gene.[1][2][3]
# Function
Retinoids exert biologic effects such as potent growth inhibitory and cell differentiation activities and are used in the treatment of hyperproliferative dermatological diseases. These effects are mediated by specific nuclear receptor proteins that are members of the steroid and thyroid hormone receptor superfamily of transcriptional regulators. RARRES1, RARRES2 (this gene), and RARRES3 are genes whose expression is upregulated by the synthetic retinoid tazarotene. RARRES2 is thought to act as a cell surface receptor.[3]
Chemerin is a chemoattractant protein that acts as a ligand for the G protein-coupled receptor CMKLR1 (also known as ChemR23). Chemerin is a 14 kDa protein secreted in an inactive form as prochemerin and is activated through cleavage of the C-terminus by inflammatory and coagulation serine proteases.[4][5]
Chemerin was found to stimulate chemotaxis of dendritic cells and macrophages to the site of inflammation.[6]
In humans, chemerin mRNA is highly expressed in white adipose tissue, liver and lung while its receptor, CMKLR1 is predominantly expressed in immune cells as well as adipose tissue.[7] Because of its role in adipocyte differentiation and glucose uptake, chemerin is classified as an adipokine.
# Role as an adipokine
Chemerin has been implicated in autocrine / paracrine signaling for adipocyte differentiation and also stimulation of lipolysis.[7][8] Studies with 3T3-L1 cells have shown chemerin expression is low in pre-differentiated adipocytes[7] but its expression and secretion increases both during and after differentiation in vitro. Genetic knockdown of chemerin or its receptor, CMKLR1 impairs differentiation into adipocytes, and reduces the expression of GLUT4 and adiponectin, while increasing expression of IL-6 and insulin receptor. Furthermore, post-differentiation knockdown of chemerin reduced GLUT4, leptin, adiponectin, perilipin, and reduced lipolysis, suggesting chemerin plays a role in metabolic function of mature adipocytes.[8] Studies using mature human adipocytes, 3T3-L1 cells, and in vivo studies in mice showed chemerin stimulates the phosphorylation of the MAPKs, ERK1, and ERK2, which are involved in mediating lipolysis.[8]
Studies in mice have shown neither chemerin nor CMKLR1 are highly expressed in brown adipose tissue, indicating that chemerin plays a role in energy storage rather than thermogenesis.2
# Role in obesity and diabetes
Given chemerin’s role as a chemoattractant and a recent finding macrophages have been implicated in chronic inflammation of adipose tissue in obesity.[9] This suggests chemerin may play an important role in the pathogenesis of obesity and insulin resistance.
Studies in mice found that feeding mice a high-fat diet, resulted in increased expression of both chemerin and CMKLR1.[2] In humans, chemerin levels are significantly different between individuals with normal glucose tolerance and individuals with type II diabetes and first degree relatives.[10] Moreover, chemerin levels show a significant correlation with body mass index, plasma triglyceride levels and blood pressure.[4]
It was found incubation of 3T3-L1 cells with recombinant human chemerin protein facilitated insulin-stimulated glucose uptake.[11] This suggests chemerin plays a role in insulin sensitivity and may be a potential therapeutic target for treating type II diabetes.[4] | https://www.wikidoc.org/index.php/Chemerin | |
4581b10da913ad8ee17ace8a29a8b503cfab83ae | wikidoc | ChestEze | ChestEze
ChestEze is a British over-the-counter pharmaceutical product manufactured by Do-Do for "relief of bronchial cough, wheezing, breathlessness and other symptoms of asthmatic bronchitis and to clear the chest of mucus following upper respiratory tract infection." It contains 30mg caffeine, 18.31mg ephedrine hydrochloride and 100mg anhydrous theophylline.
It comes in a fawn brown tablet. Recommended doses are: Adults: not more than 1 tablet in 4 hours. Maximum 4 tablets in 24 hours. Young persons over 12 years: 1 tablet and no more than 3 tablets daily with an interval of at least 4 hours between each tablet.
Because ChestEze contains ephedrine, which is illegal in its pure form in the UK, it is sometimes used illicitly in large doses by bodybuilders. This use can be dangerous, however, since theophylline can be toxic at relatively low doses. | ChestEze
ChestEze is a British over-the-counter pharmaceutical product manufactured by Do-Do for "relief of bronchial cough, wheezing, breathlessness and other symptoms of asthmatic bronchitis and to clear the chest of mucus following upper respiratory tract infection." It contains 30mg caffeine, 18.31mg ephedrine hydrochloride and 100mg anhydrous theophylline.
It comes in a fawn brown tablet. Recommended doses are: Adults: not more than 1 tablet in 4 hours. Maximum 4 tablets in 24 hours. Young persons over 12 years: 1 tablet and no more than 3 tablets daily with an interval of at least 4 hours between each tablet.
Because ChestEze contains ephedrine, which is illegal in its pure form in the UK, it is sometimes used illicitly in large doses by bodybuilders. This use can be dangerous, however, since theophylline can be toxic at relatively low doses. | https://www.wikidoc.org/index.php/ChestEze | |
236bd4e40b3091d546a2420c718b1a5568591126 | wikidoc | Chestnut | Chestnut
Chestnut (Castanea), including chinkapin, is a genus of eight or nine species of deciduous trees and shrubs in the beech family Fagaceae, native to temperate regions of the Northern Hemisphere. The name also refers to the edible nuts they produce.
Most of the species are large trees growing to 20-40 m tall, but some species (the chinkapins) are smaller, often shrubby. The leaves are simple, ovate or lanceolate, 10-30 cm long and 4-10 cm broad, with sharply pointed, widely-spaced teeth, with shallow rounded sinuses between. The flowers are catkins, produced in mid summer; they have a heavy, unpleasant odour. The fruit is a spiny cupule 5-11 cm diameter, containing one to seven nuts.
The name Castanea comes from the old Latin name for the Sweet Chestnut.
Chestnuts should not be confused with either Horse-chestnuts (family Sapindaceae; also called "buckeye"), or water-chestnuts (family Cyperaceae); both are so named for producing superficially similar nuts.
# Ecology
Chestnut trees thrive on neutral and acidic soils, such as soils derived from granite, sandstone, or schist, and do not grow well on alkaline soils such as chalk.
The nuts are an important food for jays, pigeons, and squirrels. Several insects, notably the weevil Curculio elephas (chestnut weevil), also feed on the seeds.
The leaves are used as a food plant by the larvae of some Lepidoptera species (butterflies and moths); see list of Lepidoptera that feed on chestnut trees.
## Diseases
A fungal disease, chestnut blight Cryphonectria parasitica, affects chestnuts. The eastern Asian species have co-evolved with this disease and are moderately to very resistant to it, while the European and North American species, not having been exposed to it in the past, have little or no resistance.
Early in the 20th century, chestnut blight was introduced to North America by the importation of Asian chestnut plants. This resulted in the subsequent destruction of 3.5 billion American Chestnut trees over the next 40 years, and what had been the most important tree throughout the east coast was reduced to insignificance. The American chinkapins are also very susceptible to chestnut blight. The European and west Asian Sweet Chestnut is susceptible, but less so than the American.
The resistant species, particularly Japanese Chestnut and Chinese Chestnut but also Seguin's Chestnut and Henry's Chestnut, have been used in breeding programs in the US to create hybrids with the American Chestnut that are also disease resistant.
# Uses
## Nuts
The nuts are an important food crop in southern Europe, southwestern and eastern Asia, and also in eastern North America before the arrival of chestnut blight. In southern Europe in the Middle Ages, whole forest-dwelling communities which had scarce access to wheat flour relied on chestnuts as their main source of carbohydrates.
The nuts can be eaten candied, boiled or roasted; candied chestnuts are often sold under the French name marrons glacés or Turkish name kestane şekeri. Another important use of chestnuts is to be ground into flour, which can then be used to prepare bread, cakes and pasta.
Another little known use is to eat chestnuts raw by just peeling them (almost unknown in North-America but customary at least in Northwest Europe). When chestnuts are fresh from the field/store, peeling is not easy. However, after leaving them out at room temperature for 24-48 hours, using a simple small, pointed kitchen knife will allow the consumer to easily peel away the outside shell. Next, you peel the thinner inside skin. Wash, and if present cut away contamination, and eat. Chestnuts' taste may vary slightly from one to the next but is somewhat sweet and certainly unique. After leaving chestnuts out for more than 5-7 days the quality starts to degrade.
Chestnut-based recipes and preparations are making a comeback in Italian cuisine, as part of the trend toward rediscovery of traditional dishes.
## Other products
The wood is similar to oak wood in being decorative and very durable. Due to disease, American Chestnut wood has almost disappeared from the market. Although quantities of Chestnut can still be obtained as reclaimed lumber, it is difficult to obtain large timber from the Sweet Chestnut due to the high degree of splitting and warping when it dries. The wood of the Sweet Chestnut is most commonly used in small items where durability is important, such as fencing and wooden outdoor cladding ('shingles') for buildings. In Italy, it is also used to make barrels used for aging balsamic vinegar.
The bark was also a useful source of natural tannins, used for tanning leather before the introduction of synthetic tannins.
# Cultivation
Chestnuts grown for nut production are grown in orchards with wide spacing between the trees to encourage low, broad crowns with maximum exposure to sunshine to increase nut production. On alkaline soils, chestnuts can be grown by grafting them onto oak rootstocks. Most wood production is done by coppice systems, cut on a 12 year rotation to provide small timber which does not split as badly as large logs.
Chestnuts for planting require storage in moist sand and chilling over the winter before sowing; drying kills the seed and prevents germination.
# Artistic references
- The jazz standard "April in Paris" begins, "April in Paris / Chestnuts in blossom."
- In the Polish film, Ashes and Diamonds, two characters reminisce about the chestnut trees that once lined a famous boulevard destroyed in the Warsaw Uprising.
- "The Christmas Song" begins with the phrase "Chestnuts roasting on an open fire." Nat King Cole's hit recording is now a Christmas standard.
- In the movie Howards End, Mrs. Ruth Wilcox (Vanessa Redgrave) tells of her childhood home, where superstitious farmers would place pigs' teeth in the bark of the chestnut trees and then chew on this bark to ease toothaches.
- In the novel Jane Eyre, a chestnut tree outside of Thornfield Hall is broken in two by lightning. This foreshadows the break-up of Rochester and Jane's marriage.
- The opening lines of Longfellow's poem The Village Blacksmith are "Under a spreading chestnut-tree / the village smithy stands." This famous reference is much remarked upon by those involved in projects to return the American chestnut to the wild.
- In George Orwell's 1984 the chestnut tree is used in poems recited throughout, referring to nature, modern life and lies ie the saying; 'that old chestnut'. | Chestnut
Chestnut (Castanea),[1] including chinkapin, is a genus of eight or nine species of deciduous trees and shrubs in the beech family Fagaceae, native to temperate regions of the Northern Hemisphere. The name also refers to the edible nuts they produce.[2][3][4]
Most of the species are large trees growing to 20-40 m tall, but some species (the chinkapins) are smaller, often shrubby. The leaves are simple, ovate or lanceolate, 10-30 cm long and 4-10 cm broad, with sharply pointed, widely-spaced teeth, with shallow rounded sinuses between. The flowers are catkins, produced in mid summer; they have a heavy, unpleasant odour. The fruit is a spiny cupule 5-11 cm diameter, containing one to seven nuts.[2][3][5][6]
The name Castanea comes from the old Latin name for the Sweet Chestnut.[7]
Chestnuts should not be confused with either Horse-chestnuts (family Sapindaceae; also called "buckeye"), or water-chestnuts (family Cyperaceae); both are so named for producing superficially similar nuts.
# Ecology
Chestnut trees thrive on neutral and acidic soils, such as soils derived from granite, sandstone, or schist, and do not grow well on alkaline soils such as chalk.[7]
The nuts are an important food for jays, pigeons, and squirrels. Several insects, notably the weevil Curculio elephas (chestnut weevil), also feed on the seeds.[7]
The leaves are used as a food plant by the larvae of some Lepidoptera species (butterflies and moths); see list of Lepidoptera that feed on chestnut trees.
## Diseases
A fungal disease, chestnut blight Cryphonectria parasitica, affects chestnuts. The eastern Asian species have co-evolved with this disease and are moderately to very resistant to it, while the European and North American species, not having been exposed to it in the past, have little or no resistance.[7]
Early in the 20th century, chestnut blight was introduced to North America by the importation of Asian chestnut plants. This resulted in the subsequent destruction of 3.5 billion American Chestnut trees[citation needed] over the next 40 years, and what had been the most important tree throughout the east coast was reduced to insignificance. The American chinkapins are also very susceptible to chestnut blight. The European and west Asian Sweet Chestnut is susceptible, but less so than the American.[7]
The resistant species, particularly Japanese Chestnut and Chinese Chestnut but also Seguin's Chestnut and Henry's Chestnut, have been used in breeding programs in the US to create hybrids with the American Chestnut that are also disease resistant.[7]
# Uses
## Nuts
The nuts are an important food crop in southern Europe, southwestern and eastern Asia, and also in eastern North America before the arrival of chestnut blight. In southern Europe in the Middle Ages, whole forest-dwelling communities which had scarce access to wheat flour relied on chestnuts as their main source of carbohydrates.
The nuts can be eaten candied, boiled or roasted; candied chestnuts are often sold under the French name marrons glacés or Turkish name kestane şekeri. Another important use of chestnuts is to be ground into flour, which can then be used to prepare bread, cakes and pasta.
Another little known use is to eat chestnuts raw by just peeling them (almost unknown in North-America but customary at least in Northwest Europe). When chestnuts are fresh from the field/store, peeling is not easy. However, after leaving them out at room temperature for 24-48 hours, using a simple small, pointed kitchen knife will allow the consumer to easily peel away the outside shell. Next, you peel the thinner inside skin. Wash, and if present cut away contamination, and eat. Chestnuts' taste may vary slightly from one to the next but is somewhat sweet and certainly unique. After leaving chestnuts out for more than 5-7 days the quality starts to degrade.
Chestnut-based recipes and preparations are making a comeback in Italian cuisine, as part of the trend toward rediscovery of traditional dishes.
## Other products
The wood is similar to oak wood in being decorative and very durable. Due to disease, American Chestnut wood has almost disappeared from the market. Although quantities of Chestnut can still be obtained as reclaimed lumber, it is difficult to obtain large timber from the Sweet Chestnut due to the high degree of splitting and warping when it dries.[8] The wood of the Sweet Chestnut is most commonly used in small items where durability is important, such as fencing and wooden outdoor cladding ('shingles') for buildings. In Italy, it is also used to make barrels used for aging balsamic vinegar.
The bark was also a useful source of natural tannins, used for tanning leather before the introduction of synthetic tannins.[8]
# Cultivation
Template:Expand-section
Chestnuts grown for nut production are grown in orchards with wide spacing between the trees to encourage low, broad crowns with maximum exposure to sunshine to increase nut production. On alkaline soils, chestnuts can be grown by grafting them onto oak rootstocks. Most wood production is done by coppice systems, cut on a 12 year rotation to provide small timber which does not split as badly as large logs.[8]
Chestnuts for planting require storage in moist sand and chilling over the winter before sowing; drying kills the seed and prevents germination.
# Artistic references
- The jazz standard "April in Paris" begins, "April in Paris / Chestnuts in blossom."
- In the Polish film, Ashes and Diamonds, two characters reminisce about the chestnut trees that once lined a famous boulevard destroyed in the Warsaw Uprising.
- "The Christmas Song" begins with the phrase "Chestnuts roasting on an open fire." Nat King Cole's hit recording is now a Christmas standard.
- In the movie Howards End, Mrs. Ruth Wilcox (Vanessa Redgrave) tells of her childhood home, where superstitious farmers would place pigs' teeth in the bark of the chestnut trees and then chew on this bark to ease toothaches.
- In the novel Jane Eyre, a chestnut tree outside of Thornfield Hall is broken in two by lightning. This foreshadows the break-up of Rochester and Jane's marriage.
- The opening lines of Longfellow's poem The Village Blacksmith are "Under a spreading chestnut-tree / the village smithy stands." This famous reference is much remarked upon by those involved in projects to return the American chestnut to the wild.
- In George Orwell's 1984 the chestnut tree is used in poems recited throughout, referring to nature, modern life and lies ie the saying; 'that old chestnut'. | https://www.wikidoc.org/index.php/Chestnut | |
69589c3927ef3b4af660e29fe0201baad2238c6d | wikidoc | Chitosan | Chitosan
# Overview
Chitosan is a linear polysaccharide composed of randomly distributed ß-(1-4)-linked D-glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit). It has a number of commercial and possible biomedical uses.
# Manufacture and properties
Chitosan is produced commercially by deacetylation of chitin , which is the structural element in the exoskeleton of crustaceans (crabs, shrimp, etc.). The degree of deacetylation (%DA) can be determined by NMR spectroscopy, and the %DA in commercial chitosans is in the range 60-100 %.
The amino group in chitosan has a pKa value of ~6.5, thus, chitosan is positively charged and soluble in acidic to neutral solution with a charge density dependent on pH and the %DA-value. In other words, chitosan is bioadhesive and readily binds to negatively charged surfaces such as mucosal membranes. Chitosan enhances the transport of polar drugs across epithelial surfaces, and is biocompatible and biodegradable. Purified qualities of chitosans are available for biomedical applications.
Chitosan and its derivatives such as trimethylchitosan (where the amino group has been trimethylated) have been used in non-viral gene delivery. Trimethylchitosan, or quaternised chitosan, has been shown to transfect breast cancer cells; with increased degree of trimethylation increasing the cytotoxicity and at approximately 50% trimethylation the derivative is the most efficient at gene delivery. Oligomeric derivatives (3-6 kDa) are relatively non-toxic and have good gene delivery properties.
# Usage
Chitosan is used primarily as a plant growth enhancer, and as a substance that boosts the ability of plants to defend against fungal infections. It is approved for use outdoors and indoors on many plants grown commercially and by consumers. The active ingredient is found in the shells of crustaceans, such as lobsters, crabs, and shrimp, and in certain other organisms. Given its low potential for toxicity and its abundance in the natural environment, chitosan is not expected to harm people, pets, wildlife, or the environment when used according to label directions.
Chitosan can also be used in water processing engineering as a part of a filtration process. Chitosan causes the fine sediment particles to bind together and is subsequently removed with the sediment during sand filtration. Chitosan also removes phosphorus, heavy minerals, and oils from the water.
Chitosan is an important additive in the filtration process. Sand filtration apparently can remove up to 50% of the turbidity alone while the Chitosan with sand filtration removes up to 99% turbidity.
Chitosan is also useful in other filtration situations, where one may need to remove suspended particles from a liquid. Chitosan, in combination with bentonite, gelatin, silica gel, isinglass, or other fining agents is used to clarify wine, mead, and beer. Added late in the brewing process, chitosan improves flocculation, and removes yeast cells, fruit particles, and other detritus that cause hazy wine. Chitosan combined with colloidal silica is becoming a popular fining agent for white wines, because chitosan does not require acidic tannins (found primarily in red wines) to flocculate with.
## Biomedical use
Chitosan's properties allow it to rapidly clot blood, and has recently gained approval in the USA for use in bandages and other hemostatic agents. Chitosan purified from shrimp shells is used in a granular hemostatic product, Celox, made by Medtrade Biopolymers Inc. of Crewe, England and in the chitosan dressings made by HemCon Medical Technologies Inc. of Portland, OR, USA . The Hemcon product reduces blood loss in comparison to gauze dressings and increases patient survival . Hemcon products have been sold to the United States Army, who have already used the bandages on the battlefields of Iraq. Chitosan is hypoallergenic, and has natural anti-bacterial properties, further supporting its use in field bandages.
## Claimed benefits
Chitosan is frequently sold in tablet form at health stores as a 'fat attractor' alongside weight-loss claims that it can attract fat from the digestive system and expel it from the body. There is no evidence to support this claim. | Chitosan
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Chitosan is a linear polysaccharide composed of randomly distributed ß-(1-4)-linked D-glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit). It has a number of commercial and possible biomedical uses.
# Manufacture and properties
Chitosan is produced commercially by deacetylation of chitin , which is the structural element in the exoskeleton of crustaceans (crabs, shrimp, etc.). The degree of deacetylation (%DA) can be determined by NMR spectroscopy, and the %DA in commercial chitosans is in the range 60-100 %.
The amino group in chitosan has a pKa value of ~6.5, thus, chitosan is positively charged and soluble in acidic to neutral solution with a charge density dependent on pH and the %DA-value. In other words, chitosan is bioadhesive and readily binds to negatively charged surfaces such as mucosal membranes. Chitosan enhances the transport of polar drugs across epithelial surfaces, and is biocompatible and biodegradable. Purified qualities of chitosans are available for biomedical applications.
Chitosan and its derivatives such as trimethylchitosan (where the amino group has been trimethylated) have been used in non-viral gene delivery. Trimethylchitosan, or quaternised chitosan, has been shown to transfect breast cancer cells; with increased degree of trimethylation increasing the cytotoxicity and at approximately 50% trimethylation the derivative is the most efficient at gene delivery. Oligomeric derivatives (3-6 kDa) are relatively non-toxic and have good gene delivery properties.[1]
# Usage
Chitosan is used primarily as a plant growth enhancer, and as a substance that boosts the ability of plants to defend against fungal infections. It is approved for use outdoors and indoors on many plants grown commercially and by consumers. The active ingredient is found in the shells of crustaceans, such as lobsters, crabs, and shrimp, and in certain other organisms. Given its low potential for toxicity and its abundance in the natural environment, chitosan is not expected to harm people, pets, wildlife, or the environment when used according to label directions.[2]
Chitosan can also be used in water processing engineering as a part of a filtration process. Chitosan causes the fine sediment particles to bind together and is subsequently removed with the sediment during sand filtration. Chitosan also removes phosphorus, heavy minerals, and oils from the water.
Chitosan is an important additive in the filtration process. Sand filtration apparently can remove up to 50% of the turbidity alone while the Chitosan with sand filtration removes up to 99% turbidity.[3]
Chitosan is also useful in other filtration situations, where one may need to remove suspended particles from a liquid. Chitosan, in combination with bentonite, gelatin, silica gel, isinglass, or other fining agents is used to clarify wine, mead, and beer. Added late in the brewing process, chitosan improves flocculation, and removes yeast cells, fruit particles, and other detritus that cause hazy wine. Chitosan combined with colloidal silica is becoming a popular fining agent for white wines, because chitosan does not require acidic tannins (found primarily in red wines) to flocculate with.[4]
## Biomedical use
Chitosan's properties allow it to rapidly clot blood, and has recently gained approval in the USA for use in bandages and other hemostatic agents. Chitosan purified from shrimp shells is used in a granular hemostatic product, Celox, made by Medtrade Biopolymers Inc. of Crewe, England and in the chitosan dressings made by HemCon Medical Technologies Inc. of Portland, OR, USA [5]. The Hemcon product reduces blood loss in comparison to gauze dressings and increases patient survival [6]. Hemcon products have been sold to the United States Army, who have already used the bandages on the battlefields of Iraq[7]. Chitosan is hypoallergenic, and has natural anti-bacterial properties, further supporting its use in field bandages.[8]
## Claimed benefits
Chitosan is frequently sold in tablet form at health stores as a 'fat attractor' alongside weight-loss claims that it can attract fat from the digestive system and expel it from the body. There is no evidence to support this claim.
# External links
- [2] Jamie Fritch's take on chitosan
- The Chitosanase Web Page – dedicated to the enzymatic hydrolysis of chitosan.
- ScienCentral News "But now, scientists have created a bandage that is actually able to clot a bullet wound in less than a minute. The bandages are laced with a mixture of ground shrimp shells and vinegar, a concoction that has been found to clot blood instantly. The key ingredient in the shrimp shells is called chitosan."
- A Critical look on ChitosanA critical look on the claims how chitosan can be used for weight management
# Footnotes
- ↑ Kean T, Roth S, Thanou M (2005). "Trimethylated chitosans as non-viral gene delivery vectors: cytotoxicity and transfection efficiency". J Control Release. 103 (3): 643–53. PMID 15820411. |access-date= requires |url= (help)CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ "Chitosan; Poly-D-glucosamine (128930) Fact Sheet". US Environmental Protection Agency. 2006. Retrieved 2006-07-10. Unknown parameter |month= ignored (help)
- ↑ Alan Woodmansey (Highway Engineer) (2002). "Chitosan Treatment of Sediment Laden Water - Washington State I-90 Issaquah Project". Federal Highway Administration. U.S. Department of Transportation. Retrieved 2006-07-10. Unknown parameter |month= ignored (help)
- ↑ Rayner, Terry. "Fining and Clarifying Agents". Retrieved 2006-07-18.
- ↑ "HemCon Medical Technologies Inc". 2004.
- ↑ Pusateri, A. E., S. J. McCarthy, K. W. Gregory, R. A. Harris, L. Cardenas, A. T. McManus & C. W. Goodwin Jr. (2003). "Effect of a chitosan-based hemostatic dressing on blood loss and survival in a model of severe venous hemorrhage and hepatic injury in swine". Journal of Trauma. 4 (1): 177–182. Unknown parameter |quotes= ignored (help)CS1 maint: Multiple names: authors list (link)
- ↑ Karen Lurie. "War Bandages".
- ↑ Kevin McCue (2003). "New Bandage Uses Biopolymer". chemistry.org. American Chemical Society. Retrieved 2006-07-10. Unknown parameter |month= ignored (help)
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deec4c7683b244c1da9cee8921700f17aee3208a | wikidoc | Chloride | Chloride
The chloride ion is formed when the element chlorine picks up one electron to form an anion (negatively-charged ion) Cl−. The salts of hydrochloric acid HCl contain chloride ions and can also be called chlorides. An example is table salt, which is sodium chloride with the chemical formula NaCl. In water, it dissolves into Na+ and Cl− ions.
The word chloride can also refer to a chemical compound in which one or more chlorine atoms are covalently bonded in the molecule. This means that chlorides can be either inorganic or organic compounds. The simplest example of an inorganic covalently-bonded chloride is hydrogen chloride, HCl. A simple example of an organic covalently-bonded (an organochloride) chloride is chloromethane (CH3Cl), often called methyl chloride.
Other examples of inorganic covalently-bonded chlorides that are used as reactants are:
- phosphorus trichloride, phosphorus pentachloride, and thionyl chloride, all three of which reactive chlorinating reagents that have been used in a laboratory
- disulfur dichloride (S2Cl2), used for vulcanization of rubber.
# Human health
Chloride ions have important physiological roles. For instance, in the central nervous system, the inhibitory action of glycine and some of the action of GABA relies on the entry of Cl− into specific neurons. Also, the chloride-bicarbonate exchanger biological transport protein relies on the chloride ion to increase the blood's capacity of carbon dioxide, in the form of the bicarbonate ion.
The North American Dietary Reference Intake recommends a daily intake of between 2300 and 3600 mg/day for 25-year-old males.
# Other applications
Chloride is also a useful and reliable chemical indicator of river / groundwater faecal contamination, as chloride is a non-reactive solute and ubiquitous to sewage.
bg:Хлорид
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sv:Klorid | Chloride
The chloride ion is formed when the element chlorine picks up one electron to form an anion (negatively-charged ion) Cl−. The salts of hydrochloric acid HCl contain chloride ions and can also be called chlorides. An example is table salt, which is sodium chloride with the chemical formula NaCl. In water, it dissolves into Na+ and Cl− ions.
The word chloride can also refer to a chemical compound in which one or more chlorine atoms are covalently bonded in the molecule. This means that chlorides can be either inorganic or organic compounds. The simplest example of an inorganic covalently-bonded chloride is hydrogen chloride, HCl. A simple example of an organic covalently-bonded (an organochloride) chloride is chloromethane (CH3Cl), often called methyl chloride.
Other examples of inorganic covalently-bonded chlorides that are used as reactants are:
- phosphorus trichloride, phosphorus pentachloride, and thionyl chloride, all three of which reactive chlorinating reagents that have been used in a laboratory
- disulfur dichloride (S2Cl2), used for vulcanization of rubber.
# Human health
Chloride ions have important physiological roles. For instance, in the central nervous system, the inhibitory action of glycine and some of the action of GABA relies on the entry of Cl− into specific neurons. Also, the chloride-bicarbonate exchanger biological transport protein relies on the chloride ion to increase the blood's capacity of carbon dioxide, in the form of the bicarbonate ion.
The North American Dietary Reference Intake recommends a daily intake of between 2300 and 3600 mg/day for 25-year-old males.
# Other applications
Chloride is also a useful and reliable chemical indicator of river / groundwater faecal contamination, as chloride is a non-reactive solute and ubiquitous to sewage.
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6017da7d79e97ca7cb6ef25f133882f19e3c4a92 | wikidoc | Chlorine | Chlorine
Chlorine (Template:IPAEng, from the Greek word 'χλωρóς' (khlôros) meaning 'green'), is the chemical element with atomic number 17 and symbol Cl. It is a halogen, found in the periodic table in group VII (formerly VIIa or VIIb). As the chloride ion, which is part of common salt and other compounds, it is abundant in nature and necessary to most forms of life, including humans. In its common elemental form (Cl2 or "dichlorine") under standard conditions, it is a pale green gas about 2.5 times as dense as air. It has a disagreeable, suffocating odor that is detectable in concentrations as low as 3.5 ppm and is poisonous. Chlorine is a powerful oxidant and is used in bleaching and disinfectants. As a common disinfectant, chlorine compounds are used in swimming pools to keep them clean and sanitary. In the upper atmosphere, chlorine-containing molecules have been implicated in the destruction of the ozone layer.
# Characteristics
Chlorine gas is diatomic, with the formula Cl2. It combines readily with all elements except O2 and N2 and the noble gases. Compounds with oxygen, nitrogen, and xenon are known but do not form by direct reaction of the elements. Chlorine, though very reactive, is not as extremely reactive as fluorine. Pure chlorine gas does, however, support combustion of organic compounds such as hydrocarbons, although the carbon component tends to burn incompletely, with much of it remaining as soot. At 10 °C and atmospheric pressure, one liter of water dissolves 3.10 L of gaseous chlorine, and at 30°C, 1 L of water dissolves only 1.77 liters of chlorine.
This element is a member of the salt-forming halogen series and is extracted from chlorides through oxidation often by electrolysis. As the chloride ion, Cl−, it is also the most abundant dissolved ion in ocean water.
## Isotopes
Chlorine has isotopes with mass numbers ranging from 32 to 40. There are two principal stable isotopes, 35Cl (75.77%) and 37Cl (24.23%), giving chlorine atoms in bulk an apparent atomic weight of 35.4527 g/mol.
Trace amounts of radioactive 36Cl exist in the environment, in a ratio of about 7x10−13 to 1 with stable isotopes. 36Cl is produced in the atmosphere by spallation of 36Ar by interactions with cosmic ray protons. In the subsurface environment, 36Cl is generated primarily as a result of neutron capture by 35Cl or muon capture by 40Ca. 36Cl decays to 36S and to 36Ar, with a combined half-life of 308,000 years. The half-life of this hydrophilic nonreactive isotope makes it suitable for geologic dating in the range of 60,000 to 1 million years. Additionally, large amounts of 36Cl were produced by irradiation of seawater during atmospheric detonations of nuclear weapons between 1952 and 1958. The residence time of 36Cl in the atmosphere is about 1 week. Thus, as an event marker of 1950s water in soil and ground water, 36Cl is also useful for dating waters less than 50 years before the present. 36Cl has seen use in other areas of the geological sciences, including dating ice and sediments.
## Occurrence
In nature, chlorine is found primarily as the chloride ion, a component of the salt that is deposited in the earth or dissolved in the oceans — about 1.9% of the mass of seawater is chloride ions. Even higher concentrations of chloride are found in the Dead Sea and in underground brine deposits. Most chloride salts are soluble in water, thus, chloride-containing minerals are usually only found in abundance in dry climates or deep underground. Common chloride minerals include halite (sodium chloride), sylvite (potassium chloride), and carnallite (potassium magnesium chloride hexahydrate). Over 2000 naturally-occurring organic chlorine compounds are known.
Industrially, elemental chlorine is usually produced by the electrolysis of sodium chloride dissolved in water. Along with chlorine, this chloralkali process yields hydrogen gas and sodium hydroxide, according to the following chemical equation:
# Production
## Gas extraction
Chlorine can be manufactured by electrolysis of a sodium chloride solution (brine). The production of chlorine results in the co-products caustic soda (sodium hydroxide, NaOH) and hydrogen gas (H2). These two products, as well as chlorine itself, are highly reactive. Chlorine can also be produced by the electrolysis of a solution of potassium chloride, in which case the co-products are hydrogen and caustic potash (potassium hydroxide). There are three industrial methods for the extraction of chlorine by electrolysis of chloride solutions, all proceeding according to the following equations:
Overall process: 2 NaCl (or KCl) + 2 H2O → Cl2 + H2 + 2 NaOH (or KOH)
- Mercury cell electrolysis
Mercury cell electrolysis, also known as the Castner-Kellner process, was the first method used at the end of the nineteenth century to produce chlorine on an industrial scale. The "rocking" cells used have been improved over the years. Today, in the "primary cell", titanium anodes (formerly graphite ones) are placed in a sodium (or potassium) chloride solution flowing over a liquid mercury cathode. When a potential difference is applied and current flows, chlorine is released at the titanium anode and sodium (or potassium) dissolves in the mercury cathode forming an amalgam. This flows continuously into a separate reactor ("denuder" or "secondary cell"), where it is usually converted back to mercury by reaction with water, producing hydrogen and sodium (or potassium) hydroxide at a commercially useful concentration (50% by weight). The mercury is then recycled to the primary cell.
The mercury process is the least energy-efficient of the three main technologies (mercury, diaphragm and membrane) and there are also concerns about mercury emissions.
It is estimated that there are still around 100 mercury-cell plants operating worldwide. In Japan, mercury-based chloralkali production was virtually phased out by 1987 (except for the last two potassium chloride units shut down in 2003). In the United States, there will be only five mercury plants remaining in operation by the end of 2008. In Europe, mercury cells accounted for 43% of capacity in 2006 and Western European producers have committed to closing or converting all remaining chloralkali mercury plants by 2020.
- Diaphragm cell electrolysis
In diaphragm cell electrolysis, an asbestos (or polymer-fiber) diaphragm separates a cathode and an anode, preventing the chlorine forming at the anode from re-mixing with the sodium hydroxide and the hydrogen formed at the cathode. This technology was also developed at the end of the nineteenth century. There are several variants of this process: the Le Sueur cell (1893), the Hargreaves-Bird cell (1901), the Gibbs cell (1908), and the Townsend cell (1904). The cells vary in construction and placement of the diaphragm, with some having the diaphragm in direct contact with the cathode.
The salt solution (brine) is continuously fed to the anode compartment and flows through the diaphragm to the cathode compartment, where the caustic alkali is produced and the brine is partially depleted.
As a result, diaphragm methods produce alkali that is quite dilute (about 12%) and of lower purity than do mercury cell methods. But diaphragm cells are not burdened with the problem of preventing mercury discharge into the environment. They also operate at a lower voltage, resulting in an energy savings over the mercury cell method, but large amounts of steam are required if the caustic has to be evaporated to the commercial concentration of 50%.
- Membrane cell electrolysis
Development of this technology began in the 1970s. The electrolysis cell is divided into two "rooms" by a cation permeable membrane acting as an ion exchanger. Saturated sodium (or potassium) chloride solution is passed through the anode compartment, leaving at a lower concentration. Sodium (or potassium) hydroxide solution is circulated through the cathode compartment, exiting at a higher concentration. A portion of the concentrated sodium hydroxide solution leaving the cell is diverted as product, while the remainder is diluted with deionized water and passed through the electrolysis apparatus again.
This method is more efficient than the diaphragm cell and produces very pure sodium (or potassium) hydroxide at about 32% concentration, but requires very pure brine.
- Other electrolytic processes
Although a much lower production scale is involved, electrolytic diaphragm and membrane technologies are also used industrially to recover chlorine from hydrochloric acid solutions, producing hydrogen (but no caustic alkali) as a co-product.
Furthermore, electrolysis of fused chloride salts (Downs process) also enables chlorine to be produced, in this case as a by-product of the manufacture of metallic sodium or magnesium.
## Other methods
Before electrolytic methods were used for chlorine production, the direct oxidation of hydrogen chloride with oxygen or air was exercised in the Deacon process:
This reaction is accomplished with the use of copper(II) chloride (CuCl2) as a catalyst and is performed at high temperature (about 400 °C). The amount of extracted chlorine is approximately 80%. Due to the extremely corrosive reaction mixture, industrial use of this method is difficult and several pilot trials failed in the past. Nevertheless, recent developments are promising. Recently Sumitomo patented a catalyst for the Deacon process using ruthenium(IV) oxide (RuO2).
Another earlier process to produce chlorine was to heat brine with acid and manganese dioxide.
Using this process, chemist Carl Wilhelm Scheele was the first to isolate chlorine in a laboratory. The manganese can be recovered by the Weldon process.
Small amounts of chlorine gas can be made in the laboratory by putting concentrated hydrochloric acid in a flask with a side arm and rubber tubing attached. Manganese dioxide is then added and the flask stoppered. The reaction is not greatly exothermic. As chlorine is denser than air, it can be easily collected by placing the tube inside a flask where it will displace the air. Once full, the collecting flask can be stoppered.
Another method for producing small amounts of chlorine gas in a lab is by adding concentrated hydrochloric acid (typically about 5M) to sodium hypochlorite or sodium chlorate solution.
## Industrial production
Large-scale production of chlorine involves several steps and many pieces of equipment. The description below is typical of a membrane plant. The plant also simultaneously produces sodium hydroxide (caustic soda) and hydrogen gas. A typical plant consists of brine production/treatment, cell operations, chlorine cooling & drying, chlorine compression & liquefaction, liquid chlorine storage & loading, caustic handling, evaporation, storage & loading and hydrogen handling.
- Brine
Key to the production of chlorine is the operation of the brine saturation/treatment system. Maintaining a properly saturated solution with the correct purity is vital, especially for membrane cells. Many plants have a salt pile which is sprayed with recycled brine. Others have slurry tanks that are fed raw salt.
The raw brine is partially or totally treated with sodium hydroxide, sodium carbonate and a flocculant to reduce calcium, magnesium and other impurities. The brine proceeds to a large clarifier or a filter where the impurities are removed. The total brine is additionally filtered before entering ion exchangers to further remove impurities. At several points in this process, the brine is tested for hardness and strength.
After the ion exchangers, the brine is considered pure, and is transferred to storage tanks to be pumped into the cell room. Brine, fed to the cell line, is heated to the correct temperature to control exit brine temperatures according to the electrical load. Brine exiting the cell room must be treated to remove residual chlorine and control pH levels before being returned to the saturation stage. This can be accomplished via dechlorination towers with acid and sodium bisulfite addition. Failure to remove chlorine can result in damage to the cells. Brine should be monitored for accumulation of bothchlorate anions and sulfate anions, and either have a treatment system in place, or purging of the brine loop to maintain safe levels, since chlorate anions can diffuse through the membranes and contaminate the caustic, while sulfate anions can damage the anode surface coating.
- Cell room
The building that houses the many electrolytic cells is usually called a cell room or cell house, although some plants are built outdoors. This building contains support structures for the cells, connections for supplying electrical power to the cells and piping for the fluids. Monitoring and control of the temperatures of the feed caustic and brine is done to control exit temperatures. Also monitored are the voltages of each cell which vary with the electrical load on the cell room that is used to control the rate of production. Monitoring and control of the pressures in the chlorine and hydrogen headers is also done via pressure control valves.
Direct current is supplied via a rectified power source. Plant load is controlled by varying the current to the cells. As the current is increased, flow rates for brine and caustic and deionized water are increased, while lowering the feed temperatures.
- Cooling and drying
Chlorine gas exiting the cell line must be cooled and dried since the exit gas can be over 80°C and contains moisture that allows chlorine gas to be corrosive to iron piping. Cooling the gas allows for a large amount of moisture from the brine to condense out of the gas stream. Cooling also improves the efficiency of both the compression and the liquefaction stage that follows. Chlorine exiting is ideally between 18°C and 25°C. After cooling the gas stream passes through a series of towers with counter flowing sulfuric acid. These towers progressively remove any remaining moisture from the chlorine gas. After exiting the drying towers the chlorine is filtered to remove any remaining sulfuric acid.
- Compression and liquefaction
Several methods of compression may be used: liquid ring, reciprocating, or centrifugal. The chlorine gas is compressed at this stage and may be further cooled by inter- and after-coolers. After compression it flows to the liquefiers, where it is cooled enough to liquefy. Non condensible gases and remaining chlorine gas are vented off as part of the pressure control of the liquefaction systems. These gases are routed to a gas scrubber, producing sodium hypochlorite, or used in the production of hydrochloric acid (by combustion with hydrogen) or ethylene dichloride (by reaction with ethylene).
- Storage and loading
Liquid chlorine is typically gravity-fed to storage tanks. It can be loaded into rail or road tankers via pumps or padded with compressed dry gas.
- Caustic handling, evaporation, storage and loading
Caustic, fed to the cell room flows in a loop that is simultaneously bled off to storage with a part diluted with deionized water and returned to the cell line for strengthening within the cells. The caustic exiting the cell line must be monitored for strength, to maintain safe concentrations. Too strong or too weak a solution may damage the membranes. Membrane cells typically produce caustic in the range of 30% to 33% by weight. The feed caustic flow is heated at low electrical loads to control its exit temperature. Higher loads require the caustic to be cooled, to maintain correct exit temperatures. The caustic exiting to storage is pulled from a storage tank and may be diluted for sale to customers who require weak caustic or for use on site. Another stream may be pumped into a multiple effect evaporator set to produce commercial 50% caustic. Rail cars and tanker trucks are loaded at loading stations via pumps.
- Hydrogen handling
Hydrogen produced may be vented unprocessed directly to the atmosphere or cooled, compressed and dried for use in other processes on site or sold to a customer via pipeline, cylinders or trucks. Some possible uses include the manufacture of hydrochloric acid or hydrogen peroxide, as well as desulfurization of petroleum oils, or use as a fuel in boilers or fuel cells.
In Porsgrunn the byproduct is used for the hydrogen fueling station at hynor.
- Energy consumption
Production of chlorine is extremely energy intensive. Energy consumption per unit weight of product is not far below that for iron and steel manufacture and greater than for the production of glass or cement.
Since electricity is an indispensable raw material for the production of chlorine, the energy consumption corresponding to the electrochemical reaction cannot be reduced. Energy savings arise primarily through applying more efficient technologies and reducing ancillary energy use.
# Compounds
For general references to the chloride ion (Cl−), including references to specific chlorides, see chloride. For other chlorine compounds see chlorate (ClO3−), chlorite (ClO2−), hypochlorite(ClO−), and perchlorate(ClO4−), and chloramine (NH2Cl).
Other chlorine-containing compounds include:
- Fluorides: chlorine monofluoride (ClF), chlorine trifluoride (ClF3), chlorine pentafluoride (ClF5)
- Oxides: chlorine dioxide (ClO2), dichlorine monoxide (Cl2O), dichlorine heptoxide (Cl2O7)
- Acids: hydrochloric acid (HCl), chloric acid (HClO3), and perchloric acid (HClO4)
## Oxidation states
Chlorine exists in all odd numbered oxidation states from −1 to +7, as well as the elemental state of zero. Progressing through the states, hydrochloric acid can be oxidized using manganese dioxide, or hydrogen chloride gas oxidized catalytically by air to form elemental chlorine gas. The solubility of chlorine in water is increased if the water contains dissolved alkali hydroxide. This is due to disproportionation:
In hot concentrated alkali solution disproportionation continues:
Sodium chlorate and potassium chlorate can be crystallized from solutions formed by the above reactions. If their crystals are heated, they undergo the final disproportionation step.
This same progression from chloride to perchlorate can be accomplished by electrolysis. The anode reaction progression is:
Each step is accompanied at the cathode by
# Applications and uses
## Production of industrial and consumer products
Chlorine's principal applications are in the production of a wide range of industrial and consumer products. For example, it is used in making plastics, solvents for dry cleaning and metal degreasing, textiles, agrochemicals and pharmaceuticals, insecticides, dyestuffs, etc.
## Purification and disinfection
Chlorine is an important chemical for water purification, in disinfectants, and in bleach. It is used (in the form of hypochlorous acid) to kill bacteria and other microbes in drinking water supplies and public swimming pools. However, in most private swimming pools chlorine itself is not used, but rather sodium hypochlorite (household bleach), formed from chlorine and sodium hydroxide, or solid tablets of chlorinated isocyanurates. Even small water supplies are now routinely chlorinated. (See also chlorination)
## Chemistry
Elemental chlorine is an oxidizer. It undergoes halogen substitution reactions with lower halide salts. For example, chlorine gas bubbled through a solution of bromide or iodide anions oxidizes them to bromine and iodine respectively.
Like the other halogens, chlorine participates in free-radical substitution reactions with hydrogen-containing organic compounds. This reaction is often – but not invariably – non-regioselective, and hence may result in a mixture of isomeric products. It is often difficult to control the degree of substitution as well, so multiple substitutions are common. If the different reaction products are easily separated, e.g. by distillation, substitutive free-radical chlorination (in some cases accompanied by concurrent thermal dehydrochlorination) may be a useful synthetic route. Industrial examples of this are the production of methyl chloride, methylene chloride, chloroform and carbon tetrachloride from methane, allyl chloride from propylene, and trichloroethylene and tetrachloroethylene from 1,2-dichloroethane.
Like the other halides, chlorine undergoes electrophilic additions reactions, most notably, the chlorination of alkenes and aromatic compounds with a Lewis acid catalyst. Organic chlorine compounds tend to be less reactive in nucleophilic substitution reactions than the corresponding bromine or iodine derivatives, but they tend to be cheaper. They may be activated for reaction by substituting with a tosylate group, or by the use of a catalytic amount of sodium iodide.
Chlorine is used extensively in organic and inorganic chemistry as an oxidizing agent and in substitution reactions because chlorine often imparts many desired properties to an organic compound, due to its electronegativity.
Chlorine compounds are used as intermediates in the production of a number of important commercial products that do not contain chlorine. Examples are: polycarbonates, polyurethanes, silicones, polytetrafluoroethylene, carboxymethyl cellulose and propylene oxide.
## Use as a weapon
- World War I
Chlorine gas, also known as bertholite, was first used as a weapon in World War I by Germany on April 22, 1915 in the Second Battle of Ypres. As described by the soldiers it had a distinctive smell of a mixture between pepper and pineapple. It also tasted metallic and stung the back of the throat and chest. Chlorine can react with water in the mucosa of the lungs to form hydrochloric acid, an irritant which can be lethal. The damage done by chlorine gas can be prevented by a gas mask which makes the deaths by chlorine gas much lower then those of other chemical weapons. It was pioneered by a German scientist later to be a Nobel laureate, Fritz Haber of the Kaiser Wilhelm Institute in Berlin, in collaboration with the German chemical conglomerate IG Farben, who developed methods for discharging chlorine gas against an entrenched enemy. It is alleged that Haber's role in the use of chlorine as a deadly weapon drove his wife, Clara Immerwahr, to suicide. After its first use, chlorine was utilized by both sides as a chemical weapon, but it was soon replaced by the more deadly gases phosgene and mustard gas.
- Iraq War
Chlorine gas has also been used by insurgents in the Iraq War as a chemical weapon to terrorize the local population and coalition forces. On March 17, 2007, for example, three chlorine filled trucks were detonated in the Anbar province killing 2 and sickening over 350. Other chlorine bomb attacks resulted in higher death tolls, with more than 30 deaths on two separate occasions. Most of the deaths were caused by the force of the explosions rather than the effects of chlorine, since the toxic gas is readily dispersed and diluted in the atmosphere by the blast. The Iraqi authorities have tightened up security for chlorine, which is essential for providing safe drinking water for the population.
## Other uses
Chlorine is used in the manufacture of numerous organic chlorine compounds, the most significant of which in terms of production volume are 1,2-dichloroethane and vinyl chloride, intermediates in the production of PVC. Other particularly important organochlorines are methyl chloride, methylene chloride, chloroform, vinylidene chloride, trichloroethylene, perchloroethylene, allyl chloride, epichlorohydrin, chlorobenzene, dichlorobenzenes and trichlorobenzenes.
Chlorine is also used in the production of chlorates and in bromine extraction.
# History
Chlorine was discovered in 1774 by Swedish chemist Carl Wilhelm Scheele, who called it dephlogisticated marine acid (see phlogiston theory) and mistakenly thought it contained oxygen. Scheele isolated chlorine by reacting MnO2 with HCl.
Scheele observed several of the properties of chlorine. The bleaching effect on litmus and the deadly effect on insects additional to the yellow green colour and the smell similar to aqua regia.
Chlorine was given its current name in 1810 by Sir Humphry Davy, who insisted that it was in fact an element.
# Safety
Chlorine is a toxic gas that irritates the respiratory system. Because it is heavier than air, it tends to accumulate at the bottom of poorly ventilated spaces. Chlorine gas is a strong oxidizer, which may react with flammable materials.
Chlorine is detectable in concentrations of as low as 3.5 to 4 ppm. About 1000 ppm can be fatal after a few deep breaths of the gas. Breathing lower concentrations can aggravate the respiratory system, and exposure to the gas can irritate the eyes.
Never use ABC Dry Chemical to fight a chlorine fire, the resulting chemical reaction with the ammonium phosphate will release toxic gases and/or result in an explosion. Water fogs or CAFS should be used to extinguish the material.
The number of people allergic to chlorine is very small. People who are allergic to chlorine cannot drink tap water, bathe in tap water or swim in pools. Dechlorinating bath salts are used to neutralize the chlorine in bath water. Otherwise, fresh water is boiled and cooled.
# Chlorine cracking
The element is widely used for purifying water owing to its powerful oxidising properties, especially potable water supplies and water used in swimming pools. However, some polymers are sensitive to attack, including acetal resin and polybutene. Both materials were used in hot and cold water domestic supplies, and stress corrosion cracking cause widespread failures in the USA in the 1980's and 90's. One example shows an acetal joint in a water supply system, which when it fractured, caused substantial physical damage to computers in the labs below the supply. The cracks started at injection moulding defects in the joint and grew slowly until finally triggered. The fracture surface shows iron and calcium salts which were deposited in the leaking joint from the water supply before failure | Chlorine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Template:Infobox chlorine
Chlorine (Template:IPAEng, from the Greek word 'χλωρóς' (khlôros) meaning 'green'), is the chemical element with atomic number 17 and symbol Cl. It is a halogen, found in the periodic table in group VII (formerly VIIa or VIIb). As the chloride ion, which is part of common salt and other compounds, it is abundant in nature and necessary to most forms of life, including humans. In its common elemental form (Cl2 or "dichlorine") under standard conditions, it is a pale green gas about 2.5 times as dense as air. It has a disagreeable, suffocating odor that is detectable in concentrations as low as 3.5 ppm[1] and is poisonous. Chlorine is a powerful oxidant and is used in bleaching and disinfectants. As a common disinfectant, chlorine compounds are used in swimming pools to keep them clean and sanitary. In the upper atmosphere, chlorine-containing molecules have been implicated in the destruction of the ozone layer.
# Characteristics
Chlorine gas is diatomic, with the formula Cl2. It combines readily with all elements except O2 and N2[2] and the noble gases. Compounds with oxygen, nitrogen, and xenon are known but do not form by direct reaction of the elements.[3] Chlorine, though very reactive, is not as extremely reactive as fluorine. Pure chlorine gas does, however, support combustion of organic compounds such as hydrocarbons, although the carbon component tends to burn incompletely, with much of it remaining as soot.[4] At 10 °C and atmospheric pressure, one liter of water dissolves 3.10 L of gaseous chlorine, and at 30°C, 1 L of water dissolves only 1.77 liters of chlorine.[2]
This element is a member of the salt-forming halogen series and is extracted from chlorides through oxidation often by electrolysis. As the chloride ion, Cl−, it is also the most abundant dissolved ion in ocean water.
## Isotopes
Chlorine has isotopes with mass numbers ranging from 32 to 40. There are two principal stable isotopes, 35Cl (75.77%) and 37Cl (24.23%), giving chlorine atoms in bulk an apparent atomic weight of 35.4527 g/mol.
Trace amounts of radioactive 36Cl exist in the environment, in a ratio of about 7x10−13 to 1 with stable isotopes. 36Cl is produced in the atmosphere by spallation of 36Ar by interactions with cosmic ray protons. In the subsurface environment, 36Cl is generated primarily as a result of neutron capture by 35Cl or muon capture by 40Ca. 36Cl decays to 36S and to 36Ar, with a combined half-life of 308,000 years. The half-life of this hydrophilic nonreactive isotope makes it suitable for geologic dating in the range of 60,000 to 1 million years. Additionally, large amounts of 36Cl were produced by irradiation of seawater during atmospheric detonations of nuclear weapons between 1952 and 1958. The residence time of 36Cl in the atmosphere is about 1 week. Thus, as an event marker of 1950s water in soil and ground water, 36Cl is also useful for dating waters less than 50 years before the present. 36Cl has seen use in other areas of the geological sciences, including dating ice and sediments.
## Occurrence
In nature, chlorine is found primarily as the chloride ion, a component of the salt that is deposited in the earth or dissolved in the oceans — about 1.9% of the mass of seawater is chloride ions. Even higher concentrations of chloride are found in the Dead Sea and in underground brine deposits. Most chloride salts are soluble in water, thus, chloride-containing minerals are usually only found in abundance in dry climates or deep underground. Common chloride minerals include halite (sodium chloride), sylvite (potassium chloride), and carnallite (potassium magnesium chloride hexahydrate). Over 2000 naturally-occurring organic chlorine compounds are known.[5]
Industrially, elemental chlorine is usually produced by the electrolysis of sodium chloride dissolved in water. Along with chlorine, this chloralkali process yields hydrogen gas and sodium hydroxide, according to the following chemical equation:
# Production
## Gas extraction
Chlorine can be manufactured by electrolysis of a sodium chloride solution (brine). The production of chlorine results in the co-products caustic soda (sodium hydroxide, NaOH) and hydrogen gas (H2). These two products, as well as chlorine itself, are highly reactive. Chlorine can also be produced by the electrolysis of a solution of potassium chloride, in which case the co-products are hydrogen and caustic potash (potassium hydroxide). There are three industrial methods for the extraction of chlorine by electrolysis of chloride solutions, all proceeding according to the following equations:
Overall process: 2 NaCl (or KCl) + 2 H2O → Cl2 + H2 + 2 NaOH (or KOH)
- Mercury cell electrolysis
Mercury cell electrolysis, also known as the Castner-Kellner process, was the first method used at the end of the nineteenth century to produce chlorine on an industrial scale.[6][7] The "rocking" cells used have been improved over the years.[8] Today, in the "primary cell", titanium anodes (formerly graphite ones) are placed in a sodium (or potassium) chloride solution flowing over a liquid mercury cathode. When a potential difference is applied and current flows, chlorine is released at the titanium anode and sodium (or potassium) dissolves in the mercury cathode forming an amalgam. This flows continuously into a separate reactor ("denuder" or "secondary cell"), where it is usually converted back to mercury by reaction with water, producing hydrogen and sodium (or potassium) hydroxide at a commercially useful concentration (50% by weight). The mercury is then recycled to the primary cell.
The mercury process is the least energy-efficient of the three main technologies (mercury, diaphragm and membrane) and there are also concerns about mercury emissions.
It is estimated that there are still around 100 mercury-cell plants operating worldwide. In Japan, mercury-based chloralkali production was virtually phased out by 1987 (except for the last two potassium chloride units shut down in 2003). In the United States, there will be only five mercury plants remaining in operation by the end of 2008. In Europe, mercury cells accounted for 43% of capacity in 2006 and Western European producers have committed to closing or converting all remaining chloralkali mercury plants by 2020.[9]
- Diaphragm cell electrolysis
In diaphragm cell electrolysis, an asbestos (or polymer-fiber) diaphragm separates a cathode and an anode, preventing the chlorine forming at the anode from re-mixing with the sodium hydroxide and the hydrogen formed at the cathode.[10] This technology was also developed at the end of the nineteenth century. There are several variants of this process: the Le Sueur cell (1893), the Hargreaves-Bird cell (1901), the Gibbs cell (1908), and the Townsend cell (1904).[11][12] The cells vary in construction and placement of the diaphragm, with some having the diaphragm in direct contact with the cathode.
The salt solution (brine) is continuously fed to the anode compartment and flows through the diaphragm to the cathode compartment, where the caustic alkali is produced and the brine is partially depleted.
As a result, diaphragm methods produce alkali that is quite dilute (about 12%) and of lower purity than do mercury cell methods. But diaphragm cells are not burdened with the problem of preventing mercury discharge into the environment. They also operate at a lower voltage, resulting in an energy savings over the mercury cell method[12], but large amounts of steam are required if the caustic has to be evaporated to the commercial concentration of 50%.
- Membrane cell electrolysis
Development of this technology began in the 1970s. The electrolysis cell is divided into two "rooms" by a cation permeable membrane acting as an ion exchanger. Saturated sodium (or potassium) chloride solution is passed through the anode compartment, leaving at a lower concentration.[13] Sodium (or potassium) hydroxide solution is circulated through the cathode compartment, exiting at a higher concentration. A portion of the concentrated sodium hydroxide solution leaving the cell is diverted as product, while the remainder is diluted with deionized water and passed through the electrolysis apparatus again.
This method is more efficient than the diaphragm cell and produces very pure sodium (or potassium) hydroxide at about 32% concentration, but requires very pure brine.
- Other electrolytic processes
Although a much lower production scale is involved, electrolytic diaphragm and membrane technologies are also used industrially to recover chlorine from hydrochloric acid solutions, producing hydrogen (but no caustic alkali) as a co-product.
Furthermore, electrolysis of fused chloride salts (Downs process) also enables chlorine to be produced, in this case as a by-product of the manufacture of metallic sodium or magnesium.
## Other methods
Before electrolytic methods were used for chlorine production, the direct oxidation of hydrogen chloride with oxygen or air was exercised in the Deacon process:
This reaction is accomplished with the use of copper(II) chloride (CuCl2) as a catalyst and is performed at high temperature (about 400 °C). The amount of extracted chlorine is approximately 80%. Due to the extremely corrosive reaction mixture, industrial use of this method is difficult and several pilot trials failed in the past. Nevertheless, recent developments are promising. Recently Sumitomo patented a catalyst for the Deacon process using ruthenium(IV) oxide (RuO2).[14]
Another earlier process to produce chlorine was to heat brine with acid and manganese dioxide.
Using this process, chemist Carl Wilhelm Scheele was the first to isolate chlorine in a laboratory. The manganese can be recovered by the Weldon process.[15]
Small amounts of chlorine gas can be made in the laboratory by putting concentrated hydrochloric acid in a flask with a side arm and rubber tubing attached. Manganese dioxide is then added and the flask stoppered. The reaction is not greatly exothermic. As chlorine is denser than air, it can be easily collected by placing the tube inside a flask where it will displace the air. Once full, the collecting flask can be stoppered.
Another method for producing small amounts of chlorine gas in a lab is by adding concentrated hydrochloric acid (typically about 5M) to sodium hypochlorite or sodium chlorate solution.
## Industrial production
Large-scale production of chlorine involves several steps and many pieces of equipment. The description below is typical of a membrane plant. The plant also simultaneously produces sodium hydroxide (caustic soda) and hydrogen gas. A typical plant consists of brine production/treatment, cell operations, chlorine cooling & drying, chlorine compression & liquefaction, liquid chlorine storage & loading, caustic handling, evaporation, storage & loading and hydrogen handling.
- Brine
Key to the production of chlorine is the operation of the brine saturation/treatment system. Maintaining a properly saturated solution with the correct purity is vital, especially for membrane cells. Many plants have a salt pile which is sprayed with recycled brine. Others have slurry tanks that are fed raw salt.
The raw brine is partially or totally treated with sodium hydroxide, sodium carbonate and a flocculant to reduce calcium, magnesium and other impurities. The brine proceeds to a large clarifier or a filter where the impurities are removed. The total brine is additionally filtered before entering ion exchangers to further remove impurities. At several points in this process, the brine is tested for hardness and strength.
After the ion exchangers, the brine is considered pure, and is transferred to storage tanks to be pumped into the cell room. Brine, fed to the cell line, is heated to the correct temperature to control exit brine temperatures according to the electrical load. Brine exiting the cell room must be treated to remove residual chlorine and control pH levels before being returned to the saturation stage. This can be accomplished via dechlorination towers with acid and sodium bisulfite addition. Failure to remove chlorine can result in damage to the cells. Brine should be monitored for accumulation of bothchlorate anions and sulfate anions, and either have a treatment system in place, or purging of the brine loop to maintain safe levels, since chlorate anions can diffuse through the membranes and contaminate the caustic, while sulfate anions can damage the anode surface coating.
- Cell room
The building that houses the many electrolytic cells is usually called a cell room or cell house, although some plants are built outdoors. This building contains support structures for the cells, connections for supplying electrical power to the cells and piping for the fluids. Monitoring and control of the temperatures of the feed caustic and brine is done to control exit temperatures. Also monitored are the voltages of each cell which vary with the electrical load on the cell room that is used to control the rate of production. Monitoring and control of the pressures in the chlorine and hydrogen headers is also done via pressure control valves.
Direct current is supplied via a rectified power source. Plant load is controlled by varying the current to the cells. As the current is increased, flow rates for brine and caustic and deionized water are increased, while lowering the feed temperatures.
- Cooling and drying
Chlorine gas exiting the cell line must be cooled and dried since the exit gas can be over 80°C and contains moisture that allows chlorine gas to be corrosive to iron piping. Cooling the gas allows for a large amount of moisture from the brine to condense out of the gas stream. Cooling also improves the efficiency of both the compression and the liquefaction stage that follows. Chlorine exiting is ideally between 18°C and 25°C. After cooling the gas stream passes through a series of towers with counter flowing sulfuric acid. These towers progressively remove any remaining moisture from the chlorine gas. After exiting the drying towers the chlorine is filtered to remove any remaining sulfuric acid.
- Compression and liquefaction
Several methods of compression may be used: liquid ring, reciprocating, or centrifugal. The chlorine gas is compressed at this stage and may be further cooled by inter- and after-coolers. After compression it flows to the liquefiers, where it is cooled enough to liquefy. Non condensible gases and remaining chlorine gas are vented off as part of the pressure control of the liquefaction systems. These gases are routed to a gas scrubber, producing sodium hypochlorite, or used in the production of hydrochloric acid (by combustion with hydrogen) or ethylene dichloride (by reaction with ethylene).
- Storage and loading
Liquid chlorine is typically gravity-fed to storage tanks. It can be loaded into rail or road tankers via pumps or padded with compressed dry gas.
- Caustic handling, evaporation, storage and loading
Caustic, fed to the cell room flows in a loop that is simultaneously bled off to storage with a part diluted with deionized water and returned to the cell line for strengthening within the cells. The caustic exiting the cell line must be monitored for strength, to maintain safe concentrations. Too strong or too weak a solution may damage the membranes. Membrane cells typically produce caustic in the range of 30% to 33% by weight. The feed caustic flow is heated at low electrical loads to control its exit temperature. Higher loads require the caustic to be cooled, to maintain correct exit temperatures. The caustic exiting to storage is pulled from a storage tank and may be diluted for sale to customers who require weak caustic or for use on site. Another stream may be pumped into a multiple effect evaporator set to produce commercial 50% caustic. Rail cars and tanker trucks are loaded at loading stations via pumps.
- Hydrogen handling
Hydrogen produced may be vented unprocessed directly to the atmosphere or cooled, compressed and dried for use in other processes on site or sold to a customer via pipeline, cylinders or trucks. Some possible uses include the manufacture of hydrochloric acid or hydrogen peroxide, as well as desulfurization of petroleum oils, or use as a fuel in boilers or fuel cells.
In Porsgrunn the byproduct is used for the hydrogen fueling station at hynor.
- Energy consumption
Production of chlorine is extremely energy intensive.[16] Energy consumption per unit weight of product is not far below that for iron and steel manufacture[17] and greater than for the production of glass[18] or cement.[19]
Since electricity is an indispensable raw material for the production of chlorine, the energy consumption corresponding to the electrochemical reaction cannot be reduced. Energy savings arise primarily through applying more efficient technologies and reducing ancillary energy use.
# Compounds
For general references to the chloride ion (Cl−), including references to specific chlorides, see chloride. For other chlorine compounds see chlorate (ClO3−), chlorite (ClO2−), hypochlorite(ClO−), and perchlorate(ClO4−), and chloramine (NH2Cl).[20]
Other chlorine-containing compounds include:
- Fluorides: chlorine monofluoride (ClF), chlorine trifluoride (ClF3), chlorine pentafluoride (ClF5)
- Oxides: chlorine dioxide (ClO2), dichlorine monoxide (Cl2O), dichlorine heptoxide (Cl2O7)
- Acids: hydrochloric acid (HCl), chloric acid (HClO3), and perchloric acid (HClO4)
## Oxidation states
Chlorine exists in all odd numbered oxidation states from −1 to +7, as well as the elemental state of zero. Progressing through the states, hydrochloric acid can be oxidized using manganese dioxide, or hydrogen chloride gas oxidized catalytically by air to form elemental chlorine gas. The solubility of chlorine in water is increased if the water contains dissolved alkali hydroxide. This is due to disproportionation:
In hot concentrated alkali solution disproportionation continues:
Sodium chlorate and potassium chlorate can be crystallized from solutions formed by the above reactions. If their crystals are heated, they undergo the final disproportionation step.
This same progression from chloride to perchlorate can be accomplished by electrolysis. The anode reaction progression is:[21]
Each step is accompanied at the cathode by
# Applications and uses
## Production of industrial and consumer products
Chlorine's principal applications are in the production of a wide range of industrial and consumer products.[22] [23] For example, it is used in making plastics, solvents for dry cleaning and metal degreasing, textiles, agrochemicals and pharmaceuticals, insecticides, dyestuffs, etc.
## Purification and disinfection
Chlorine is an important chemical for water purification, in disinfectants, and in bleach. It is used (in the form of hypochlorous acid) to kill bacteria and other microbes in drinking water supplies and public swimming pools. However, in most private swimming pools chlorine itself is not used, but rather sodium hypochlorite (household bleach), formed from chlorine and sodium hydroxide, or solid tablets of chlorinated isocyanurates. Even small water supplies are now routinely chlorinated.[24] (See also chlorination)
## Chemistry
Elemental chlorine is an oxidizer. It undergoes halogen substitution reactions with lower halide salts. For example, chlorine gas bubbled through a solution of bromide or iodide anions oxidizes them to bromine and iodine respectively.
Like the other halogens, chlorine participates in free-radical substitution reactions with hydrogen-containing organic compounds. This reaction is often – but not invariably – non-regioselective, and hence may result in a mixture of isomeric products. It is often difficult to control the degree of substitution as well, so multiple substitutions are common. If the different reaction products are easily separated, e.g. by distillation, substitutive free-radical chlorination (in some cases accompanied by concurrent thermal dehydrochlorination) may be a useful synthetic route. Industrial examples of this are the production of methyl chloride, methylene chloride, chloroform and carbon tetrachloride from methane, allyl chloride from propylene, and trichloroethylene and tetrachloroethylene from 1,2-dichloroethane.
Like the other halides, chlorine undergoes electrophilic additions reactions, most notably, the chlorination of alkenes and aromatic compounds with a Lewis acid catalyst. Organic chlorine compounds tend to be less reactive in nucleophilic substitution reactions than the corresponding bromine or iodine derivatives, but they tend to be cheaper. They may be activated for reaction by substituting with a tosylate group, or by the use of a catalytic amount of sodium iodide.
Chlorine is used extensively in organic and inorganic chemistry as an oxidizing agent and in substitution reactions because chlorine often imparts many desired properties to an organic compound, due to its electronegativity.
Chlorine compounds are used as intermediates in the production of a number of important commercial products that do not contain chlorine. Examples are: polycarbonates, polyurethanes, silicones, polytetrafluoroethylene, carboxymethyl cellulose and propylene oxide.
## Use as a weapon
- World War I
Chlorine gas, also known as bertholite, was first used as a weapon in World War I by Germany on April 22, 1915 in the Second Battle of Ypres. As described by the soldiers it had a distinctive smell of a mixture between pepper and pineapple. It also tasted metallic and stung the back of the throat and chest. Chlorine can react with water in the mucosa of the lungs to form hydrochloric acid, an irritant which can be lethal. The damage done by chlorine gas can be prevented by a gas mask which makes the deaths by chlorine gas much lower then those of other chemical weapons. It was pioneered by a German scientist later to be a Nobel laureate, Fritz Haber of the Kaiser Wilhelm Institute in Berlin, in collaboration with the German chemical conglomerate IG Farben, who developed methods for discharging chlorine gas against an entrenched enemy. It is alleged that Haber's role in the use of chlorine as a deadly weapon drove his wife, Clara Immerwahr, to suicide. After its first use, chlorine was utilized by both sides as a chemical weapon, but it was soon replaced by the more deadly gases phosgene and mustard gas.[25]
- Iraq War
Chlorine gas has also been used by insurgents in the Iraq War as a chemical weapon to terrorize the local population and coalition forces. On March 17, 2007, for example, three chlorine filled trucks were detonated in the Anbar province killing 2 and sickening over 350.[26] Other chlorine bomb attacks resulted in higher death tolls, with more than 30 deaths on two separate occasions.[27] Most of the deaths were caused by the force of the explosions rather than the effects of chlorine, since the toxic gas is readily dispersed and diluted in the atmosphere by the blast. The Iraqi authorities have tightened up security for chlorine, which is essential for providing safe drinking water for the population.
## Other uses
Chlorine is used in the manufacture of numerous organic chlorine compounds, the most significant of which in terms of production volume are 1,2-dichloroethane and vinyl chloride, intermediates in the production of PVC. Other particularly important organochlorines are methyl chloride, methylene chloride, chloroform, vinylidene chloride, trichloroethylene, perchloroethylene, allyl chloride, epichlorohydrin, chlorobenzene, dichlorobenzenes and trichlorobenzenes.
Chlorine is also used in the production of chlorates and in bromine extraction.
# History
Chlorine was discovered in 1774 by Swedish chemist Carl Wilhelm Scheele, who called it dephlogisticated marine acid (see phlogiston theory) and mistakenly thought it contained oxygen. Scheele isolated chlorine by reacting MnO2 with HCl.
Scheele observed several of the properties of chlorine. The bleaching effect on litmus and the deadly effect on insects additional to the yellow green colour and the smell similar to aqua regia.
Chlorine was given its current name in 1810 by Sir Humphry Davy, who insisted that it was in fact an element.
# Safety
Chlorine is a toxic gas that irritates the respiratory system. Because it is heavier than air, it tends to accumulate at the bottom of poorly ventilated spaces. Chlorine gas is a strong oxidizer, which may react with flammable materials.[28]
Chlorine is detectable in concentrations of as low as 3.5 to 4 ppm. About 1000 ppm can be fatal after a few deep breaths of the gas[2]. Breathing lower concentrations can aggravate the respiratory system, and exposure to the gas can irritate the eyes.
Never use ABC Dry Chemical to fight a chlorine fire, the resulting chemical reaction with the ammonium phosphate will release toxic gases and/or result in an explosion. Water fogs or CAFS should be used to extinguish the material.[28]
The number of people allergic to chlorine is very small. People who are allergic to chlorine cannot drink tap water, bathe in tap water or swim in pools. Dechlorinating bath salts are used to neutralize the chlorine in bath water. Otherwise, fresh water is boiled and cooled.
# Chlorine cracking
The element is widely used for purifying water owing to its powerful oxidising properties, especially potable water supplies and water used in swimming pools. However, some polymers are sensitive to attack, including acetal resin and polybutene. Both materials were used in hot and cold water domestic supplies, and stress corrosion cracking cause widespread failures in the USA in the 1980's and 90's. One example shows an acetal joint in a water supply system, which when it fractured, caused substantial physical damage to computers in the labs below the supply. The cracks started at injection moulding defects in the joint and grew slowly until finally triggered. The fracture surface shows iron and calcium salts which were deposited in the leaking joint from the water supply before failure | https://www.wikidoc.org/index.php/Chlorine | |
cc9d18093ea42b0a0939d900b50613a89763f402 | wikidoc | Chlorite | Chlorite
The chlorite ion is ClO2−. A chlorite (compound) is a compound that contains this group,
with chlorine in oxidation state +3. Chlorites are also known as salts of chlorous acid.
# Oxidation states
Chlorine can assume oxidation states of −1, +1, +3, +5, or +7 corresponding to the anions Cl−, ClO−, ClO2−, ClO3−, or ClO4−, respectively (known as chloride, hypochlorite, chlorite, chlorate, and perchlorate.)
# Some chlorite compounds
- sodium chlorite, NaClO2
- magnesium chlorite, Mg(ClO2)2
# Manufacture
The free acid, chlorous acid, HClO2, is only stable at low concentrations. Since it cannot be concentrated, it is not a commercial product. However, the corresponding sodium salt, sodium chlorite, NaClO2 is stable and inexpensive enough to be commercially available. The corresponding salts of heavy metals (Ag+, Hg+, Tl+, Pb2+, and also Cu2+ and NH4+) decompose explosively with heat or shock.
Sodium chlorite is derived indirectly from sodium chlorate, NaClO3. First, the explosively unstable gas chlorine dioxide, ClO2 is produced by reducing sodium chlorate in a strong acid solution with a suitable reducing agent (for example, sodium chloride, sulfur dioxide, or hydrochloric acid). The chlorine dioxide is then absorbed into an alkaline solution and reduced with hydrogen peroxide, H2O2 yielding sodium chlorite.
# Usage
The main application of sodium chlorite is the generation of chlorine dioxide for bleaching and stripping of textiles, pulp, and paper. It is also used for disinfection in a few municipal water treatment plants after conversion to chlorine dioxide. An advantage in this application, as compared to the more commonly used chlorine, is that trihalomethanes are not produced from organic contaminants. Sodium chlorite, NaClO2 also finds application as a component of contact lens cleaning solution under the trade name purite.
Sodium chlorite, like many oxidizers, should be protected from inadvertent contamination by organic materials to avoid the formation of an explosive mixture. | Chlorite
The chlorite ion is ClO2−. A chlorite (compound) is a compound that contains this group,
with chlorine in oxidation state +3. Chlorites are also known as salts of chlorous acid.
# Oxidation states
Chlorine can assume oxidation states of −1, +1, +3, +5, or +7 corresponding to the anions Cl−, ClO−, ClO2−, ClO3−, or ClO4−, respectively (known as chloride, hypochlorite, chlorite, chlorate, and perchlorate.)
# Some chlorite compounds
- sodium chlorite, NaClO2
- magnesium chlorite, Mg(ClO2)2
# Manufacture
The free acid, chlorous acid, HClO2, is only stable at low concentrations. Since it cannot be concentrated, it is not a commercial product. However, the corresponding sodium salt, sodium chlorite, NaClO2 is stable and inexpensive enough to be commercially available. The corresponding salts of heavy metals (Ag+, Hg+, Tl+, Pb2+, and also Cu2+ and NH4+) decompose explosively with heat or shock.
Sodium chlorite is derived indirectly from sodium chlorate, NaClO3. First, the explosively unstable gas chlorine dioxide, ClO2 is produced by reducing sodium chlorate in a strong acid solution with a suitable reducing agent (for example, sodium chloride, sulfur dioxide, or hydrochloric acid). The chlorine dioxide is then absorbed into an alkaline solution and reduced with hydrogen peroxide, H2O2 yielding sodium chlorite.
# Usage
The main application of sodium chlorite is the generation of chlorine dioxide for bleaching and stripping of textiles, pulp, and paper. It is also used for disinfection in a few municipal water treatment plants after conversion to chlorine dioxide. An advantage in this application, as compared to the more commonly used chlorine, is that trihalomethanes are not produced from organic contaminants. Sodium chlorite, NaClO2 also finds application as a component of contact lens cleaning solution under the trade name purite.
Sodium chlorite, like many oxidizers, should be protected from inadvertent contamination by organic materials to avoid the formation of an explosive mixture. | https://www.wikidoc.org/index.php/Chlorite | |
ef3b20e917a03f4d6e81084feb98f447af38fddd | wikidoc | Chromate | Chromate
# Overview
Chromates and dichromates are salts of chromic acid and dichromic acid, respectively. Chromate salts contain the chromate ion, CrO42−, and have an intense yellow color. Dichromate salts contain the dichromate ion, Cr2O72−, and have an intense orange color.
# Characteristics
- The chromium atoms are in oxidation state +6 in both, and the chromate and dichromate ions are fairly strong oxidizing agents. Chromium in the +6 (or VI) oxidation state is often referred to as hexavalent chromium.
- In an aqueous solution, chromate and dichromate anions are in a chemical equilibrium.
- They are used in environmental analysis to measure chemical oxygen demand (COD).
- They are carcinogenic. All hexavalent chromium compounds are considered toxic and carcinogenic.
- When used as oxidizing agents or titrants in a redox chemical reaction, they will turn into trivalent chromium, Cr3+, which has a distinctively different blue-green color.
- The sodium (Na+), potassium (K+), and ammonium (NH4+) salts are water soluble granular solids and are the most commonly used chromate or dichromate chemical reagents. Most chromate and dichromate salts of heavy metals, lanthanides or alkaline earth metals are only very slightly soluble in water and are thus of much less usefulness.
- Chromate conversion coatings are applied to metals for corrosion protection, and to improve paint adhesion.
- The use of chromate compounds in manufactured goods is restricted in the EU (and by market commonality the rest of the world) by EU Parliament directive 2002/95/EC
# Structures | Chromate
# Overview
Chromates and dichromates are salts of chromic acid and dichromic acid, respectively. Chromate salts contain the chromate ion, CrO42−, and have an intense yellow color. Dichromate salts contain the dichromate ion, Cr2O72−, and have an intense orange color.
# Characteristics
- The chromium atoms are in oxidation state +6 in both, and the chromate and dichromate ions are fairly strong oxidizing agents. Chromium in the +6 (or VI) oxidation state is often referred to as hexavalent chromium.
- In an aqueous solution, chromate and dichromate anions are in a chemical equilibrium.
- They are used in environmental analysis to measure chemical oxygen demand (COD).
- They are carcinogenic. All hexavalent chromium compounds are considered toxic and carcinogenic.
- When used as oxidizing agents or titrants in a redox chemical reaction, they will turn into trivalent chromium, Cr3+, which has a distinctively different blue-green color.
- The sodium (Na+), potassium (K+), and ammonium (NH4+) salts are water soluble granular solids and are the most commonly used chromate or dichromate chemical reagents. Most chromate and dichromate salts of heavy metals, lanthanides or alkaline earth metals are only very slightly soluble in water and are thus of much less usefulness.
- Chromate conversion coatings are applied to metals for corrosion protection, and to improve paint adhesion.
- The use of chromate compounds in manufactured goods is restricted in the EU (and by market commonality the rest of the world) by EU Parliament directive 2002/95/EC
# Structures | https://www.wikidoc.org/index.php/Chromate | |
7cc866910965a4ba87a54725960ab45dae2d0cee | wikidoc | Chromium | Chromium
# Overview
Chromium (Template:PronEng) is a chemical element which has the symbol Cr and atomic number 24. It is a steel-gray, lustrous, hard metal that takes a high polish and has a high melting point. It is also odourless, tasteless, and malleable.
# History
On 26 July 1761, Johann Gottlob Lehmann found an orange-red mineral in the Ural Mountains which he named Siberian red lead. Though misidentified as a lead compound with selenium and iron components, the material was in fact lead chromate with a formula of PbCrO4, now known as the mineral crocoite.
In 1770, Peter Simon Pallas visited the same site as Lehmann and found a red "lead" mineral that had very useful properties as a pigment in paints. The use of Siberian red lead as a paint pigment developed rapidly. A bright yellow made from crocoite became a color in fashion.
In 1797, Louis Nicolas Vauquelin received samples of crocoite ore. He was able to produce chromium oxide with a chemical formula of CrO3, by mixing crocoite with hydrochloric acid. In 1798, Vauquelin discovered that he could isolate metallic chromium by heating the oxide in a charcoal oven. He was also able to detect traces of chromium in precious gemstones, such as ruby, or emerald. Later that year he successfully isolated chromium atoms.
During the 1800s chromium was primarily used as a component of paints and in tanning salts but now metal alloys account for 85% of the use of chromium. The remainder is used in the chemical industry and refractory and foundry industries.
Chromium was named after the Greek word "Chrôma" meaning color, because of the many colorful compounds made from it.
# Occurrence and production
Chromium is mined as chromite (FeCr2O4) ore. About two-fifths of the chromite ores and concentrates in the world are produced in South Africa. Kazakhstan, India, Russia and Turkey are also substantial producers. Untapped chromite deposits are plentiful, but geographically concentrated in Kazakhstan and southern Africa.
Approximately 15 million tons of marketable chromite ore were produced in 2000, and converted into approximately 4 million tons of ferro-chrome with an approximate market value of 2.5 billion United States dollars.
Though native chromium deposits are rare, some native chromium metal has been discovered. The Udachnaya Mine in Russia produces samples of the native metal. This mine is a kimberlite pipe rich in diamonds, and the reducing environment so provided helped produce both elemental chromium and diamond. (See also chromium minerals)
Chromium is obtained commercially by heating the ore in the presence of aluminium or silicon.
# Chemical properties
Chromium is a member of the transition metals, in group 6. Chromium(0) has an electronic configuration of 4s13d5, due to the lower energy of the high spin configuration. Chromium exhibits a wide range of possible oxidation states. The most common oxidation states of chromium are +2, +3, and +6, with +3 being the most stable. +1, +4 and +5 are rare. Chromium compounds of oxidation state +6 are powerful oxidants.
Chromium is passivated by oxygen, forming a thin (usually a few atoms thick being transparent because of thickness) protective oxide surface layer with another element such as nickel, and/or iron. It forms a compound called a spinal structure which, being very dense, prevents diffusion of oxygen into the underlying layer. (In iron or plain carbon steels the oxygen actually migrates into the underlying material.) Chromium is usually plated on top of a nickel layer which may or may not have been copper plated first. Chromium as opposite to most other metals such as iron and nickel does not suffer from hydrogen embrittlement. It does though suffer from nitrogen embrittlement and hence no straight chromium alloy has ever been developed. Below the pourbaix diagram can be seen, it is important to understand that the diagram only displays the thermodynamic data and it does not display any details of the rates of reaction.
# Compounds
Potassium dichromate is a powerful oxidizing agent and is the preferred compound for cleaning laboratory glassware of any trace organics. It is used as a saturated solution in concentrated sulfuric acid for washing the apparatus. For this purpose, however, sodium dichromate is sometimes used because of its higher solubility (5 g/100 ml vs. 20 g/100 ml respectively).
Chrome green is the green oxide of chromium, Cr2O3, used in enamel painting, and glass staining. Chrome yellow is a brilliant yellow pigment, PbCrO4, used by painters.
Chromic acid has the hypothetical structure H2CrO4. Neither chromic nor dichromic acid is found in nature, but their anions are found in a variety of compounds. Chromium trioxide, CrO3, the acid anhydride of chromic acid, is sold industrially as "chromic acid".
## Chromium and the quintuple bond
Chromium is notable for its ability to form quintuple covalent bonds. The synthesis of a compound of chromium(I) and a hydrocarbon radical was shown via X-ray diffraction to contain a quintuple bond of length 183.51(4) pm (1.835 angstroms) joining the two central chromium atoms. This was accomplished through the use of an extremely bulky monodentate ligand which through its sheer size prevents further coordination. Chromium currently remains the only element for which quintuple bonds have been observed.
# Applications
Uses of chromium:
- In metallurgy, to impart corrosion resistance and a shiny finish:
as an alloy constituent, such as in stainless steel in cutlery
in chrome plating,
in anodized aluminium, literally turning the surface of aluminium into ruby.
- as an alloy constituent, such as in stainless steel in cutlery
- in chrome plating,
- in anodized aluminium, literally turning the surface of aluminium into ruby.
- As dyes and paints :
Chromium(III) oxide is a metal polish known as green rouge.
Chromium salts color glass an emerald green.
Chromium is what makes a ruby red, and therefore is used in producing synthetic rubies.
also makes a brilliant yellow for painting
- Chromium(III) oxide is a metal polish known as green rouge.
- Chromium salts color glass an emerald green.
- Chromium is what makes a ruby red, and therefore is used in producing synthetic rubies.
- also makes a brilliant yellow for painting
- As a catalyst.
- Chromite is used to make molds for the firing of bricks.
- Chromium salts are used in the tanning of leather.
- Potassium dichromate is a chemical reagent, used in cleaning laboratory glassware and as a titrating agent. It is also used as a mordant (i.e., a fixing agent) for dyes in fabric.
- Chromium(IV) oxide (CrO2) is used to manufacture magnetic tape, where its higher coercivity than iron oxide tapes gives better performance.
- In well drilling muds as an anti-corrosive.
- In medicine, as a dietary supplement or slimming aid, usually as chromium (III) chloride or chromium(III) picolinate.
- Chromium hexacarbonyl (Cr(CO)6) is used as a gasoline additive.
- Chromium boride (CrB) is used as a high-temperature electrical conductor.
- Chromium (III) sulfate (Cr2(SO4)3) is used as a green pigment in paints, in ceramic, varnishes and inks as well as in chrome plating.
- Chromium (VI) is used in the post Ballard preparation of Gravure (rotogravure) printing Forme Cylinders. By electroplating the metal onto the second coat of copper (after the Ballard skin), the longevity of the printing cylinder is increased.
- Micronutrient, in "health" aware drinks, known to improve the amount of energy you get from food.
# Biological role
Trivalent chromium (Cr(III), or Cr3+) is required in trace amounts for sugar metabolism in humans (Glucose Tolerance Factor) and its deficiency may cause a disease called chromium deficiency. In contrast, hexavalent chromium is very toxic and mutagenic when inhaled as publicized by the film Erin Brockovich. Cr(VI) has not been established as a carcinogen when not inhaled but in solution it is well established as a cause of allergic contact dermatitis (ACD).
Recently it was shown that the popular dietary supplement chromium picolinate complex generates chromosome damage in hamster cells. In the United States the dietary guidelines for daily chromium uptake were lowered from 50-200 µg for an adult to 35 µg (adult male) and to 25 µg (adult female).
# Isotopes
Naturally occurring chromium is composed of three stable isotopes; 52Cr, 53Cr, and 54Cr with 52Cr being the most abundant (83.789% natural abundance). Nineteen radioisotopes have been characterized with the most stable being 50Cr with a half-life of (more than) 1.8x1017 years, and 51Cr with a half-life of 27.7 days. All of the remaining radioactive isotopes have half-lives that are less than 24 hours and the majority of these have half-lives that are less than 1 minute. This element also has 2 meta states.
53Cr is the radiogenic decay product of 53Mn. Chromium isotopic contents are typically combined with manganese isotopic contents and have found application in isotope geology. Mn-Cr isotope ratios reinforce the evidence from 26Al and 107Pd for the early history of the solar system. Variations in 53Cr/52Cr and Mn/Cr ratios from several meteorites indicate an initial 53Mn/55Mn ratio that suggests Mn-Cr isotope systematics must result from in-situ decay of 53Mn in differentiated planetary bodies. Hence 53Cr provides additional evidence for nucleosynthetic processes immediately before coalescence of the solar system.
The isotopes of chromium range in atomic weight from 43 u (43Cr) to 67 u (67Cr). The primary decay mode before the most abundant stable isotope, 52Cr, is electron capture and the primary mode after is beta decay.
# Precautions
Chromium metal and chromium(III) compounds are not usually considered health hazards; chromium is an essential trace mineral. However, hexavalent chromium (chromium VI) compounds can be toxic if orally ingested or inhaled. The lethal dose of poisonous chromium (VI) compounds is about one half teaspoon of material. Most chromium (VI) compounds are irritating to eyes, skin and mucous membranes. Chronic exposure to chromium (VI) compounds can cause permanent eye injury, unless properly treated. Chromium(VI) is an established human carcinogen. An investigation into hexavalent chromium release into drinking water formed the plot of the motion picture Erin Brockovich.
World Health Organization recommended maximum allowable concentration in drinking water for chromium (VI) is 0.05 milligrams per liter. Hexavalent chromium is also one of the substances whose use is restricted by the European Restriction of Hazardous Substances Directive.
As chromium compounds were used in dyes and paints and the tanning of leather, these compounds are often found in soil and groundwater at abandoned industrial site, now needing environmental cleanup and remediation per the treatment of brownfield land. Primer paint containing hexavalent chromium is still widely used for aerospace and automobile refinishing applications. | Chromium
Template:Infobox chromium
# Overview
Chromium (Template:PronEng) is a chemical element which has the symbol Cr and atomic number 24. It is a steel-gray, lustrous, hard metal that takes a high polish and has a high melting point. It is also odourless, tasteless, and malleable.
# History
On 26 July 1761, Johann Gottlob Lehmann found an orange-red mineral in the Ural Mountains which he named Siberian red lead. Though misidentified as a lead compound with selenium and iron components, the material was in fact lead chromate with a formula of PbCrO4, now known as the mineral crocoite.
In 1770, Peter Simon Pallas visited the same site as Lehmann and found a red "lead" mineral that had very useful properties as a pigment in paints. The use of Siberian red lead as a paint pigment developed rapidly. A bright yellow made from crocoite became a color in fashion.
In 1797, Louis Nicolas Vauquelin received samples of crocoite ore. He was able to produce chromium oxide with a chemical formula of CrO3, by mixing crocoite with hydrochloric acid. In 1798, Vauquelin discovered that he could isolate metallic chromium by heating the oxide in a charcoal oven. He was also able to detect traces of chromium in precious gemstones, such as ruby, or emerald. Later that year he successfully isolated chromium atoms.
During the 1800s chromium was primarily used as a component of paints and in tanning salts but now metal alloys account for 85% of the use of chromium. The remainder is used in the chemical industry and refractory and foundry industries.
Chromium was named after the Greek word "Chrôma" meaning color, because of the many colorful compounds made from it.
# Occurrence and production
Chromium is mined as chromite (FeCr2O4) ore. About two-fifths of the chromite ores and concentrates in the world are produced in South Africa. Kazakhstan, India, Russia and Turkey are also substantial producers. Untapped chromite deposits are plentiful, but geographically concentrated in Kazakhstan and southern Africa.
Approximately 15 million tons of marketable chromite ore were produced in 2000, and converted into approximately 4 million tons of ferro-chrome with an approximate market value of 2.5 billion United States dollars.
Though native chromium deposits are rare, some native chromium metal has been discovered. The Udachnaya Mine in Russia produces samples of the native metal. This mine is a kimberlite pipe rich in diamonds, and the reducing environment so provided helped produce both elemental chromium and diamond. (See also chromium minerals)
Chromium is obtained commercially by heating the ore in the presence of aluminium or silicon.
# Chemical properties
Chromium is a member of the transition metals, in group 6. Chromium(0) has an electronic configuration of 4s13d5, due to the lower energy of the high spin configuration. Chromium exhibits a wide range of possible oxidation states. The most common oxidation states of chromium are +2, +3, and +6, with +3 being the most stable. +1, +4 and +5 are rare. Chromium compounds of oxidation state +6 are powerful oxidants.
Chromium is passivated by oxygen, forming a thin (usually a few atoms thick being transparent because of thickness) protective oxide surface layer with another element such as nickel, and/or iron. It forms a compound called a spinal structure which, being very dense, prevents diffusion of oxygen into the underlying layer. (In iron or plain carbon steels the oxygen actually migrates into the underlying material.) Chromium is usually plated on top of a nickel layer which may or may not have been copper plated first. Chromium as opposite to most other metals such as iron and nickel does not suffer from hydrogen embrittlement. It does though suffer from nitrogen embrittlement and hence no straight chromium alloy has ever been developed. Below the pourbaix diagram can be seen, it is important to understand that the diagram only displays the thermodynamic data and it does not display any details of the rates of reaction.
# Compounds
Potassium dichromate is a powerful oxidizing agent and is the preferred compound for cleaning laboratory glassware of any trace organics. It is used as a saturated solution in concentrated sulfuric acid for washing the apparatus. For this purpose, however, sodium dichromate is sometimes used because of its higher solubility (5 g/100 ml vs. 20 g/100 ml respectively).
Chrome green is the green oxide of chromium, Cr2O3, used in enamel painting, and glass staining. Chrome yellow is a brilliant yellow pigment, PbCrO4, used by painters.
Chromic acid has the hypothetical structure H2CrO4. Neither chromic nor dichromic acid is found in nature, but their anions are found in a variety of compounds. Chromium trioxide, CrO3, the acid anhydride of chromic acid, is sold industrially as "chromic acid".
## Chromium and the quintuple bond
Chromium is notable for its ability to form quintuple covalent bonds. The synthesis of a compound of chromium(I) and a hydrocarbon radical was shown via X-ray diffraction to contain a quintuple bond of length 183.51(4) pm (1.835 angstroms) joining the two central chromium atoms.[2] This was accomplished through the use of an extremely bulky monodentate ligand which through its sheer size prevents further coordination. Chromium currently remains the only element for which quintuple bonds have been observed.
# Applications
Uses of chromium:
- In metallurgy, to impart corrosion resistance and a shiny finish:
as an alloy constituent, such as in stainless steel in cutlery
in chrome plating,
in anodized aluminium, literally turning the surface of aluminium into ruby.
- as an alloy constituent, such as in stainless steel in cutlery
- in chrome plating,
- in anodized aluminium, literally turning the surface of aluminium into ruby.
- As dyes and paints :
Chromium(III) oxide is a metal polish known as green rouge.
Chromium salts color glass an emerald green.
Chromium is what makes a ruby red, and therefore is used in producing synthetic rubies.
also makes a brilliant yellow for painting
- Chromium(III) oxide is a metal polish known as green rouge.
- Chromium salts color glass an emerald green.
- Chromium is what makes a ruby red, and therefore is used in producing synthetic rubies.
- also makes a brilliant yellow for painting
- As a catalyst.
- Chromite is used to make molds for the firing of bricks.
- Chromium salts are used in the tanning of leather.
- Potassium dichromate is a chemical reagent, used in cleaning laboratory glassware and as a titrating agent. It is also used as a mordant (i.e., a fixing agent) for dyes in fabric.
- Chromium(IV) oxide (CrO2) is used to manufacture magnetic tape, where its higher coercivity than iron oxide tapes gives better performance.
- In well drilling muds as an anti-corrosive.
- In medicine, as a dietary supplement or slimming aid, usually as chromium (III) chloride or chromium(III) picolinate.
- Chromium hexacarbonyl (Cr(CO)6) is used as a gasoline additive.
- Chromium boride (CrB) is used as a high-temperature electrical conductor.
- Chromium (III) sulfate (Cr2(SO4)3) is used as a green pigment in paints, in ceramic, varnishes and inks as well as in chrome plating.
- Chromium (VI) is used in the post Ballard preparation of Gravure (rotogravure) printing Forme Cylinders. By electroplating the metal onto the second coat of copper (after the Ballard skin), the longevity of the printing cylinder is increased.
- Micronutrient, in "health" aware drinks, known to improve the amount of energy you get from food.
# Biological role
Trivalent chromium (Cr(III), or Cr3+) is required in trace amounts for sugar metabolism in humans (Glucose Tolerance Factor) and its deficiency may cause a disease called chromium deficiency. In contrast, hexavalent chromium is very toxic and mutagenic when inhaled as publicized by the film Erin Brockovich. Cr(VI) has not been established as a carcinogen when not inhaled but in solution it is well established as a cause of allergic contact dermatitis (ACD).[3]
Recently it was shown that the popular dietary supplement chromium picolinate complex generates chromosome damage in hamster cells. In the United States the dietary guidelines for daily chromium uptake were lowered from 50-200 µg for an adult to 35 µg (adult male) and to 25 µg (adult female).[4]
# Isotopes
Naturally occurring chromium is composed of three stable isotopes; 52Cr, 53Cr, and 54Cr with 52Cr being the most abundant (83.789% natural abundance). Nineteen radioisotopes have been characterized with the most stable being 50Cr with a half-life of (more than) 1.8x1017 years, and 51Cr with a half-life of 27.7 days. All of the remaining radioactive isotopes have half-lives that are less than 24 hours and the majority of these have half-lives that are less than 1 minute. This element also has 2 meta states.
53Cr is the radiogenic decay product of 53Mn. Chromium isotopic contents are typically combined with manganese isotopic contents and have found application in isotope geology. Mn-Cr isotope ratios reinforce the evidence from 26Al and 107Pd for the early history of the solar system. Variations in 53Cr/52Cr and Mn/Cr ratios from several meteorites indicate an initial 53Mn/55Mn ratio that suggests Mn-Cr isotope systematics must result from in-situ decay of 53Mn in differentiated planetary bodies. Hence 53Cr provides additional evidence for nucleosynthetic processes immediately before coalescence of the solar system.
The isotopes of chromium range in atomic weight from 43 u (43Cr) to 67 u (67Cr). The primary decay mode before the most abundant stable isotope, 52Cr, is electron capture and the primary mode after is beta decay.
# Precautions
Chromium metal and chromium(III) compounds are not usually considered health hazards; chromium is an essential trace mineral.[5] However, hexavalent chromium (chromium VI) compounds can be toxic if orally ingested or inhaled. The lethal dose of poisonous chromium (VI) compounds is about one half teaspoon of material. Most chromium (VI) compounds are irritating to eyes, skin and mucous membranes. Chronic exposure to chromium (VI) compounds can cause permanent eye injury, unless properly treated. Chromium(VI) is an established human carcinogen. An investigation into hexavalent chromium release into drinking water formed the plot of the motion picture Erin Brockovich.
World Health Organization recommended maximum allowable concentration in drinking water for chromium (VI) is 0.05 milligrams per liter. Hexavalent chromium is also one of the substances whose use is restricted by the European Restriction of Hazardous Substances Directive.
As chromium compounds were used in dyes and paints and the tanning of leather, these compounds are often found in soil and groundwater at abandoned industrial site, now needing environmental cleanup and remediation per the treatment of brownfield land. Primer paint containing hexavalent chromium is still widely used for aerospace and automobile refinishing applications. | https://www.wikidoc.org/index.php/Chromium | |
ac8a0548db5324822f61660bf1ddb3d3d8cef735 | wikidoc | Chyluria | Chyluria
# Overview
Chyluria (also chylous urine) is a medical condition involving the presence of chyle in the urine stream. Chyluria results in milky white urine.
# Causes
- Often caused by filariasis, caused by the parasite Wuchereria bancrofti lodging in the lymph channels, the condition especially affects the people of the Africa and Indian subcontinent. The affected are infected by the parasite and it lodges in the lymph channels draining chyle (digested food absorbed as a milky solution into the blood).
- Chyluria can occur for the first time, or as a relapse, in pregnancy or after childbirth.
# Symptoms
Once the channels are blocked, one of the channels may open into the kidney hilum or ureter or sometimes into the bladder and chyle can leak into the urinary tract resulting in passage of milky white urine, which is frightening at the first sight. Sometimes even blood can mix with the urine resulting in haemato-chyluria.
Usually the condition is self limiting and sometimes can lead onto complications. If left untreated chronic chyluria can lead to malnutrition and vitamin deficiency.
# Treatment
Diet modifications to reduce the formation of chylomicrons (reduction of fat in food). Anti-fillarial drugs are often prescribed and surgery may be considered if the lymph channel blockage or damage is severe enough. | Chyluria
# Overview
Template:SignSymptom infobox
Chyluria (also chylous urine) is a medical condition involving the presence of chyle in the urine stream.[1] Chyluria results in milky white urine. [2]
# Causes
- Often caused by filariasis, caused by the parasite Wuchereria bancrofti lodging in the lymph channels, the condition especially affects the people of the Africa and Indian subcontinent. The affected are infected by the parasite and it lodges in the lymph channels draining chyle (digested food absorbed as a milky solution into the blood).
- Chyluria can occur for the first time, or as a relapse, in pregnancy or after childbirth.
# Symptoms
Once the channels are blocked, one of the channels may open into the kidney hilum or ureter or sometimes into the bladder and chyle can leak into the urinary tract resulting in passage of milky white urine, which is frightening at the first sight. Sometimes even blood can mix with the urine resulting in haemato-chyluria.
Usually the condition is self limiting and sometimes can lead onto complications. If left untreated chronic chyluria can lead to malnutrition and vitamin deficiency.
# Treatment
Diet modifications to reduce the formation of chylomicrons (reduction of fat in food). Anti-fillarial drugs are often prescribed and surgery may be considered if the lymph channel blockage or damage is severe enough. | https://www.wikidoc.org/index.php/Chyluria | |
9b3176112adf089ea01b12444098c6736d307160 | wikidoc | Chymosin | Chymosin
Chymosin /ˈkaɪməsɪn/ or rennin /ˈrɛnɪn/ is a protease found in rennet. It is an aspartic endopeptidase belonging to MEROPS A1 family. It is produced by newborn ruminant animals in the lining of the abomasum to curdle the milk they ingest, allowing a longer residence in the bowels and better absorption. It is widely used in the production of cheese. Bovine chymosin is now produced recombinantly in E. coli, Aspergillus niger var awamori, and K. lactis as alternative resource.
# Occurrence
Chymosin is produced by ruminant animals in the lining of the abomasum. Chymosin is produced by gastric chief cells in young ruminants and some other newborn animals to curdle the milk they ingest, allowing a longer residence in the bowels and better absorption. Some other non-ruminant species, including pigs, cats, and seals, produce it.
One study reported finding a chymosin-like enzyme in some human infants, but others have failed to replicate this finding. Humans have a pseudogene for chymosin that does not generate a protein, found on chromosome 1. Humans have other proteins to digest milk, such as pepsin and lipase.:262
# Enzymatic reaction
Chymosin is used to bring about the extensive precipitation and curd formation in cheese-making. The native substrate of chymosin is K-casein which is specifically cleaved at the peptide bond between amino acid residues 105 and 106, phenylalanine and methionine. The resultant product is calcium phosphocaseinate. When the specific linkage between the hydrophobic (para-casein) and hydrophilic (acidic glycopeptide) groups of casein is broken, the hydrophobic groups unite and form a 3D network that traps the aqueous phase of the milk.
Charge interactions between histidines on the kappa-casein and glutamates and aspartates of chymosin initiate enzyme binding to the substrate. When chymosin is not binding substrate, a beta-hairpin, sometimes referred to as "the flap," can hydrogen bond with the active site, therefore covering it and not allowing further binding of substrate.
# Examples
Listed below are the ruminant Cym gene and corresponding human pseudogene:
# Recombinant chymosin
Because of the imperfections and scarcity of microbial and animal rennets, producers sought replacements. With the development of genetic engineering, it became possible to extract rennet-producing genes from animal stomach and insert them into certain bacteria, fungi or yeasts to make them produce chymosin during fermentation. The genetically modified microorganism is killed after fermentation and chymosin is isolated from the fermentation broth, so that the fermentation-produced chymosin (FPC) used by cheese producers does not contain any GM component or ingredient. FPC contains the identical chymosin as the animal source, but produced in a more efficient way. FPC products have been on the market since 1990 and are considered the ideal milk-clotting enzyme.
FPC was the first artificially produced enzyme to be registered and allowed by the US Food and Drug Administration. In 1999, about 60% of US hard cheese was made with FPC and it has up to 80% of the global market share for rennet.
By 2008, approximately 80% to 90% of commercially made cheeses in the US and Britain were made using FPC. The most widely used fermentation-produced chymosin is produced either using the fungus Aspergillus niger or using Kluyveromyces lactis.
FPC contains only chymosin B, achieving a high degree of purity compared with animal rennet. FPC can deliver several benefits to the cheese producer compared with animal or microbial rennet, such as higher production yield, better curd texture and reduced bitterness. | Chymosin
Chymosin /ˈkaɪməsɪn/ or rennin /ˈrɛnɪn/ is a protease found in rennet. It is an aspartic endopeptidase belonging to MEROPS A1 family. It is produced by newborn ruminant animals in the lining of the abomasum to curdle the milk they ingest, allowing a longer residence in the bowels and better absorption. It is widely used in the production of cheese. Bovine chymosin is now produced recombinantly in E. coli, Aspergillus niger var awamori, and K. lactis as alternative resource.
# Occurrence
Chymosin is produced by ruminant animals in the lining of the abomasum. Chymosin is produced by gastric chief cells in young ruminants and some other newborn animals[2] to curdle the milk they ingest, allowing a longer residence in the bowels and better absorption. Some other non-ruminant species, including pigs, cats, and seals, produce it.[3]
One study reported finding a chymosin-like enzyme in some human infants,[4] but others have failed to replicate this finding.[5] Humans have a pseudogene for chymosin that does not generate a protein, found on chromosome 1.[3][6] Humans have other proteins to digest milk, such as pepsin and lipase.[7]:262
# Enzymatic reaction
Chymosin is used to bring about the extensive precipitation and curd formation in cheese-making. The native substrate of chymosin is K-casein which is specifically cleaved at the peptide bond between amino acid residues 105 and 106, phenylalanine and methionine.[8] The resultant product is calcium phosphocaseinate.[citation needed] When the specific linkage between the hydrophobic (para-casein) and hydrophilic (acidic glycopeptide) groups of casein is broken, the hydrophobic groups unite and form a 3D network that traps the aqueous phase of the milk.
Charge interactions between histidines on the kappa-casein and glutamates and aspartates of chymosin initiate enzyme binding to the substrate.[8] When chymosin is not binding substrate, a beta-hairpin, sometimes referred to as "the flap," can hydrogen bond with the active site, therefore covering it and not allowing further binding of substrate.[1]
# Examples
Listed below are the ruminant Cym gene and corresponding human pseudogene:
# Recombinant chymosin
Because of the imperfections and scarcity of microbial and animal rennets, producers sought replacements. With the development of genetic engineering, it became possible to extract rennet-producing genes from animal stomach and insert them into certain bacteria, fungi or yeasts to make them produce chymosin during fermentation.[10][11] The genetically modified microorganism is killed after fermentation and chymosin is isolated from the fermentation broth, so that the fermentation-produced chymosin (FPC) used by cheese producers does not contain any GM component or ingredient.[12] FPC contains the identical chymosin as the animal source, but produced in a more efficient way. FPC products have been on the market since 1990 and are considered the ideal milk-clotting enzyme.[13]
FPC was the first artificially produced enzyme to be registered and allowed by the US Food and Drug Administration. In 1999, about 60% of US hard cheese was made with FPC[14] and it has up to 80% of the global market share for rennet.[15]
By 2008, approximately 80% to 90% of commercially made cheeses in the US and Britain were made using FPC.[12] The most widely used fermentation-produced chymosin is produced either using the fungus Aspergillus niger or using Kluyveromyces lactis.
FPC contains only chymosin B, achieving a high degree of purity compared with animal rennet. FPC can deliver several benefits to the cheese producer compared with animal or microbial rennet, such as higher production yield, better curd texture and reduced bitterness.[13] | https://www.wikidoc.org/index.php/Chymosin | |
1b260f2b300733c45fc3c4b9d5e7b8893c37f927 | wikidoc | Pyridine | Pyridine
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# Overview
Pyridine is a chemical compound with the formula C5H5N. It is a liquid with a distinctively putrid, fishy odour. Pyridine is a simple and fundamentally important heterocyclic aromatic organic compound that is structurally related to benzene, wherein one CH group in the six-membered ring is replaced by a nitrogen atom. The pyridine ring occurs in many important compounds, including the nicotinamides. Pyridine is sometimes used as a ligand in coordination chemistry. As a ligand, it is usually abbreviated py.
# Basicity
Pyridine has a lone pair of electrons at the nitrogen atom. Because this lone pair is not delocalized into the aromatic pi-system, pyridine is basic with chemical properties similar to tertiary amines. The pKa of the conjugate acid is 5.30. Pyridine is protonated by reaction with acids and forms a positively charged aromatic polyatomic ion called pyridinium cation. The bond lengths and bond angles in pyridine and the pyridinium ion are almost identical because protonation does not affect the aromatic pi system.
# Pyridine as a solvent
Pyridine is widely used as a versatile solvent, since it is polar but aprotic. It is fully miscible with a very broad range of solvents including hexane and water. Deuterated pyridine, called pyridine-d5, is a common solvent for1H NMR spectroscopy.
# Role in chemical synthesis
Pyridine is important in industrial organic chemistry, both as a fundamental building block and as a solvent and reagent in organic synthesis. It is used as a solvent in Knoevenagel condensations.
Pyridine-borane, C5H5NBH3 (m.p. 10–11 °C) is a mild reducing agent with improved stability vs NaBH4 in protic solvents and improved solubility in aprotic organic solvents. Pyridine-sulfur trioxide, C5H5NSO3 (mp 175 °C) is a sulfonation agent used to convert alcohols to sulfonates, which in turn undergo C-O bond scission upon reduction with hydride agents.
It is also a starting material in the synthesis of compounds used as an intermediate in making insecticides, herbicides, pharmaceuticals, food flavorings, dyes, rubber chemicals, adhesives, paints, explosives and disinfectants. Pyridine is also used as a denaturant for antifreeze mixtures, for ethyl alcohol, and for fungicides, and as a dyeing aid for textiles.
# Preparation and occurrence
Many methods exist in industry and in the laboratory (some of them named reactions) for the synthesis of pyridine and its derivatives:
- Pyridine is obtained industrially from crude coal tar or is synthesized from acetaldehyde, formaldehyde and ammonia.
- The Hantzsch pyridine synthesis is a multicomponent reaction involving formaldehyde, a keto-ester and a nitrogen donor.
- Other examples of the pyridine class can be formed by the reaction of 1,5-diketones with ammonium acetate in acetic acid followed by oxidation. This reaction is called the Kröhnke pyridine synthesis.
- Pyridium salts can be obtained in the Zincke reaction.
- The Ciamician-Dennstedt Rearrangement (1881) is the ring-expansion of pyrrole with dichlorocarbene to 3-chloropyridine and HCl
- In the Chichibabin pyridine synthesis (Aleksei Chichibabin, 1906) the reactants are three equivalents of a linear aldehyde and ammonia
# Organic reactions
In organic reactions pyridine behaves both as a tertiary amine with protonation, alkylation, acylation and N-oxidation at nitrogen and as an aromatic compound with Nucleophilic substitutions.
- Pyridine is a good nucleophile with a donor number of 33.1. It is easily attacked by alkylating agents to give N-alkylpyridinium salts.
- Nucleophilic aromatic substitution takes place at C2 and C4 for example in the Chichibabin reaction of pyridine with sodium amide to 2-aminopyridine. In the Emmert reaction (B. Emmert, 1939) pyridine is reacted with a ketone in presence of aluminium or magnesium and mercuric chloride to the carbinol also at C2.
# Safety and Environmental
Pyridine is toxic with LD50 in rats (oral) of 891 mg kg–1. It is volatile and can be absorbed through skin. Available data indicate that "exposure to pyridine in drinking-water led to reduction of sperm motility at all dose levels in mice and increased estrous cycle length at the highest dose level in rats". Currently its evaluations as a possible carcinogenic agent showed there is inadequate evidence in humans for the carcinogenicity of pyridine, albeit there is limited evidence of carcinogenic effects on animals. Effects of an acute pyridine intoxication include dizziness, headache, nausea and anorexia. Further symptoms include abdominal pain and pulmonary congestion. Though resistant to oxidation, pyridine is readily degraded by bacteria, releasing ammonium and carbon dioxide as terminal degradation products.
# Related compounds
Structurally or chemically related compounds are
- DMAP is short for 4-dimethylaminopyridine
- Bipyridine and viologen are simple polypyridine compounds consisting of two pyridine molecules joined by a single bond
- Terpyridine, a molecule of three pyridine rings connected together by two single bonds.
- Quinoline and Isoquinoline have pyridine and a benzene ring fused together.
- Aniline is a benzene derivative with an attached NH2 group and NOT a pyridine
- Diazines are compounds with one more carbon replaced by nitrogen such as Pyrazine and Pyramidine
- Triazines are compounds with two more carbons replaced by nitrogen and a tetrazine has four nitrogen atoms
- 2,6-Lutidine is a trivial name for 2,6-dimethylpyridine.
- Collidine is the trivial name for 2,4,6-trimethylpyridine.
- Pyridinium p-toluenesulfonate (PPTS) is a salt formed by proton exchange between pyridine and p-toluenesulfonic acid
- 2-Chloropyridine is a toxic environmentally significant component of the breakdown of the pesticide imidacloprid. | Pyridine
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# Overview
Pyridine is a chemical compound with the formula C5H5N. It is a liquid with a distinctively putrid, fishy odour. Pyridine is a simple and fundamentally important heterocyclic aromatic organic compound that is structurally related to benzene, wherein one CH group in the six-membered ring is replaced by a nitrogen atom. The pyridine ring occurs in many important compounds, including the nicotinamides. Pyridine is sometimes used as a ligand in coordination chemistry. As a ligand, it is usually abbreviated py.
# Basicity
Pyridine has a lone pair of electrons at the nitrogen atom. Because this lone pair is not delocalized into the aromatic pi-system, pyridine is basic with chemical properties similar to tertiary amines. The pKa of the conjugate acid is 5.30. Pyridine is protonated by reaction with acids and forms a positively charged aromatic polyatomic ion called pyridinium cation. The bond lengths and bond angles in pyridine and the pyridinium ion are almost identical[1] because protonation does not affect the aromatic pi system.
# Pyridine as a solvent
Pyridine is widely used as a versatile solvent, since it is polar but aprotic. It is fully miscible with a very broad range of solvents including hexane and water. Deuterated pyridine, called pyridine-d5, is a common solvent for1H NMR spectroscopy.
# Role in chemical synthesis
Pyridine is important in industrial organic chemistry, both as a fundamental building block and as a solvent and reagent in organic synthesis.[2] It is used as a solvent in Knoevenagel condensations.
Pyridine-borane, C5H5NBH3 (m.p. 10–11 °C) is a mild reducing agent with improved stability vs NaBH4 in protic solvents and improved solubility in aprotic organic solvents. Pyridine-sulfur trioxide, C5H5NSO3 (mp 175 °C) is a sulfonation agent used to convert alcohols to sulfonates, which in turn undergo C-O bond scission upon reduction with hydride agents.
It is also a starting material in the synthesis of compounds used as an intermediate in making insecticides, herbicides, pharmaceuticals, food flavorings, dyes, rubber chemicals, adhesives, paints, explosives and disinfectants. Pyridine is also used as a denaturant for antifreeze mixtures, for ethyl alcohol, and for fungicides, and as a dyeing aid for textiles.
# Preparation and occurrence
Many methods exist in industry and in the laboratory (some of them named reactions) for the synthesis of pyridine and its derivatives:[3]
- Pyridine is obtained industrially from crude coal tar or is synthesized from acetaldehyde, formaldehyde and ammonia.
- The Hantzsch pyridine synthesis is a multicomponent reaction involving formaldehyde, a keto-ester and a nitrogen donor.
- Other examples of the pyridine class can be formed by the reaction of 1,5-diketones with ammonium acetate in acetic acid followed by oxidation. This reaction is called the Kröhnke pyridine synthesis.
- Pyridium salts can be obtained in the Zincke reaction.
- The Ciamician-Dennstedt Rearrangement (1881) is the ring-expansion of pyrrole with dichlorocarbene to 3-chloropyridine and HCl[4]
- In the Chichibabin pyridine synthesis (Aleksei Chichibabin, 1906) the reactants are three equivalents of a linear aldehyde and ammonia
# Organic reactions
In organic reactions pyridine behaves both as a tertiary amine with protonation, alkylation, acylation and N-oxidation at nitrogen and as an aromatic compound with Nucleophilic substitutions.
- Pyridine is a good nucleophile with a donor number of 33.1. It is easily attacked by alkylating agents to give N-alkylpyridinium salts.
- Nucleophilic aromatic substitution takes place at C2 and C4 for example in the Chichibabin reaction of pyridine with sodium amide to 2-aminopyridine. In the Emmert reaction (B. Emmert, 1939) pyridine is reacted with a ketone in presence of aluminium or magnesium and mercuric chloride to the carbinol also at C2[5].
# Safety and Environmental
Pyridine is toxic with LD50 in rats (oral) of 891 mg kg–1. It is volatile and can be absorbed through skin. Available data indicate that "exposure to pyridine in drinking-water led to reduction of sperm motility at all dose levels in mice and increased estrous cycle length at the highest dose level in rats".[6] Currently its evaluations as a possible carcinogenic agent showed there is inadequate evidence in humans for the carcinogenicity of pyridine, albeit there is limited evidence of carcinogenic effects on animals.[6] Effects of an acute pyridine intoxication include dizziness, headache, nausea and anorexia. Further symptoms include abdominal pain and pulmonary congestion.[6] Though resistant to oxidation, pyridine is readily degraded by bacteria, releasing ammonium and carbon dioxide as terminal degradation products.[7]
# Related compounds
Structurally or chemically related compounds are
- DMAP is short for 4-dimethylaminopyridine
- Bipyridine and viologen are simple polypyridine compounds consisting of two pyridine molecules joined by a single bond
- Terpyridine, a molecule of three pyridine rings connected together by two single bonds.
- Quinoline and Isoquinoline have pyridine and a benzene ring fused together.
- Aniline is a benzene derivative with an attached NH2 group and NOT a pyridine
- Diazines are compounds with one more carbon replaced by nitrogen such as Pyrazine and Pyramidine
- Triazines are compounds with two more carbons replaced by nitrogen and a tetrazine has four nitrogen atoms
- 2,6-Lutidine is a trivial name for 2,6-dimethylpyridine.
- Collidine is the trivial name for 2,4,6-trimethylpyridine.
- Pyridinium p-toluenesulfonate (PPTS) is a salt formed by proton exchange between pyridine and p-toluenesulfonic acid
- 2-Chloropyridine is a toxic environmentally significant component of the breakdown of the pesticide imidacloprid. | https://www.wikidoc.org/index.php/Ciamician-Dennstedt_rearrangement | |
2451874fd1395725e35a6320fe0481a609f7426b | wikidoc | Cinchona | Cinchona
Cinchona is a genus of about 25 species in the family Rubiaceae, native to tropical South America. They are large shrubs or small trees growing to 5-15 metres tall with evergreen foliage.
The leaves are opposite, rounded to lanceolate, 10-40 cm long. The flowers are white, pink or red, produced in terminal panicles. The fruit is a small capsule containing numerous seeds.
The name of the genus is due to Linnaeus, who named the tree in 1742 after a Countess of Chinchon, the wife of a viceroy of Peru, who, in 1638, was introduced by natives to the medicinal properties of the bark. Stories of the medicinal properties of this bark, however, are perhaps noted in journals as far back as the 1560s-1570s (see the Ortiz link below).
Cinchona species are used as food plants by the larvae of some Lepidoptera species including The Engrailed, The Commander, and members of the genus Endoclita including E. damor, E. purpurescens and E. sericeus.
# Species
# Cinchona alkaloids
The bark of trees in this genus are the source of a variety of alkaloids, the most familiar of which is quinine, an anti-fever agent especially useful in treating malaria.
Cinchona alkaloids such as quinine (R = vinyl, R' = methoxy), cinchonidine (R = vinyl, R' = hydrogen) and dihydroquinidine & dihydroquinine (enantiomers with R = ethyl, R' = methoxy) and find use in organic chemistry as organocatalysts in asymmetric synthesis.
## Medicinal use
The medicinally active bark, which is stripped from the tree, dried and powdered, includes other alkaloids that are closely related to quinine but react differently in treating malaria. As a medicinal herb, cinchona bark is also known as Jesuit's bark or Peruvian bark.
The plants are cultivated in their native South America, and also in other tropical regions, notably in India and Java.
## History
The Italian botanist Pietro Castelli wrote a pamphlet noteworthy as being the first Italian publication that mentions the cinchona. By the 1630s (or 1640s, depending on the reference), the bark was being exported to Europe. In the late 1640s, the method of use of the bark was noted in the Schedula Romana, and in 1677 the use of the bark was noted in the London Pharmacopoeia.
The legend says that the first European ever to be cured from malaria fever was the wife of the Spanish Viceroy, the countess of Chinchon. The court physician was summoned and urged to save the countess from the wave of fever and chill which was proving fatal for her. Every effort failed to relieve her from this ailed condition. At last the court physician collected a medicine from the local Indians, that grew on the Andes mountain slopes. They had been using this medicine for similar syndromes. The medicine was given to her and surprisingly she survived the malarial attack. When she returned to Europe in the 1640s, she reportedly brought the bark with her.
In 1753 Carolus Linnaeus named the bark Cinchona after the countess of Chinchon. The story of the cure of the countess, however, is doubtful.
Charles II called upon Mr Robert Talbor, who had become famous for his miraculous malaria cure. Because at that time the bark was in religious controversy, Talbor gave the king the bitter bark decoction in great secrecy. The treatment gave the king complete relief from the malaria fever. In return, he was offered membership of the prestigious Royal College of Physicians.
In 1679 Talbor was called by the King of France, Louis XIV, whose son was suffering from malaria fever. After a successful treatment, Talbor was rewarded by the king with 3,000 gold crowns. At the same time he was given a lifetime pension for this prescription. Talbor was requested to keep the entire episode secret.
After the death of Talbor, the French king found this formula : six drahm of rose leaves, two ounces of lemon juice and a strong decoction of the chinchona bark served with wine. Wine was used because some alkaloids of the cinchona bark are not soluble in water, but soluble in wine.
The birth of homoeopathy was based on quinine testing. The founder of homoeopathy, Dr. Samuel Hahnemann, when translating the Cullen's Materia medica, noticed that Dr. Cullen wrote that quinine cures malaria and can also produce malaria. Dr. Hahnemann took daily a large non-homeopathic dose of quinine bark. After two weeks, he said he felt malaria-like symptoms. This idea of "like cures like" was the starting point of his writing on "Homoeopathy".
# History of cultivation
The bark was very valuable to Europeans in expanding their access to and exploitation of resources in far off colonies, and at home. Bark gathering was often environmentally destructive, destroying huge expanses of trees for their bark, with difficult conditions for low wages that did not allow the indigenous bark gatherers to settle debts even upon death.
# Treatments
Cinchona has been used for a number of medical reasons such as:
- Treats malaria
- Kills parasites
- Reduces fever
- Regulates heartbeat
- Calms nerves
- Stimulates digestion
- Kills germs
- Reduces spasms
- Kills insects
- Relieves pain
- Kills bacteria and fungi
- Dries secretions
The main reason for its use is to treat malaria, but it is rarely used today as many people think it is dangerous, as it can kill if taken in large amounts.
# References and external links
- Cinchona project - Ortiz
- Maricela Argudo's Cinchona Project
- Cinchona Bark
- Using Bark to Cure the Bite
- Cinchona Alkaloids
- Peruvian Bark
- Cinchona photo
- Photos of Cinchona pubescens
- Reader's Digest, Strange Stories, Amazing Facts II; Title : "The Bark of Barks" -Reader's digest publication
- The Journals of Hipólito Ruiz: Spanish Botanist in Peru and Chile 1777-1788, translated by Richard Evans Schultes and María José Nemry von Thenen de Jaramillo-Arango, Timber Press, 1998
- Druilhe, P., et al., Activity of a combination of three Cinchona bark alkaloids against Plasmodium falciparum in vitro. Antimicrobial Agents and Chemotherapy 32(2):25-254.
bg:Хининово дърво
ca:Quina
da:Kinatræ
de:Chinarindenbäume
eo:Kinkono
it:Cinchona
qu:Kina-kina | Cinchona
Cinchona is a genus of about 25 species in the family Rubiaceae, native to tropical South America. They are large shrubs or small trees growing to 5-15 metres tall with evergreen foliage.
The leaves are opposite, rounded to lanceolate, 10-40 cm long. The flowers are white, pink or red, produced in terminal panicles. The fruit is a small capsule containing numerous seeds.
The name of the genus is due to Linnaeus, who named the tree in 1742 after a Countess of Chinchon, the wife of a viceroy of Peru, who, in 1638, was introduced by natives to the medicinal properties of the bark. Stories of the medicinal properties of this bark, however, are perhaps noted in journals as far back as the 1560s-1570s (see the Ortiz link below).
Cinchona species are used as food plants by the larvae of some Lepidoptera species including The Engrailed, The Commander, and members of the genus Endoclita including E. damor, E. purpurescens and E. sericeus.
# Species
# Cinchona alkaloids
The bark of trees in this genus are the source of a variety of alkaloids, the most familiar of which is quinine, an anti-fever agent especially useful in treating malaria.
Cinchona alkaloids such as quinine (R = vinyl, R' = methoxy), cinchonidine (R = vinyl, R' = hydrogen) and dihydroquinidine & dihydroquinine (enantiomers with R = ethyl, R' = methoxy) and find use in organic chemistry as organocatalysts in asymmetric synthesis.
## Medicinal use
The medicinally active bark, which is stripped from the tree, dried and powdered, includes other alkaloids that are closely related to quinine but react differently in treating malaria. As a medicinal herb, cinchona bark is also known as Jesuit's bark or Peruvian bark.
The plants are cultivated in their native South America, and also in other tropical regions, notably in India and Java.
## History
The Italian botanist Pietro Castelli wrote a pamphlet noteworthy as being the first Italian publication that mentions the cinchona. By the 1630s (or 1640s, depending on the reference), the bark was being exported to Europe. In the late 1640s, the method of use of the bark was noted in the Schedula Romana, and in 1677 the use of the bark was noted in the London Pharmacopoeia.
The legend says that the first European ever to be cured from malaria fever was the wife of the Spanish Viceroy, the countess of Chinchon. The court physician was summoned and urged to save the countess from the wave of fever and chill which was proving fatal for her. Every effort failed to relieve her from this ailed condition. At last the court physician collected a medicine from the local Indians, that grew on the Andes mountain slopes. They had been using this medicine for similar syndromes. The medicine was given to her and surprisingly she survived the malarial attack. When she returned to Europe in the 1640s, she reportedly brought the bark with her.
In 1753 Carolus Linnaeus named the bark Cinchona after the countess of Chinchon. The story of the cure of the countess, however, is doubtful.
Charles II called upon Mr Robert Talbor, who had become famous for his miraculous malaria cure. Because at that time the bark was in religious controversy, Talbor gave the king the bitter bark decoction in great secrecy. The treatment gave the king complete relief from the malaria fever. In return, he was offered membership of the prestigious Royal College of Physicians.
In 1679 Talbor was called by the King of France, Louis XIV, whose son was suffering from malaria fever. After a successful treatment, Talbor was rewarded by the king with 3,000 gold crowns. At the same time he was given a lifetime pension for this prescription. Talbor was requested to keep the entire episode secret.
After the death of Talbor, the French king found this formula : six drahm of rose leaves, two ounces of lemon juice and a strong decoction of the chinchona bark served with wine. Wine was used because some alkaloids of the cinchona bark are not soluble in water, but soluble in wine.
The birth of homoeopathy was based on quinine testing. The founder of homoeopathy, Dr. Samuel Hahnemann, when translating the Cullen's Materia medica, noticed that Dr. Cullen wrote that quinine cures malaria and can also produce malaria. Dr. Hahnemann took daily a large non-homeopathic dose of quinine bark. After two weeks, he said he felt malaria-like symptoms. This idea of "like cures like" was the starting point of his writing on "Homoeopathy".
# History of cultivation
The bark was very valuable to Europeans in expanding their access to and exploitation of resources in far off colonies, and at home. Bark gathering was often environmentally destructive, destroying huge expanses of trees for their bark, with difficult conditions for low wages that did not allow the indigenous bark gatherers to settle debts even upon death.[citation needed]
# Treatments
Cinchona has been used for a number of medical reasons such as:
- Treats malaria
- Kills parasites
- Reduces fever
- Regulates heartbeat
- Calms nerves
- Stimulates digestion
- Kills germs
- Reduces spasms
- Kills insects
- Relieves pain
- Kills bacteria and fungi
- Dries secretions
The main reason for its use is to treat malaria, but it is rarely used today as many people think it is dangerous, as it can kill if taken in large amounts.
# References and external links
- Cinchona project - Ortiz
- Maricela Argudo's Cinchona Project
- Cinchona Bark
- Using Bark to Cure the Bite
- Cinchona Alkaloids
- Peruvian Bark
- Cinchona photo
- Photos of Cinchona pubescens
- Reader's Digest, Strange Stories, Amazing Facts II; Title : "The Bark of Barks" -Reader's digest publication
- The Journals of Hipólito Ruiz: Spanish Botanist in Peru and Chile 1777-1788, translated by Richard Evans Schultes and María José Nemry von Thenen de Jaramillo-Arango, Timber Press, 1998
- Druilhe, P., et al., Activity of a combination of three Cinchona bark alkaloids against Plasmodium falciparum in vitro. Antimicrobial Agents and Chemotherapy 32(2):25-254.
bg:Хининово дърво
ca:Quina
da:Kinatræ
de:Chinarindenbäume
eo:Kinkono
it:Cinchona
qu:Kina-kina | https://www.wikidoc.org/index.php/Cinchona | |
472e489a475123fd4d4910dfa7b6a24bf827aabe | wikidoc | Cingulin | Cingulin
Cingulin (CGN; from the Latin cingere “to form a belt around”) is a cytosolic protein encoded by the CGN gene in humans localized at tight junctions (TJs) of vertebrate epithelial and endothelial cells.
# Discovery
Cingulin was originally discovered at the MRC Laboratory of Molecular Biology (Cambridge, UK) by Dr. Sandra Citi, as a protein present in chicken intestinal epithelial cells, that co-purified with non-muscle myosin II and was specifically localized at tight junctions (zonulae occludentes).
# Structure & interactions
Cingulin is a homodimer, each subunit containing a N-terminal globular "head" domain, a long α-helical coiled-coil "rod" domain and a small globular C-terminal "tail" region. This organization is highly conserved throughout vertebrates. However, cingulin homologs have not been detected in invertebrates.
In vitro, cingulin can bind to and bundle actin filaments, and interact with myosin II and several TJ proteins including ZO-1, ZO-2, ZO-3, paracingulin and occludin. Moreover, cingulin forms a complex with JAM-A, a tight junction membrane protein. Most of cingulin protein interactions are through the globular head domain. Cingulin interacts with ZO-1 through an N-terminal ZO-1 interacting motif (ZIM) in its head region. The rod domain is involved in dimerization and interaction with the RhoA activator, GEF-H1.
Cingulin has also been found to interact with microtubules (MTs) through the N-terminal head region, and these interactions was regulated by phosphorylation by the adenosine monophosphate-activated protein kinase (AMPK).
# Function
The function of cingulin has been studied by knockout (KO), knockdown (KD) and over-expression approaches. Embryoid bodies derived from embryonic stem cells where one or both cingulin alleles were targeted by homologous recombination show apparently normal tight junctions, but changes in the expression of a large number of genes, including tight junction protein genes (claudin-2, claudin-6, claudin-7 and occludin) and transcription factors (including GATA4). Changes in the expression of claudin-2 and ZO-3 are also observed in cultured kidney cells (MDCK) depleted of cingulin by shRNA.
In 2012, the phenotype of cingulin-knockout mice was described, proving that functional TJ in vivo can be formed in the absence of cingulin. Together with paracingulin, cingulin also was reported to regulate claudin-2 expression through RhoA-dependent and independent mechanisms.
The role of cingulin in development has been studied by morpholino. oligonucleotide-mediated depletion in chicken, indicating that cingulin is involved in neural crest development. In early mouse and frog embryos, maternal cingulin is localized in the cell cortex. Through early mouse development, cytocortical cingulin in present from oogenesis (cumulus-oocyte contact sites) until 16-cells morulae stage (apical microvillous zones) during early embryogenesis; then maternal cingulin is degraded by endocytic turn-over from the 32-cells stage. Regarding the zygotic cingulin, it accumulates at the tight junctions from 16-cells stage, 10 hours after ZO-1 assembly. Furthermore, the synthesis of cingulin in early mouse embryos is tissue-specific and it occurs in blastocyst (up-regulated in trophectoderm and down-regulated in inner-cells). In Xenopus laevis embryos, maternal cingulin is recruited to apical cell-cell junctions from 2-cells stage.
# Homologs
In 2004, a protein homologous to cingulin was discovered and named JACOP (also known as paracingulin, or cingulin-like 1 protein; CGNL1).
# Human diseases
Although cingulin has been involved in regulation of RhoA signaling and gene expression in cultured cells and KO mice, nothing is known about the specific role of cingulin in human diseases.
Cingulin expression has been studied in human carcinomas and shown to be expressed in adenocarcinomas and down-regulated in squamous carcinomas. Furthermore, histone deacetylase inhibitors, such as sodium butyrate, strongly upregulate its expression in some cultured cells. Cingulin, as other junctional proteins could be used as a marker of epithelial differentiation, and as a diagnostic marker to distinguish adenocarcinomas from squamous carcinomas. | Cingulin
Cingulin (CGN; from the Latin cingere “to form a belt around”) is a cytosolic protein encoded by the CGN gene in humans[1][2][3] localized at tight junctions (TJs) of vertebrate epithelial and endothelial cells.
# Discovery
Cingulin was originally discovered at the MRC Laboratory of Molecular Biology (Cambridge, UK) by Dr. Sandra Citi, as a protein present in chicken intestinal epithelial cells, that co-purified with non-muscle myosin II and was specifically localized at tight junctions (zonulae occludentes).[4]
# Structure & interactions
Cingulin is a homodimer, each subunit containing a N-terminal globular "head" domain, a long α-helical coiled-coil "rod" domain and a small globular C-terminal "tail" region.[5] This organization is highly conserved throughout vertebrates.[1] However, cingulin homologs have not been detected in invertebrates.
In vitro, cingulin can bind to and bundle actin filaments, and interact with myosin II and several TJ proteins including ZO-1, ZO-2, ZO-3, paracingulin and occludin.[6][7][8] Moreover, cingulin forms a complex with JAM-A, a tight junction membrane protein.[6] Most of cingulin protein interactions are through the globular head domain. Cingulin interacts with ZO-1 through an N-terminal ZO-1 interacting motif (ZIM) in its head region.[9][10] The rod domain is involved in dimerization and interaction with the RhoA activator, GEF-H1.[11][12][13]
Cingulin has also been found to interact with microtubules (MTs) through the N-terminal head region, and these interactions was regulated by phosphorylation by the adenosine monophosphate-activated protein kinase (AMPK).[14]
# Function
The function of cingulin has been studied by knockout (KO), knockdown (KD) and over-expression approaches. Embryoid bodies derived from embryonic stem cells where one or both cingulin alleles were targeted by homologous recombination show apparently normal tight junctions, but changes in the expression of a large number of genes, including tight junction protein genes (claudin-2, claudin-6, claudin-7 and occludin) and transcription factors (including GATA4).[9] Changes in the expression of claudin-2 and ZO-3 are also observed in cultured kidney cells (MDCK) depleted of cingulin by shRNA.[12]
In 2012, the phenotype of cingulin-knockout mice was described, proving that functional TJ in vivo can be formed in the absence of cingulin.[15] Together with paracingulin, cingulin also was reported to regulate claudin-2 expression through RhoA-dependent and independent mechanisms.[15][16]
The role of cingulin in development has been studied by morpholino.[17] oligonucleotide-mediated depletion in chicken, indicating that cingulin is involved in neural crest development. In early mouse and frog embryos, maternal cingulin is localized in the cell cortex. Through early mouse development, cytocortical cingulin in present from oogenesis (cumulus-oocyte contact sites) until 16-cells morulae stage (apical microvillous zones) during early embryogenesis; then maternal cingulin is degraded by endocytic turn-over from the 32-cells stage. Regarding the zygotic cingulin, it accumulates at the tight junctions from 16-cells stage, 10 hours after ZO-1 assembly. Furthermore, the synthesis of cingulin in early mouse embryos is tissue-specific and it occurs in blastocyst (up-regulated in trophectoderm and down-regulated in inner-cells).[18][19] In Xenopus laevis embryos, maternal cingulin is recruited to apical cell-cell junctions from 2-cells stage.[20][21]
# Homologs
In 2004, a protein homologous to cingulin was discovered and named JACOP (also known as paracingulin, or cingulin-like 1 protein; CGNL1).[13]
# Human diseases
Although cingulin has been involved in regulation of RhoA signaling and gene expression in cultured cells and KO mice, nothing is known about the specific role of cingulin in human diseases.[11][12][15]
Cingulin expression has been studied in human carcinomas and shown to be expressed in adenocarcinomas and down-regulated in squamous carcinomas.[22][23] Furthermore, histone deacetylase inhibitors, such as sodium butyrate, strongly upregulate its expression in some cultured cells.[24] Cingulin, as other junctional proteins could be used as a marker of epithelial differentiation, and as a diagnostic marker to distinguish adenocarcinomas from squamous carcinomas. | https://www.wikidoc.org/index.php/Cingulin | |
bb2ebc718fd63db00b9e93e894f8c7c40de16172 | wikidoc | Cinnamon | Cinnamon
Cinnamon (Cinnamomum verum, synonym C. zeylanicum) is a small evergreen tree 10-15 meters (32.8-49.2 feet) tall, belonging to the family Lauraceae, native to Sri Lanka and South India. The bark is widely used as a spice due to its distinct odour. In India it is also known as "Daalchini".
The leaves are ovate-oblong in shape, 7-18 cm (2.75-7.1 inches) long. The flowers, which are arranged in panicles, have a greenish color, and have a distinct odor. The fruit is a purple one-centimetre berry containing a single seed.
Its flavour is due to an aromatic essential oil which makes up 0.5 to 1% of its composition. This oil is prepared by roughly pounding the bark, macerating it in sea-water, and then quickly distilling the whole. It is of a golden-yellow colour, with the characteristic odour of cinnamon and a very hot aromatic taste. The pungent taste and scent come from cinnamic aldehyde or cinnamaldehyde and, by the absorption of oxygen as it ages, it darkens in colour and develops resinous compounds. Chemical components of the essential oil include ethyl cinnamate, eugenol, cinnamaldehyde, beta-caryophyllene, linalool and methyl chavicol.
The name cinnamon comes from Greek kinnámōmon, from Phoenician and akin to Hebrew qinnâmôn, itself ultimately from a Malaysian language, cf. Malay and Indonesian kayu manis which means sweet wood.
# History
Cinnamon has been known from remote antiquity, and it was so highly prized among ancient nations that it was regarded as a gift fit for monarchs and other great potentates. It was imported to Egypt from China as early as 2000 BC, and is mentioned in the Bible in Exodus 30:23, where Moses is commanded to use both sweet cinnamon (Hebrew קִנָּמוֹן, qinnāmôn) and cassia, and in Proverbs 7:17-18, where the lover's bed is perfumed with myrrh, aloe and cinnamon. It is also alluded to by Herodotus and other classical writers. It was commonly used on funeral pyres in Rome, and the Emperor Nero is said to have burned a year's supply of cinnamon at the funeral for his wife Poppaea Sabina, in 65 AD.
In the Middle Ages, the source of cinnamon was a mystery to the Western world. Arab traders brought the spice via overland trade routes to Alexandria in Egypt, where it was bought by Venetian traders from Italy who held a monopoly on the spice trade in Europe. The disruption of this trade by the rise of other Mediterranean powers such as the Mameluks Sultans and the Ottoman Empire was one of many factors that led Europeans to search more widely for other routes to Asia.
Portuguese traders finally discovered Ceylon (Sri Lanka) at the end of the fifteenth century, and restructured the traditional production of cinnamon by the salagama caste. The Portuguese established a fort on the island in 1518, and protected their own monopoly for over a hundred years.
Dutch traders finally dislodged the Portuguese by allying with the inland Ceylon kingdom of Kandy. They established a trading post in 1638, took control of the factories by 1640, and expelled all remaining Portuguese by 1658. "The shores of the island are full of it", a Dutch captain reported, "and it is the best in all the Orient: when one is downwind of the island, one can still smell cinnamon eight leagues out to sea" (Braudel 1984, p. 215).
The Dutch East India Company continued to overhaul the methods of harvesting in the wild, and eventually began to cultivate its own trees.
The British took control of the island from the Dutch in 1796. However, the importance of the monopoly of Ceylon was already declining, as cultivation of the cinnamon tree spread to other areas, the more common cassia bark became more acceptable to consumers, and coffee, tea, sugar and chocolate began to outstrip the popularity of traditional spices.
According to FAO, Indonesia produced almost 40% of the world cinnamon (canella) output in 2005 followed by China, India and Vietnam.
# Cultivation
Cinnamon is harvested by growing the tree for two years and then coppicing it. The next year a dozen or so shoots will form from the roots. These shoots are then stripped of their bark which is left to dry. Only the thin (0.5 mm) inner bark is used; the outer woody portion is removed, leaving metre long cinnamon strips that curl into rolls ("quills") on drying; each dried quill comprises strips from numerous shoots packed together. These quills are then cut to 5-10 cm long pieces for sale.
Cinnamon comes from Sri Lanka, and the tree is also grown commercially at Tellicherry in southern India, Java, Sumatra, the West Indies, Brazil, Vietnam, Madagascar, Zanzibar, and Egypt. Sri Lanka cinnamon is a very thin smooth bark, with a light-yellowish brown colour, a highly fragrant aroma.
# Cinnamon and cassia
The name cinnamon is correctly used to refer to Ceylon Cinnamon, also known as "true cinnamon" (from the botanical name C. verum). However, the related species Cassia (Cinnamomum aromaticum) and Cinnamomum burmannii are sometimes sold labeled as cinnamon, sometimes distinguished from true cinnamon as "Indonesian cinnamon" or, at least for Cassia, "Bastard cinnamon". Ceylon cinnamon, using only the thin inner bark, has a finer, less dense and more crumbly texture, and is considered to be less strong than cassia. Cassia is generally a medium to light reddish brown, is hard and woody in texture, and is thicker (2-3 mm thick), as all of the layers of bark are used. All of the powdered cinnamon sold in supermarkets in the United States is actually Cassia. In the United States, true cinnamon is available commercially only in stick form. European health agencies have recently warned against consuming high amounts of cassia, due to a toxic component called coumarin. This is contained in much lower dosages in Ceylon cinnamon and in Cinnamomum burmannii. Coumarin is known to cause liver and kidney damage in high concentrations.
The two barks when whole are easily distinguished, and their microscopic characteristics are also quite distinct. Cinnamon sticks (or quills) have many thin layers and can easily be made into powder using a coffee or spice grinder whereas cassia sticks are much harder, made up of one thick layer, capable of damaging a spice or coffee grinder. It is a bit harder to tell powdered cinnamon from powdered cassia. When powdered bark is treated with tincture of iodine (a test for starch), little effect is visible in the case of pure cinnamon of good quality, but when cassia is present a deep-blue tint is produced, the intensity of the coloration depending on the proportion of cassia.
Cinnamon is also sometimes confused with Malabathrum (Cinnamomum tamala) and Saigon Cinnamon (Cinnamomum loureiroi).
# Uses
Cinnamon bark is widely used as a spice. It is principally employed in cookery as a condiment and flavouring material, being largely used in the preparation of some kinds of desserts, chocolate, spicy candies, tea, hot cocoa and liqueurs. In the Middle East, it is often used in savoury dishes of chicken and lamb. In the United States, cinnamon and sugar are often used to flavour cereals, bread-based dishes, and fruits, especially apples; a cinnamon-sugar mixture is even sold separately for such purposes. Cinnamon can also be used in pickling. Cinnamon bark is one of the few spices which can be consumed directly.
In medicine it acts like other volatile oils and once had a reputation as a cure for colds. It has also been used to treat diarrhea and other problems of the digestive system. Cinnamon is high in antioxidant activity (PMID 16190627, PMID 10077878). The essential oil of cinnamon also has antimicrobial properties (PMID 16104824), which aid in the preservation of certain foods.
In the media, "cinnamon" has been reported to have remarkable pharmacological effects in the treatment of type II diabetes. However, the plant material used in the study (PMID 14633804) was actually cassia, as opposed to true cinnamon (see cassia's medicinal uses for more information about its health benefits). Cinnamon has traditionally been used to treat toothache and fight bad breath and its regular use is believed to stave off common cold and aid digestion.
Cinnamon is used in the system of Thelemic Magick for the invocation of Apollo, according to the correspondences listed in Aleister Crowley's work Liber 777.
Cinnamon is also used as an insect repellent. | Cinnamon
Cinnamon (Cinnamomum verum, synonym C. zeylanicum) is a small evergreen tree 10-15 meters (32.8-49.2 feet) tall, belonging to the family Lauraceae, native to Sri Lanka and South India. The bark is widely used as a spice due to its distinct odour. In India it is also known as "Daalchini".
The leaves are ovate-oblong in shape, 7-18 cm (2.75-7.1 inches) long. The flowers, which are arranged in panicles, have a greenish color, and have a distinct odor. The fruit is a purple one-centimetre berry containing a single seed.
Its flavour is due to an aromatic essential oil which makes up 0.5 to 1% of its composition. This oil is prepared by roughly pounding the bark, macerating it in sea-water, and then quickly distilling the whole. It is of a golden-yellow colour, with the characteristic odour of cinnamon and a very hot aromatic taste. The pungent taste and scent come from cinnamic aldehyde or cinnamaldehyde and, by the absorption of oxygen as it ages, it darkens in colour and develops resinous compounds. Chemical components of the essential oil include ethyl cinnamate, eugenol, cinnamaldehyde, beta-caryophyllene, linalool and methyl chavicol.
The name cinnamon comes from Greek kinnámōmon, from Phoenician and akin to Hebrew qinnâmôn, itself ultimately from a Malaysian language, cf. Malay and Indonesian kayu manis which means sweet wood.
# History
Cinnamon has been known from remote antiquity, and it was so highly prized among ancient nations that it was regarded as a gift fit for monarchs and other great potentates. It was imported to Egypt from China as early as 2000 BC, and is mentioned in the Bible in Exodus 30:23, where Moses is commanded to use both sweet cinnamon (Hebrew קִנָּמוֹן, qinnāmôn) and cassia, and in Proverbs 7:17-18, where the lover's bed is perfumed with myrrh, aloe and cinnamon. It is also alluded to by Herodotus and other classical writers. It was commonly used on funeral pyres in Rome, and the Emperor Nero is said to have burned a year's supply of cinnamon at the funeral for his wife Poppaea Sabina, in 65 AD.
In the Middle Ages, the source of cinnamon was a mystery to the Western world. Arab traders brought the spice via overland trade routes to Alexandria in Egypt, where it was bought by Venetian traders from Italy who held a monopoly on the spice trade in Europe. The disruption of this trade by the rise of other Mediterranean powers such as the Mameluks Sultans and the Ottoman Empire was one of many factors that led Europeans to search more widely for other routes to Asia.
Portuguese traders finally discovered Ceylon (Sri Lanka) at the end of the fifteenth century, and restructured the traditional production of cinnamon by the salagama caste. The Portuguese established a fort on the island in 1518, and protected their own monopoly for over a hundred years.
Dutch traders finally dislodged the Portuguese by allying with the inland Ceylon kingdom of Kandy. They established a trading post in 1638, took control of the factories by 1640, and expelled all remaining Portuguese by 1658. "The shores of the island are full of it", a Dutch captain reported, "and it is the best in all the Orient: when one is downwind of the island, one can still smell cinnamon eight leagues out to sea" (Braudel 1984, p. 215).
The Dutch East India Company continued to overhaul the methods of harvesting in the wild, and eventually began to cultivate its own trees.
The British took control of the island from the Dutch in 1796. However, the importance of the monopoly of Ceylon was already declining, as cultivation of the cinnamon tree spread to other areas, the more common cassia bark became more acceptable to consumers, and coffee, tea, sugar and chocolate began to outstrip the popularity of traditional spices.
According to FAO, Indonesia produced almost 40% of the world cinnamon (canella) output in 2005 followed by China, India and Vietnam.
# Cultivation
Cinnamon is harvested by growing the tree for two years and then coppicing it. The next year a dozen or so shoots will form from the roots. These shoots are then stripped of their bark which is left to dry. Only the thin (0.5 mm) inner bark is used; the outer woody portion is removed, leaving metre long cinnamon strips that curl into rolls ("quills") on drying; each dried quill comprises strips from numerous shoots packed together. These quills are then cut to 5-10 cm long pieces for sale.
Cinnamon comes from Sri Lanka, and the tree is also grown commercially at Tellicherry in southern India, Java, Sumatra, the West Indies, Brazil, Vietnam, Madagascar, Zanzibar, and Egypt. Sri Lanka cinnamon is a very thin smooth bark, with a light-yellowish brown colour, a highly fragrant aroma.
# Cinnamon and cassia
The name cinnamon is correctly used to refer to Ceylon Cinnamon, also known as "true cinnamon" (from the botanical name C. verum). However, the related species Cassia (Cinnamomum aromaticum) and Cinnamomum burmannii are sometimes sold labeled as cinnamon, sometimes distinguished from true cinnamon as "Indonesian cinnamon" or, at least for Cassia, "Bastard cinnamon". Ceylon cinnamon, using only the thin inner bark, has a finer, less dense and more crumbly texture, and is considered to be less strong than cassia. Cassia is generally a medium to light reddish brown, is hard and woody in texture, and is thicker (2-3 mm thick), as all of the layers of bark are used. All of the powdered cinnamon sold in supermarkets in the United States is actually Cassia. In the United States, true cinnamon is available commercially only in stick form. European health agencies have recently warned against consuming high amounts of cassia, due to a toxic component called coumarin.[1] This is contained in much lower dosages in Ceylon cinnamon and in Cinnamomum burmannii. Coumarin is known to cause liver and kidney damage in high concentrations.
The two barks when whole are easily distinguished, and their microscopic characteristics are also quite distinct. Cinnamon sticks (or quills) have many thin layers and can easily be made into powder using a coffee or spice grinder whereas cassia sticks are much harder, made up of one thick layer, capable of damaging a spice or coffee grinder. It is a bit harder to tell powdered cinnamon from powdered cassia. When powdered bark is treated with tincture of iodine (a test for starch), little effect is visible in the case of pure cinnamon of good quality, but when cassia is present a deep-blue tint is produced, the intensity of the coloration depending on the proportion of cassia.
Cinnamon is also sometimes confused with Malabathrum (Cinnamomum tamala) and Saigon Cinnamon (Cinnamomum loureiroi).
# Uses
Cinnamon bark is widely used as a spice. It is principally employed in cookery as a condiment and flavouring material, being largely used in the preparation of some kinds of desserts, chocolate, spicy candies, tea, hot cocoa and liqueurs. In the Middle East, it is often used in savoury dishes of chicken and lamb. In the United States, cinnamon and sugar are often used to flavour cereals, bread-based dishes, and fruits, especially apples; a cinnamon-sugar mixture is even sold separately for such purposes. Cinnamon can also be used in pickling. Cinnamon bark is one of the few spices which can be consumed directly.
In medicine it acts like other volatile oils and once had a reputation as a cure for colds. It has also been used to treat diarrhea and other problems of the digestive system.[2] Cinnamon is high in antioxidant activity (PMID 16190627, PMID 10077878). The essential oil of cinnamon also has antimicrobial properties (PMID 16104824), which aid in the preservation of certain foods.[3]
In the media, "cinnamon" has been reported to have remarkable pharmacological effects in the treatment of type II diabetes. However, the plant material used in the study (PMID 14633804) was actually cassia, as opposed to true cinnamon (see cassia's medicinal uses for more information about its health benefits). Cinnamon has traditionally been used to treat toothache and fight bad breath and its regular use is believed to stave off common cold and aid digestion.[4]
Cinnamon is used in the system of Thelemic Magick for the invocation of Apollo, according to the correspondences listed in Aleister Crowley's work Liber 777.
Cinnamon is also used as an insect repellent.[5] | https://www.wikidoc.org/index.php/Cinnamon | |
a4c18e6d76582d5e23552ef3c2044f64a2c15bd0 | wikidoc | Citrinin | Citrinin
Citrinin is a mycotoxin originally isolated from Penicillium citrinum. It has since been found to be produced by a variety of other fungi which are used in the production of human foods such as grain, cheese, sake and red pigments. It is a sometimes toxic byproduct of the fermentation process when making red yeast rice.
# Toxicity
Citrinin acts as a nephrotoxin in all species in which it has been tested, but its acute toxicity varies. It causes mycotoxic nephropathy in livestock and has been implicated as a cause of Balkan nephropathy and yellow rice fever in humans.
Citrinin is used as a reagent in biological research. It induces mitochondrial permeability pore opening and inhibits respiration by interfering with complex I of the respiratory chain.
# Citrinin producers
Citrinin is produced by a variety of fungi including:
- Aspergillus niveus
- Aspergillus ochraceus
- Aspergillus oryzae
- Aspergillus terreus
- Monascus ruber
- Monascus purpureus
- Penicillium citrinum
- Penicillium camemberti
# Notes
- ↑ Heston T. Omega-3 Fatty Acids, Red Yeast Rice, and Sudden Cardiac Death. Internet Med J, 2012.
- ↑ Bennett, J. W.; Klich, M. Mycotoxins. Clinical Microbiology Reviews (2003), 16(3), 497-516. | Citrinin
Template:Chembox new
Citrinin is a mycotoxin originally isolated from Penicillium citrinum. It has since been found to be produced by a variety of other fungi which are used in the production of human foods such as grain, cheese, sake and red pigments. It is a sometimes toxic byproduct of the fermentation process when making red yeast rice[1].
# Toxicity
Citrinin acts as a nephrotoxin in all species in which it has been tested, but its acute toxicity varies.[2] It causes mycotoxic nephropathy in livestock and has been implicated as a cause of Balkan nephropathy and yellow rice fever in humans.
Citrinin is used as a reagent in biological research. It induces mitochondrial permeability pore opening and inhibits respiration by interfering with complex I of the respiratory chain.
# Citrinin producers
Citrinin is produced by a variety of fungi including:
- Aspergillus niveus
- Aspergillus ochraceus
- Aspergillus oryzae
- Aspergillus terreus
- Monascus ruber
- Monascus purpureus
- Penicillium citrinum
- Penicillium camemberti
# Notes
- ↑ Heston T. Omega-3 Fatty Acids, Red Yeast Rice, and Sudden Cardiac Death. Internet Med J, 2012.
- ↑ Bennett, J. W.; Klich, M. Mycotoxins. Clinical Microbiology Reviews (2003), 16(3), 497-516. | https://www.wikidoc.org/index.php/Citrinin | |
5c2058e556fe41d3a9e868b11537f33aef66b7cd | wikidoc | Data set | Data set
A data set (or dataset) is a collection of data, usually presented in tabular form. Each column represents a particular variable. Each row corresponds to a given member of the data set in question. It lists values for each of the variables, such as height and weight of an object or values of random numbers. The data set may comprise data for one or more members, corresponding to the number of rows.
Historically, the term originated in the mainframe field, where it had a well-defined meaning, very close to contemporary computer file. This topic is not covered here.
In the simplest case, there is only one variable, and then the data set consists of a single column of values, often represented as a list.
The values may be numbers, such as real numbers or integers, for example representing a person's height in centimeters, but may also be nominal data (i.e., not consisting of numerical values), for example representing a person's ethnicity. More generally, values may be of any of the kinds described as a level of measurement. For each variable, the values will normally all be of the same kind. However, there may also be "missing values", which need to be indicated in some way.
In statistics data sets usually come from actual observations obtained by sampling a statistical population, and each row corresponds to the observations on one element of that population. Data sets may further be generated by algorithms for the purpose of testing certain kinds of software.
# Classic data sets
Several classic data sets have been used extensively in the statistical literature:
- Iris flower data set - multivariate data set introduced by Ronald Fisher (1936).
- Categorical data analysis - Data sets used in the book, An Introduction to Categorical Data Analysis, by Agresti are provided on-line by StatLib.
- Robust statistics - Data sets used in Robust Regression and Outlier Detection (Rousseeuw and Leroy, 1986). Provided on-line at the University of Cologne.
- Time series - Data used in Chatfield's book, The Analysis of Time Series, are provided on-line by StatLib.
- Extreme values - Data used in the book, An Introduction to the Statistical Modeling of Extreme Values are provided on-line by Stuart Coles, the book's author.
- Bayesian Data Analysis - Data used in the book, Bayesian Data Analysis, are provided on-line by Andrew Gelman, one of the book's authors.
- The Bupa liver data, used in several papers in the machine learning (data mining) literature. | Data set
A data set (or dataset) is a collection of data, usually presented in tabular form. Each column represents a particular variable. Each row corresponds to a given member of the data set in question. It lists values for each of the variables, such as height and weight of an object or values of random numbers. The data set may comprise data for one or more members, corresponding to the number of rows.
Historically, the term originated in the mainframe field, where it had a well-defined meaning, very close to contemporary computer file. This topic is not covered here.
In the simplest case, there is only one variable, and then the data set consists of a single column of values, often represented as a list.
The values may be numbers, such as real numbers or integers, for example representing a person's height in centimeters, but may also be nominal data (i.e., not consisting of numerical values), for example representing a person's ethnicity. More generally, values may be of any of the kinds described as a level of measurement. For each variable, the values will normally all be of the same kind. However, there may also be "missing values", which need to be indicated in some way.
In statistics data sets usually come from actual observations obtained by sampling a statistical population, and each row corresponds to the observations on one element of that population. Data sets may further be generated by algorithms for the purpose of testing certain kinds of software.
# Classic data sets
Several classic data sets have been used extensively in the statistical literature:
- Iris flower data set - multivariate data set introduced by Ronald Fisher (1936).[1]
- Categorical data analysis - Data sets used in the book, An Introduction to Categorical Data Analysis, by Agresti are provided on-line by StatLib.
- Robust statistics - Data sets used in Robust Regression and Outlier Detection (Rousseeuw and Leroy, 1986). Provided on-line at the University of Cologne.
- Time series - Data used in Chatfield's book, The Analysis of Time Series, are provided on-line by StatLib.
- Extreme values - Data used in the book, An Introduction to the Statistical Modeling of Extreme Values are provided on-line by Stuart Coles, the book's author.
- Bayesian Data Analysis - Data used in the book, Bayesian Data Analysis, are provided on-line by Andrew Gelman, one of the book's authors.
- The Bupa liver data, used in several papers in the machine learning (data mining) literature. | https://www.wikidoc.org/index.php/Classic_data_sets | |
f623d439682d4c2a4bd5fc9aaffeffa56c49d0f3 | wikidoc | Clathrin | Clathrin
Clathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated and named by Barbara Pearse in 1976. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When the triskelia interact they form a polyhedral lattice that surrounds the vesicle. This is how clathrin gets its name, from the Latin clathratus meaning like a lattice. Coat-proteins, like clathrin, are used to build small vesicles in order to transport molecules within cells. The endocytosis and exocytosis of vesicles allows cells to communicate, to transfer nutrients, to import signaling receptors, to mediate an immune response after sampling the extracellular world, and to clean up the cell debris left by tissue inflammation. The endocytic pathway can be hijacked by viruses and other pathogens in order to gain entry to the cell during infection.
# Structure
The clathrin triskelion is composed of three clathrin heavy chains interacting at their C-termini, each ~190 kDa heavy chain has a ~25 kDa light chain tightly bound to it. The three heavy chains provide the structural backbone of the clathrin lattice, and the three light chains are thought to regulate the formation and disassembly of a clathrin lattice. There are two forms of clathrin light chains, designated a and b. The main clathrin heavy chain, located on chromosome 17 in humans, is found in all cells. A second clathrin heavy chain gene, on chromosome 22, is expressed in muscle.
Clathrin heavy chain is often described as a leg, with subdomains, representing the foot (the N-terminal domain), followed by the ankle, distal leg, knee, proximal leg, and trimerization domains. The N-terminal domain consists of a seven-bladed β-propeller structure. The other domains form a super-helix of short alpha helices. This was originally determined from the structure of the proximal leg domain that identified and is composed of a smaller structural module referred to as clathrin heavy chain repeat motifs. The light chains bind primarily to the proximal leg portion of the heavy chain with some interaction near the trimerization domain. The β-propeller at the 'foot' of clathrin contains multiple binding sites for interaction with other proteins.
When triskelia assemble together in solution, they can interact with enough flexibility to form 6-sided rings (hexagons) that yield a flat lattice, or 5-sided rings (pentagons) that are necessary for curved lattice formation. When many triskelions connect, they can form a basket-like structure. The structure shown, is built of 36 triskelia, one of which is shown in blue. Another common assembly is a truncated icosahedron. To enclose a vesicle, exactly 12 pentagons must be present in the lattice.
In a cell, clathrin triskelion in the cytoplasm binds to an adaptor protein that has bound membrane, linking one of its three feet to the membrane at a time. Clathrin cannot bind to membrane or cargo directly and instead uses adaptor proteins to do this. This triskelion will bind to other membrane-attached triskelia to form a rounded lattice of hexagons and pentagons, reminiscent of the panels on a soccer ball, that pulls the membrane into a bud. By constructing different combinations of 5-sided and 6-sided rings, vesicles of different sizes may assemble. The smallest clathrin cage commonly imaged, called a mini-coat, has 12 pentagons and only two hexagons. Even smaller cages with zero hexagons probably do not form from the native protein, because the feet of the triskelia are too bulky.
# Function
Clathrin performs critical roles in shaping rounded vesicles in the cytoplasm for intracellular trafficking. Clathrin-coated vesicles (CCV) selectively sort cargo at the cell membrane, trans-Golgi network, and endosomal compartments for multiple membrane traffic pathways. After a vesicle buds into the cytoplasm, the coat rapidly disassembles, allowing the clathrin to recycle while the vesicle gets transported to a variety of locations.
Adaptor molecules are responsible for self-assembly and recruitment. Two examples of adaptor proteins are AP180 and epsin. AP180 is used in synaptic vesicle formation. It recruits clathrin to membranes and also promotes its polymerization. Epsin also recruits clathrin to membranes and promotes its polymerization, and can help deform the membrane, and thus clathrin-coated vesicles can bud. In a cell, a triskelion floating in the cytoplasm binds to an adaptor protein, linking one of its feet to the membrane at a time. The skelion will bind to other ones attached to the membrane to form a polyhedral lattice, skelion, which pulls the membrane into a bud. The skelion does not bind directly to the membrane, but binds to the adaptor proteins that recognize the molecules on the membrane surface.
Clathrin has another function aside from the coating of organelles. In non-dividing cells, the formation of clathrin-coated vesicles occurs continuously. Formation of clathrin-coated vesicles is shut down in cells undergoing mitosis. During mitosis, clathrin binds to the spindle apparatus, in complex with two other proteins: TACC3 and ch-TOG/CKAP5. Clathrin aids in the congression of chromosomes by stabilizing kinetochore fibers of the mitotic spindle. The amino-terminal domain of the clathrin heavy chain and the TACC domain of TACC3 make the microtubule binding surface for TACC3/ch-TOG/clathrin to bind to the mitotic spindle. The stabilization of kinetochore fibers requires the trimeric structure of clathrin in order to crosslink microtubules.
Clathrin-mediated endocytosis (CME) regulates many cellular physiological processes such as the internalization of growth factors and receptors, entry of pathogens, and synaptic transmission. It is believed that cellular invaders use the nutrient pathway to gain access to a cell's replicating mechanisms. Certain signalling molecules open the nutrients pathway. Two chemical compounds called Pitstop 1 and Pitstop 2, selective clathrin inhibitors, can interfere with the pathogenic activity, and thus protect the cells against invasion. These two compounds selectively block the endocytic ligand association with the clathrin terminal domain in vitro. However, the specificity of these compounds to block clathrin-mediated endocytosis has been questioned. | Clathrin
Clathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated and named by Barbara Pearse in 1976.[1] It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When the triskelia interact they form a polyhedral lattice that surrounds the vesicle. This is how clathrin gets its name, from the Latin clathratus meaning like a lattice. Coat-proteins, like clathrin, are used to build small vesicles in order to transport molecules within cells. The endocytosis and exocytosis of vesicles allows cells to communicate, to transfer nutrients, to import signaling receptors, to mediate an immune response after sampling the extracellular world, and to clean up the cell debris left by tissue inflammation. The endocytic pathway can be hijacked by viruses and other pathogens in order to gain entry to the cell during infection.[2]
# Structure
The clathrin triskelion is composed of three clathrin heavy chains interacting at their C-termini, each ~190 kDa heavy chain has a ~25 kDa light chain tightly bound to it. The three heavy chains provide the structural backbone of the clathrin lattice, and the three light chains are thought to regulate the formation and disassembly of a clathrin lattice. There are two forms of clathrin light chains, designated a and b. The main clathrin heavy chain, located on chromosome 17 in humans, is found in all cells. A second clathrin heavy chain gene, on chromosome 22, is expressed in muscle.
Clathrin heavy chain is often described as a leg, with subdomains, representing the foot (the N-terminal domain), followed by the ankle, distal leg, knee, proximal leg, and trimerization domains. The N-terminal domain consists of a seven-bladed β-propeller structure. The other domains form a super-helix of short alpha helices. This was originally determined from the structure of the proximal leg domain that identified and is composed of a smaller structural module referred to as clathrin heavy chain repeat motifs. The light chains bind primarily to the proximal leg portion of the heavy chain with some interaction near the trimerization domain. The β-propeller at the 'foot' of clathrin contains multiple binding sites for interaction with other proteins.
When triskelia assemble together in solution, they can interact with enough flexibility to form 6-sided rings (hexagons) that yield a flat lattice, or 5-sided rings (pentagons) that are necessary for curved lattice formation. When many triskelions connect, they can form a basket-like structure. The structure shown, is built of 36 triskelia, one of which is shown in blue. Another common assembly is a truncated icosahedron. To enclose a vesicle, exactly 12 pentagons must be present in the lattice.
In a cell, clathrin triskelion in the cytoplasm binds to an adaptor protein that has bound membrane, linking one of its three feet to the membrane at a time. Clathrin cannot bind to membrane or cargo directly and instead uses adaptor proteins to do this. This triskelion will bind to other membrane-attached triskelia to form a rounded lattice of hexagons and pentagons, reminiscent of the panels on a soccer ball, that pulls the membrane into a bud. By constructing different combinations of 5-sided and 6-sided rings, vesicles of different sizes may assemble. The smallest clathrin cage commonly imaged, called a mini-coat, has 12 pentagons and only two hexagons. Even smaller cages with zero hexagons probably do not form from the native protein, because the feet of the triskelia are too bulky.
# Function
Clathrin performs critical roles in shaping rounded vesicles in the cytoplasm for intracellular trafficking. Clathrin-coated vesicles (CCV) selectively sort cargo at the cell membrane, trans-Golgi network, and endosomal compartments for multiple membrane traffic pathways. After a vesicle buds into the cytoplasm, the coat rapidly disassembles, allowing the clathrin to recycle while the vesicle gets transported to a variety of locations.
Adaptor molecules are responsible for self-assembly and recruitment. Two examples of adaptor proteins are AP180[3] and epsin.[4][5][6] AP180 is used in synaptic vesicle formation. It recruits clathrin to membranes and also promotes its polymerization. Epsin also recruits clathrin to membranes and promotes its polymerization, and can help deform the membrane, and thus clathrin-coated vesicles can bud. In a cell, a triskelion floating in the cytoplasm binds to an adaptor protein, linking one of its feet to the membrane at a time. The skelion will bind to other ones attached to the membrane to form a polyhedral lattice, skelion, which pulls the membrane into a bud. The skelion does not bind directly to the membrane, but binds to the adaptor proteins that recognize the molecules on the membrane surface.
Clathrin has another function aside from the coating of organelles. In non-dividing cells, the formation of clathrin-coated vesicles occurs continuously. Formation of clathrin-coated vesicles is shut down in cells undergoing mitosis. During mitosis, clathrin binds to the spindle apparatus, in complex with two other proteins: TACC3 and ch-TOG/CKAP5. Clathrin aids in the congression of chromosomes by stabilizing kinetochore fibers of the mitotic spindle. The amino-terminal domain of the clathrin heavy chain and the TACC domain of TACC3 make the microtubule binding surface for TACC3/ch-TOG/clathrin to bind to the mitotic spindle. The stabilization of kinetochore fibers requires the trimeric structure of clathrin in order to crosslink microtubules.[7][8]
Clathrin-mediated endocytosis (CME) regulates many cellular physiological processes such as the internalization of growth factors and receptors, entry of pathogens, and synaptic transmission. It is believed that cellular invaders use the nutrient pathway to gain access to a cell's replicating mechanisms. Certain signalling molecules open the nutrients pathway. Two chemical compounds called Pitstop 1 and Pitstop 2, selective clathrin inhibitors, can interfere with the pathogenic activity, and thus protect the cells against invasion. These two compounds selectively block the endocytic ligand association with the clathrin terminal domain in vitro.[9] However, the specificity of these compounds to block clathrin-mediated endocytosis has been questioned.[10] | https://www.wikidoc.org/index.php/Clathrin | |
0957d126b35bd0c94f08909842c2c4d2ccb66b58 | wikidoc | Clavicle | Clavicle
# Overview
In human anatomy, the clavicle or collar bone is classified as a long bone that makes up part of the shoulder girdle (pectoral girdle). It receives its name from the Latin clavicula ("little key") because the bone rotates along its axis like a key when the shoulder is abducted. (This movement is palpable with the opposite hand). In some people, particularly females who may have less fat in this region, the location of the bone is clearly visible as it creates a bulge in the skin.
# Overview
The clavicle is a doubly-curved long bone (the only horizontal long bone in the human body) that connects the arm (upper limb) to the body (trunk), located directly above the first rib. Medially, it articulates with the manubrium of the sternum (breast-bone) at the sternoclavicular joint. At its lateral end it articulates with the acromion of the scapula (shoulder blade) at the acromioclavicular joint. It has a rounded medial end and a flattened lateral end.
From the roughly pyramidal sternal end, each clavicle curves laterally and posteriorly for roughly half its length. It then forms a smooth posterior curve to articulate with a process of the scapula (acromion). The flat, acromial end of the clavicle is broader than the sternal end. The acromial end has a rough inferior surface that bears prominent lines and tubercles. These surface features are attachment sites for muscles and ligaments of the shoulder.
# Functions
The clavicle serves several functions:
- It serves as a rigid support from which the scapula and free limb are suspended. This arrangement keeps the upper limb (arm) away from the thorax so that the arm has maximum range of movement.
- Covers the cervicoaxillary canal (passageway between the neck and arm), through which several important structures pass.
- Transmits physical impacts from the upper limb to the axial skeleton.
Even though it is classified as a long bone, the clavicle has no medullary (bone marrow) cavity like other long bones. It is made up of spongy (cancellous) bone with a shell of compact bone. It is a dermal bone derived from elements originally attached to the skull.
# Attachments
Muscles and ligaments that attach to the clavicle include:
# Development
The clavicle is the first bone to begin the process of hardening (ossification) during development of the embryo, during the 5th and 6th weeks of gestation. However, it is the last of the long bones to finish ossification, at about 21 years of age. It forms by intramembranous ossification.
# Common clavicle injuries
- acromioclavicular dislocation
- sternoclavicular dislocations
- clavicle fractures
- osteolysis
- degeneration of the clavicle
# Additional images
- Pectoral girdle - front
- Diagram of the human shoulder joint
- Sternoclavicular articulation. Anterior view.
- The left shoulder and acromioclavicular joints, and the proper ligaments of the scapula.
- Muscles of the neck. Lateral view.
- Muscles of the neck. Anterior view.
- Anterolateral view of head and neck.
- Front view of neck. | Clavicle
Template:Infobox Bone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In human anatomy, the clavicle or collar bone is classified as a long bone that makes up part of the shoulder girdle (pectoral girdle). It receives its name from the Latin clavicula ("little key") because the bone rotates along its axis like a key when the shoulder is abducted. (This movement is palpable with the opposite hand). In some people, particularly females who may have less fat in this region, the location of the bone is clearly visible as it creates a bulge in the skin.
# Overview
The clavicle is a doubly-curved long bone (the only horizontal long bone in the human body) that connects the arm (upper limb) to the body (trunk), located directly above the first rib. Medially, it articulates with the manubrium of the sternum (breast-bone) at the sternoclavicular joint. At its lateral end it articulates with the acromion of the scapula (shoulder blade) at the acromioclavicular joint. It has a rounded medial end and a flattened lateral end.
From the roughly pyramidal sternal end, each clavicle curves laterally and posteriorly for roughly half its length. It then forms a smooth posterior curve to articulate with a process of the scapula (acromion). The flat, acromial end of the clavicle is broader than the sternal end. The acromial end has a rough inferior surface that bears prominent lines and tubercles. These surface features are attachment sites for muscles and ligaments of the shoulder.
# Functions
The clavicle serves several functions:
- It serves as a rigid support from which the scapula and free limb are suspended. This arrangement keeps the upper limb (arm) away from the thorax so that the arm has maximum range of movement.
- Covers the cervicoaxillary canal (passageway between the neck and arm), through which several important structures pass.
- Transmits physical impacts from the upper limb to the axial skeleton.
Even though it is classified as a long bone, the clavicle has no medullary (bone marrow) cavity like other long bones. It is made up of spongy (cancellous) bone with a shell of compact bone. It is a dermal bone derived from elements originally attached to the skull.
# Attachments
Muscles and ligaments that attach to the clavicle include:
# Development
The clavicle is the first bone to begin the process of hardening (ossification) during development of the embryo, during the 5th and 6th weeks of gestation. However, it is the last of the long bones to finish ossification, at about 21 years of age. It forms by intramembranous ossification.
# Common clavicle injuries
- acromioclavicular dislocation
- sternoclavicular dislocations
- clavicle fractures
- osteolysis
- degeneration of the clavicle
# Additional images
- Pectoral girdle - front
- Diagram of the human shoulder joint
- Sternoclavicular articulation. Anterior view.
- The left shoulder and acromioclavicular joints, and the proper ligaments of the scapula.
- Muscles of the neck. Lateral view.
- Muscles of the neck. Anterior view.
- Anterolateral view of head and neck.
- Front view of neck. | https://www.wikidoc.org/index.php/Clavicle | |
28e5bfd55b22b7132c9919eb42b82beac821c465 | wikidoc | Cleanser | Cleanser
A cleanser is a facial care product that is used to remove make-up, dead skin cells, oil, dirt and other types of pollutants from the skin of the face. This helps to unclog pores and prevent skin conditions such as acne.
Many people use a cleanser once or more times a day as part of their skin care regimen together with a toner and moisturiser.
Using a cleanser to remove dirt is considered to be a better alternative to bar soap or another form of skin cleanser not specifically formulated for the face for the following reasons:
- Bar soap has a high pH (in the area of 9 to 10), and skin's natural pH is 5.5. This means that soap can change the balance present in the skin to favor the overgrowth of some types of bacteria, exacerbating acne.
- Bar cleansers in general, soap or not, have thickeners that allow them to assume a bar shape can clog pores, leading (once again) to acne.
- Using bar soap on the face can remove natural oils from the skin that form a barrier against water loss. This causes the sebaceous glands to subsequently overproduce oil, a condition known as reactive seborrhoea, which will lead to clogged pores. Conversely, in order to prevent drying out the skin, many cleansers incorporate moisturisers. It is important to remember to always wash your face in luke warm water, use a milky cleanser and a hydrating toner, such as a spritz which should be applied before moisturising, try not to leave the skin un-moisturisied for too long after cleansing. It is imperative not to de-hydrate the skin. Cleanse, tone and moisturise twice a day, once at night and once in the morning.
# Types of cleansers
Different types of cleansers have been developed for people with different skin types. Strong cleansers are more suitable for oily skins to prevent breakouts, but they may overdry and irritate dry skin. Very dry skin may require a creamy lotion-type cleanser, as long as it doesn't make skin feel oily afterward. These are too gentle to be effective on oily (or even normal) skin, but dry skin requires much less cleansing power, always select a cleanser that is alochol free if you have dry or dehydrated skin.
Some cleansers may incorporate fragrance or essential oils. However, for some people these cleansers may irritate the skin and often provoking allergic responses. | Cleanser
A cleanser is a facial care product that is used to remove make-up, dead skin cells, oil, dirt and other types of pollutants from the skin of the face. This helps to unclog pores and prevent skin conditions such as acne.
Many people use a cleanser once or more times a day as part of their skin care regimen together with a toner and moisturiser.
Using a cleanser to remove dirt is considered to be a better alternative to bar soap or another form of skin cleanser not specifically formulated for the face for the following reasons:
- Bar soap has a high pH (in the area of 9 to 10), and skin's natural pH is 5.5. This means that soap can change the balance present in the skin to favor the overgrowth of some types of bacteria, exacerbating acne.
- Bar cleansers in general, soap or not, have thickeners that allow them to assume a bar shape can clog pores, leading (once again) to acne.
- Using bar soap on the face can remove natural oils from the skin that form a barrier against water loss. This causes the sebaceous glands to subsequently overproduce oil, a condition known as reactive seborrhoea, which will lead to clogged pores. Conversely, in order to prevent drying out the skin, many cleansers incorporate moisturisers. It is important to remember to always wash your face in luke warm water, use a milky cleanser and a hydrating toner, such as a spritz which should be applied before moisturising, try not to leave the skin un-moisturisied for too long after cleansing. It is imperative not to de-hydrate the skin. Cleanse, tone and moisturise twice a day, once at night and once in the morning.
# Types of cleansers
Different types of cleansers have been developed for people with different skin types. Strong cleansers are more suitable for oily skins to prevent breakouts, but they may overdry and irritate dry skin. Very dry skin may require a creamy lotion-type cleanser, as long as it doesn't make skin feel oily afterward. These are too gentle to be effective on oily (or even normal) skin, but dry skin requires much less cleansing power, always select a cleanser that is alochol free if you have dry or dehydrated skin.
Some cleansers may incorporate fragrance or essential oils. However, for some people these cleansers may irritate the skin and often provoking allergic responses. | https://www.wikidoc.org/index.php/Cleanser | |
de7d6ecbc1d90eee4fcc7caa4165327012e75b58 | wikidoc | Medicine | Medicine
Medicine is the science and "art" of maintaining and/or restoring human health through the study, diagnosis, and treatment of patients.
The term is derived from the Latin ars medicina meaning the art of healing.
The modern practice of medicine occurs at the many interfaces between the art of healing and various sciences. Medicine is directly connected to the health sciences and biomedicine. Broadly speaking, the term 'Medicine' today refers to the fields of clinical medicine, medical research and surgery, thereby covering the challenges of disease and injury.
# Overview
Since the 19th century, only those with a medical degree have been considered worthy to practice medicine. Clinicians (licensed professionals who deal with patients) can be physicians, physical therapists, physician assistants, nurses or others. The medical profession is the social and occupational structure of the group of people formally trained and authorized to apply medical knowledge. Many countries and legal jurisdictions have legal limitations on who may practice medicine.
Medicine comprises various specialized sub-branches, such as cardiology, pulmonology, neurology, or other fields such as sports medicine, research or public health.
Human societies have had various different systems of health care practice since at least the beginning of recorded history. Medicine, in the modern period, is the mainstream scientific tradition which developed in the Western world since the early Renaissance (around 1450). Many other traditions of health care are still practiced throughout the world; most of these are separate from Western medicine, which is also called biomedicine, allopathic medicine or the Hippocratic tradition. The most highly developed of these are traditional Chinese medicine, Traditional Tibetan medicine and the Ayurvedic traditions of India and Sri Lanka. Various non-mainstream traditions of health care have also developed in the Western world. These systems are sometimes considered companions to Hippocratic medicine, and sometimes are seen as competition to the Western tradition. Few of them have any scientific confirmation of their tenets, because if they did they would be brought into the fold of Western medicine.
"Medicine" is also often used amongst medical professionals as shorthand for internal medicine. Veterinary medicine is the practice of health care in animal species other than human beings.
# History of medicine
The earliest type of medicine in most cultures was the use of plants (Herbalism) and animal parts. This was usually in concert with 'magic' of various kinds in which: animism (the notion of inanimate objects having spirits); spiritualism (here meaning an appeal to gods or communion with ancestor spirits); shamanism (the vesting of an individual with mystic powers); and divination (the supposed obtaining of truth by magic means), played a major role.
The practice of medicine developed gradually, and separately, in Ancient Egypt, Ancient India, Ancient China, Ancient Greece, Ancient Persia and elsewhere. Medicine as it is practiced now developed largely in the late eighteenth century and early nineteenth century in England (William Harvey, seventeenth century), Germany (Rudolf Virchow) and France (Jean-Martin Charcot, Claude Bernard and others). The new, "scientific" medicine (where results are testable and repeatable) replaced early Western traditions of medicine, based on herbalism, the Greek "four humours" and other pre-modern theories. The focal points of development of clinical medicine shifted to the United Kingdom and the USA by the early 1900s (Canadian-born) Sir William Osler, Harvey Cushing). Possibly the major shift in medical thinking was the gradual rejection in the 1400s during the Black Death of what may be called the 'traditional authority' approach to science and medicine. This was the notion that because some prominent person in the past said something must be so, then that was the way it was, and anything one observed to the contrary was an anomaly (which was paralleled by a similar shift in European society in general - see Copernicus's rejection of Ptolemy's theories on astronomy). People like Vesalius led the way in improving upon or indeed rejecting the theories of great authorities from the past such as Galen, Hippocrates, and Avicenna/Ibn Sina, all of whose theories were in time almost totally discredited. Such new attitudes were also only made possible by the weakening of the Roman Catholic church's power in society, especially in the Republic of Venice.
Evidence-based medicine is a recent movement to establish the most effective algorithms of practice (ways of doing things) through the use of the scientific method and modern global information science by collating all the evidence and developing standard protocols which are then disseminated to healthcare providers. One problem with this 'best practice' approach is that it could be seen to stifle novel approaches to treatment.
Genomics and knowledge of human genetics is already having some influence on medicine, as the causative genes of most monogenic genetic disorders have now been identified, and the development of techniques in molecular biology and genetics are influencing medical practice and decision-making.
Pharmacology has developed from herbalism and many drugs are still derived from plants (atropine, ephedrine, warfarin, aspirin, digoxin, vinca alkaloids, taxol, hyoscine, etc). The modern era began with Robert Koch's discoveries around 1880 of the transmission of disease by bacteria, and then the discovery of antibiotics shortly thereafter around 1900. The first of these was arsphenamine / Salvarsan discovered by Paul Ehrlich in 1908 after he observed that bacteria took up toxic dyes that human cells did not. The first major class of antibiotics was the sulfa drugs, derived by French chemists originally from azo dyes. Throughout the twentieth century, major advances in the treatment of infectious diseases were observable in (Western) societies. The medical establishment is now developing drugs targeted towards one particular disease process. Thus drugs are being developed to minimise the side effects of prescribed drugs, to treat cancer, geriatric problems, long-term problems (such as high cholesterol), chronic diseases type 2 diabetes, lifestyle and degenerative diseases such as arthritis and Alzheimer's disease.
# Practice of medicine
The practice of medicine combines both science as the evidence base and art in the application of this medical knowledge in combination with intuition and clinical judgment to determine the treatment plan for each patient.
Central to medicine is the patient-physician relationship established when a person with a health concern seeks a physician's help; the 'medical encounter'. Other health professionals similarly establish a relationship with a patient and may perform various interventions, e.g. nurses, radiographers and therapists.
As part of the medical encounter, the healthcare provider needs to:
- develop a relationship with the patient
- gather data (medical history, systems enquiry, and physical examination, combined with laboratory or imaging studies (investigations))
- analyze and synthesize that data (assessment and/or differential diagnoses), and then:
- develop a treatment plan (further testing, therapy, watchful observation, referral and follow-up)
- treat the patient accordingly
- assess the progress of treatment and alter the plan as necessary (management).
The medical encounter is documented in a medical record, which is a legal document in many jurisdictions.
## Health care delivery systems
Medicine is practiced within the medical system, which is a legal, credentialing and financing framework, established by a particular culture or government. The characteristics of a health care system have significant effect on the way medical care is delivered.
Financing has a great influence as it defines who pays the costs. Aside from tribal cultures, the most significant divide in developed countries is between universal health care and market-based health care (such as practiced in the U.S.). Universal health care might allow or ban a parallel private market. The latter is described as single-payer system.
Transparency of information is another factor defining a delivery system. Access to information on conditions, treatments, quality and pricing greatly affects the choice by patients / consumers and therefore the incentives of medical professionals. While US health care system has come under fire for lack of openness, new legislation may encourage greater openness. There is a perceived tension between the need for transparency on the one hand and such issues as patient confidentiality and the possible exploitation of information for commercial gain on the other.
## Health care delivery
Medical care delivery is classified into primary, secondary and tertiary care.
Primary care medical services are provided by physicians or other health professionals who have first contact with a patient seeking medical treatment or care. These occur in physician offices, clinics, nursing homes, schools, home visits and other places close to patients. About 90% of medical visits can be treated by the primary care provider. These include treatment of acute and chronic illnesses, preventive care and health education for all ages and both sexes.
Secondary care medical services are provided by medical specialists in their offices or clinics or at local community hospitals for a patient referred by a primary care provider who first diagnosed or treated the patient. Referrals are made for those patients who required the expertise or procedures performed by specialists. These include both ambulatory care and inpatient services, emergency rooms, intensive care medicine, surgery services, physical therapy, labor and delivery, endoscopy units, diagnostic laboratory and medical imaging services, hospice centers, etc. Some primary care providers may also take care of hospitalized patients and deliver babies in a secondary care setting.
Tertiary care medical services are provided by specialist hospitals or regional centers equipped with diagnostic and treatment facilities not generally available at local hospitals. These include trauma centers, burn treatment centers, advanced neonatology unit services, organ transplants, high-risk pregnancy, radiation oncology, etc.
Modern medical care also depends on information - still delivered in many health care settings on paper records, but increasingly nowadays by electronic means.
## Patient-physician-relationship
This kind of relationship and interaction is a central process in the practice of medicine. There are many perspectives from which to understand and describe it.
An idealized physician's perspective, such as is taught in medical school, sees the core aspects of the process as the physician learning the patient's symptoms, concerns and values; in response the physician examines the patient, interprets the symptoms, and formulates a diagnosis to explain the symptoms and their cause to the patient and to propose a treatment. The job of a physician is similar to a human biologist: that is, to know the human frame and situation in terms of normality. Once the physician knows what is normal and can measure the patient against those norms, he or she can then determine the particular departure from the normal and the degree of departure. This is called the diagnosis.
The four great cornerstones of diagnostic medicine are anatomy (structure: what is there), physiology (how the structure/s work), pathology (what goes wrong with the anatomy and physiology) and psychology (mind and behavior). In addition, the physician should consider the patient in their 'well' context rather than simply as a walking medical condition. This means the socio-political context of the patient (family, work, stress, beliefs) should be assessed as it often offers vital clues to the patient's condition and further management. In more detail, the patient presents a set of complaints (the symptoms) to the physician, who then obtains further information about the patient's symptoms, previous state of health, living conditions, and so forth. The physician then makes a review of systems (ROS) or systems inquiry, which is a set of ordered questions about each major body system in order: general (such as weight loss), endocrine, cardio-respiratory, etc. Next comes the actual physical examination; the findings are recorded, leading to a list of possible diagnoses. These will be in order of probability. The next task is to enlist the patient's agreement to a management plan, which will include treatment as well as plans for follow-up. Importantly, during this process the healthcare provider educates the patient about the causes, progression, outcomes, and possible treatments of his ailments, as well as often providing advice for maintaining health. This teaching relationship is the basis of calling the physician doctor, which originally meant "teacher" in Latin. The patient-physician relationship is additionally complicated by the patient's suffering (patient derives from the Latin patior, "suffer") and limited ability to relieve it on his/her own. The physician's expertise comes from his knowledge of what is healthy and normal contrasted with knowledge and experience of other people who have suffered similar symptoms (unhealthy and abnormal), and the proven ability to relieve it with medicines (pharmacology) or other therapies about which the patient may initially have little knowledge.
The physician-patient relationship can be analyzed from the perspective of ethical concerns, in terms of how well the goals of non-maleficence, beneficence, autonomy, and justice are achieved. Many other values and ethical issues can be added to these. In different societies, periods, and cultures, different values may be assigned different priorities. For example, in the last 30 years medical care in the Western World has increasingly emphasized patient autonomy in decision making.
The relationship and process can also be analyzed in terms of social power relationships (e.g., by Michel Foucault), or economic transactions. Physicians have been accorded gradually higher status and respect over the last century, and they have been entrusted with control of access to prescription medicines as a public health measure. This represents a concentration of power and carries both advantages and disadvantages to particular kinds of patients with particular kinds of conditions. A further twist has occurred in the last 25 years as costs of medical care have risen, and a third party (an insurance company or government agency) now often insists upon a share of decision-making power for a variety of reasons, reducing freedom of choice of healthcare providers and patients in many ways.
The quality of the patient-physician relationship is important to both parties. The better the relationship in terms of mutual respect, knowledge, trust, shared values and perspectives about disease and life, and time available, the better will be the amount and quality of information about the patient's disease transferred in both directions, enhancing accuracy of diagnosis and increasing the patient's knowledge about the disease. Where such a relationship is poor the physician's ability to make a full assessment is compromised and the patient is more likely to distrust the diagnosis and proposed treatment. In these circumstances and also in cases where there is genuine divergence of medical opinions, a second opinion from another physician may be sought.
In some settings, e.g. the hospital ward, the patient-physician relationship is much more complex, and many other people are involved when somebody is ill: relatives, neighbors, rescue specialists, nurses, technical personnel, social workers and others.
## Clinical skills
A complete medical evaluation includes a medical history, a systems enquiry, a physical examination, appropriate laboratory or imaging studies, analysis of data and medical decision making to obtain diagnoses, and a treatment plan.
The components of the medical history are:
- Chief complaint (CC): the reason for the current medical visit. These are the 'symptoms.' They are in the patient's own words and are recorded along with the duration of each one. Also called 'presenting complaint.'
- History of present illness / complaint (HPI): the chronological order of events of symptoms and further clarification of each symptom.
- Current activity: occupation, hobbies, what the patient actually does.
- Medications (DHx): what drugs the patient takes including prescribed, over-the-counter, and home remedies, as well as alternative and herbal medicines/herbal remedies such as St John's wort. Allergies are also recorded.
- Past medical history (PMH/PMHx): concurrent medical problems, past hospitalizations and operations, injuries, past infectious diseases and/or vaccinations, history of known allergies.
- Social history (SH): birthplace, residences, marital history, social and economic status, habits (including diet, medications, tobacco, alcohol).
- Family history (FH): listing of diseases in the family that may impact the patient. A family tree is sometimes used.
- Review of systems (ROS) or systems inquiry: a set of additional questions to ask which may be missed on HPI: a general enquiry (have you noticed any weight loss, fevers, lumps and bumps? etc), followed by questions on the body's main organ systems (heart, lungs, digestive tract, urinary tract, etc).
The physical examination is the examination of the patient looking for signs of disease ('Symptoms' are what the patient volunteers, 'Signs' are what the healthcare provider detects by examination). The healthcare provider uses the senses of sight, hearing, touch, and sometimes smell (taste has been made redundant by the availability of modern lab tests). Four chief methods are used: inspection, palpation (feel), percussion (tap to determine resonance characteristics), and auscultation (listen); smelling may be useful (e.g. infection, uremia, diabetic ketoacidosis). The clinical examination involves study of:
- Vital signs including height, weight, body temperature, blood pressure, pulse, respiration rate, hemoglobin oxygen saturation
- General appearance of the patient and specific indicators of disease (nutritional status, presence of jaundice, pallor or clubbing)
- Skin
- Head, eye, ear, nose, and throat (HEENT)
- Cardiovascular (heart and blood vessels)
- Respiratory (large airways and lungs)
- Abdomen and rectum
- Genitalia (and pregnancy if the patient is or could be pregnant)
- Musculoskeletal (spine and extremities)
- Neurological (consciousness, awareness, brain, cranial nerves, spinal cord and peripheral nerves)
- Psychiatric (orientation, mental state, evidence of abnormal perception or thought)
Laboratory and imaging studies results may be obtained, if necessary.
The medical decision-making (MDM) process involves analysis and synthesis of all the above data to come up with a list of possible diagnoses (the differential diagnoses), along with an idea of what needs to be done to obtain a definitive diagnosis that would explain the patient's problem.
The treatment plan may include ordering additional laboratory tests and studies, starting therapy, referral to a specialist, or watchful observation. Follow-up may be advised.
This process is used by primary care providers as well as specialists. It may take only a few minutes if the problem is simple and straightforward. On the other hand, it may take weeks in a patient who has been hospitalized with bizarre symptoms or multi-system problems, with involvement by several specialists.
On subsequent visits, the process may be repeated in an abbreviated manner to obtain any new history, symptoms, physical findings, and lab or imaging results or specialist consultations.
# Branches of medicine
Working together as an interdisciplinary team, many highly trained health profession also besides medical practitioners are involved in the delivery of modern health care. Some examples include: nurse(s) emergency medical technicians and paramedics, laboratory scientists, (pharmacy, pharmacists), (physiotherapy,physiotherapists), respiratory therapists, speech therapists, occupational therapists, radiographers, dietitians and bioengineers.
The scope and sciences underpinning human medicine overlap many other fields. Dentistry and psychology, while separate disciplines from medicine, are considered medical fields.
Physicians have many specializations and subspecializations which are listed below. There are variations from country to country regarding which specialties certain subspecialities are in.
## Diagnostic specialties
- Clinical laboratory sciences are the clinical diagnostic services which apply laboratory techniques to diagnosis and management of patients. In the United States these services are supervised by a pathologist. The personnel that work in these medical laboratory departments are technically trained staff, each of whom usually hold a medical technology degree, who actually perform the tests, assays, and procedures needed for providing the specific services.
- Pathology is the branch of medicine that deals with the study of diseases and the morphologic, physiologic changes produced by them. As a diagnostic specialty, pathology can be considered the basis of modern scientific medical knowledge and plays a large role in evidence-based medicine. Many modern molecular tests such as flow cytometry, polymerase chain reaction (PCR), immunohistochemistry, cytogenetics, gene rearragements studies and fluorescent in situ hybridization (FISH) fall within the territory of pathology.
- Radiology is concerned with imaging of the human body, e.g. by x-rays, x-ray computed tomography, ultrasonography, and nuclear magnetic resonance tomography.
## Clinical disciplines
- Anesthesiology (AE) or anaesthesia (BE) is the clinical discipline concerned with providing anesthesia. Pain medicine is often practiced by specialised anesthesiologists/anesthetists.
- Dermatology is concerned with the skin and its diseases. In the UK, dermatology is a subspeciality of general medicine.
- Emergency medicine is concerned with the diagnosis and treatment of acute or life-threatening conditions, including trauma, surgical, medical, pediatric, and psychiatric emergencies.
- Gender-based medicine studies the biological and physiological differences between the human sexes and how that affects differences in disease.
- General practice, family practice, family medicine or primary care is, in many countries, the first port-of-call for patients with non-emergency medical problems. Family practitioners are usually able to treat over 90% of all complaints without referring to specialists.
- Geriatrics focuses on health promotion and the prevention and treatment of disease and disability in later life.
- Hospital medicine is the general medical care of hospitalized patients. Physicians whose primary professional focus is hospital medicine are called hospitalists in the USA.
- Internal medicine is concerned with systemic diseases of adults, i.e. those diseases that affect the body as a whole (restrictive, current meaning), or with all adult non-operative somatic medicine (traditional, inclusive meaning), thus excluding pediatrics, surgery, gynaecology and obstetrics, and psychiatry. There are several subdisciplines of internal medicine:
- Cardiology
Critical Care
Endocrinology
Gastroenterology
Hematology
Infectious Diseases
Intensive care medicine
Nephrology
Oncology
Pulmonology
Rheumatology
Urology
- Cardiology
- Critical Care
- Endocrinology
- Gastroenterology
- Hematology
- Infectious Diseases
- Intensive care medicine
- Nephrology
- Oncology
- Pulmonology
- Rheumatology
- Urology
- Neurology is concerned with the diagnosis and treatment of nervous system diseases. It is a subspeciality of general medicine in the UK.
- Obstetrics and gynaecology (often abbreviated as Ob/Gyn) are concerned respectively with childbirth and the female reproductive and associated organs. Reproductive medicine and fertility medicine are generally practiced by gynecological specialists.
- Palliative care is a relatively modern branch of clinical medicine that deals with pain and symptom relief and emotional support in patients with terminal illnesses including cancer and heart failure.
- Pediatrics (AE) or paediatrics (BE) is devoted to the care of infants, children, and adolescents. Like internal medicine, there are many pediatric subspecialities for specific age ranges, organ systems, disease classes, and sites of care delivery. Most subspecialities of adult medicine have a pediatric equivalent such as pediatric cardiology, pediatric endocrinology, pediatric gastroenterology, pediatric hematology, pediatric oncology, pediatric ophthalmology, and neonatology.
- Physical medicine and rehabilitation (or physiatry) is concerned with functional improvement after injury, illness, or congenital disorders.
- Preventive medicine is the branch of medicine concerned with preventing disease.
- Psychiatry is the branch of medicine concerned with the bio-psycho-social study of the etiology, diagnosis, treatment and prevention of cognitive, perceptual, emotional and behavioral disorders. Related non-medical fields include psychotherapy and clinical psychology.
- Radiation therapy is concerned with the therapeutic use of ionizing radiation and high energy elementary particle beams in patient treatment.
- Radiology is concerned with the interpretation of imaging modalities including x-rays, ultrasound, radioisotopes, and MRI (Magnetic Resonance Imaging). A newer branch of radiology, interventional radiology, is concerned with using medical devices to access areas of the body with minimally invasive techniques.
- Surgical specialties employ operative treatment. These include Orthopedics, Urology, Ophthalmology, Neurosurgery, Plastic Surgery, Otolaryngology and various subspecialties such as transplant and cardiothoracic. Some disciplines are highly specialized and are often not considered subdisciplines of surgery, although their naming might suggest so.
- Urgent care focuses on delivery of unscheduled, walk-in care outside of the hospital emergency department for injuries and illnesses that are not severe enough to require care in an emergency department.
## Interdisciplinary fields
Interdisciplinary sub-specialties of medicine are:
- Aerospace medicine deals with medical problems related to flying and space travel.
- Bioethics is a field of study which concerns the relationship between biology, science, medicine and ethics, philosophy and theology.
- Biomedical Engineering is a field dealing with the application of engineering principles to medical practice.
- Clinical pharmacology is concerned with how systems of therapeutics interact with patients.
- Conservation medicine studies the relationship between human and animal health, and environmental conditions. Also known as ecological medicine, environmental medicine, or medical geology.
- Disaster medicine deals with medical aspects of emergency preparedness, disaster mitigation and management.
- Diving medicine (or hyperbaric medicine) is the prevention and treatment of diving-related problems.
- Evolutionary medicine is a perspective on medicine derived through applying evolutionary theory.
- Forensic medicine deals with medical questions in legal context, such as determination of the time and cause of death.
- Keraunomedicine is the medical study of lightning casualties.
- Medical humanities includes the humanities (literature, philosophy, ethics, history and religion), social science (anthropology, cultural studies, psychology, sociology), and the arts (literature, theater, film, and visual arts) and their application to medical education and practice.
- Medical informatics, medical computer science, medical information and eHealth are relatively recent fields that deal with the application of computers and information technology to medicine.
- Naturopathic medicine is concerned with primary care, natural remedies, patient education and disease prevention.
- Nosology is the classification of diseases for various purposes.
- Occupational Medicine deals with medical problems related to work and the working environment.
- Osteopathic medicine claims that much disease results from problems with bones and joints.
- Pharmacogenomics is a form of individualized medicine.
- Sports medicine deals with the treatment and preventive care of athletes, amateur and professional. The team includes specialty physicians and surgeons, athletic trainers, physical therapists, coaches, other personnel, and, of course, the athlete.
- Therapeutics is the field, more commonly referenced in earlier periods of history, of the various remedies that can be used to treat disease and promote health .
- Travel medicine or emporiatrics deals with health problems of international travelers or travelers across highly different environments.
# Medical education
Medical education is education connected to the practice of being a medical practitioner, either the initial training to become a physician or further training thereafter.
Medical education and training varies considerably across the world, however typically involves entry level education at a university medical school, followed by a period of supervised practice (Internship and/or Residency) and possibly postgraduate vocational training. Continuing medical education is a requirement of many regulatory authorities.
Various teaching methodologies have been utilised in medical education, which is an active area of educational research.
Presently, in England, a typical medicine course at university is 5 years (4 if the student already holds a degree). Amongst some institutions and for some students, it may be 6 years (including the selection of an intercalated BSc - taking one year - at some point after the pre-clinical studies). This is followed by 2 Foundation years afterwards, namely F1 and F2. Students register with the UK General Medical Council at the end of F1. At the end of F2, they may pursue further years of study.
In the USA, a potential medical student must first complete an undergraduate degree (Typically a BSc with a major in biology, biochemistry or medical science), before applying to a graduate medical school to pursue the M.D.
In Australia, students have two options. They can choose to take a six-year undergraduate Bachelor of Medicine/Bachelor of Surgery (MBBS) straight from high school, or complete a undergraduate degree and and then a four year Bachelor of Medicine/Bachelor of Surgery (BMBS) program.
# Legal restrictions
In most countries, it is a legal requirement for medical doctors to be licensed or registered. In general, this entails a medical degree from a university and accreditation by a medical board or an equivalent national organization, which may ask the applicant to pass exams. This restricts the considerable legal authority of the medical profession to physicians that are trained and qualified by national standards. It is also intended as an assurance to patients and as a safeguard against charlatans that practice inadequate medicine for personal gain. While the laws generally require medical doctors to be trained in "evidence based", Western, or Hippocratic Medicine, they are not intended to discourage different paradigms of health.
# Criticism
Criticism of medicine has a long history. In the Middle Ages, some people did not consider it a profession suitable for Christians, as disease was often considered God-sent. God was considered to be the 'divine physician' who sent illness or healing depending on his will. However many monastic orders, particularly the Benedictines, considered the care of the sick as their chief work of mercy. Barber-surgeons generally had a bad reputation that was not to improve until the development of academic surgery as a speciality of medicine, rather than an accessory field.
Through the course of the twentieth century, healthcare providers focused increasingly on the technology that was enabling them to make dramatic improvements in patients' health. The ensuing development of a more mechanistic, detached practice, with the perception of an attendant loss of patient-focused care, known as the medical model of health, led to further criticisms. This issue started to reach collective professional consciousness in the 1970s and the profession had begun to respond by the 1980s and 1990s.
The noted anarchist Ivan Illich heavily criticized modern medicine. In his 1976 work Medical Nemesis, Illich stated that modern medicine only medicalises disease and causes loss of health and wellness, while generally failing to restore health by eliminating disease. This medicalisation of disease forces the human to become a lifelong patient.Other less radical philosophers have voiced similar views, but none were as virulent as Illich. Another example can be found in Technopoly: The Surrender of Culture to Technology by Neil Postman, 1992, which criticises overreliance on technological means in medicine.
Criticism of modern medicine has led to some improvements in the curricula of medical schools, which now teach students systematically on medical ethics, holistic approaches to medicine, the biopsychosocial model and similar concepts.
The inability of modern medicine to properly address some common complaints continues to prompt many people to seek support from alternative medicine. Although most alternative approaches lack scientific validation, some may be effective in individual cases. Some physicians combine alternative medicine with orthodox approaches.
Medical errors and overmedication are also the focus of many complaints and negative coverage. Practitioners of human factors engineering believe that there is much that medicine may usefully gain by emulating concepts in aviation safety, where it was long ago realized that it is dangerous to place too much responsibility on one "superhuman" individual and expect him or her not to make errors. Reporting systems and checking mechanisms are becoming more common in identifying sources of error and improving practice. | Medicine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Medicine is the science and "art" of maintaining and/or restoring human health through the study, diagnosis, and treatment of patients.
The term is derived from the Latin ars medicina meaning the art of healing. [1][2]
The modern practice of medicine occurs at the many interfaces between the art of healing and various sciences. Medicine is directly connected to the health sciences and biomedicine. Broadly speaking, the term 'Medicine' today refers to the fields of clinical medicine, medical research and surgery, thereby covering the challenges of disease and injury.
# Overview
Since the 19th century, only those with a medical degree have been considered worthy to practice medicine. Clinicians (licensed professionals who deal with patients) can be physicians, physical therapists, physician assistants, nurses or others. The medical profession is the social and occupational structure of the group of people formally trained and authorized to apply medical knowledge. Many countries and legal jurisdictions have legal limitations on who may practice medicine.
Medicine comprises various specialized sub-branches, such as cardiology, pulmonology, neurology, or other fields such as sports medicine, research or public health.
Human societies have had various different systems of health care practice since at least the beginning of recorded history. Medicine, in the modern period, is the mainstream scientific tradition which developed in the Western world since the early Renaissance (around 1450). Many other traditions of health care are still practiced throughout the world; most of these are separate from Western medicine, which is also called biomedicine, allopathic medicine or the Hippocratic tradition. The most highly developed of these are traditional Chinese medicine, Traditional Tibetan medicine and the Ayurvedic traditions of India and Sri Lanka. Various non-mainstream traditions of health care have also developed in the Western world. These systems are sometimes considered companions to Hippocratic medicine, and sometimes are seen as competition to the Western tradition. Few of them have any scientific confirmation of their tenets, because if they did they would be brought into the fold of Western medicine.
"Medicine" is also often used amongst medical professionals as shorthand for internal medicine. Veterinary medicine is the practice of health care in animal species other than human beings.
# History of medicine
The earliest type of medicine in most cultures was the use of plants (Herbalism) and animal parts. This was usually in concert with 'magic' of various kinds in which: animism (the notion of inanimate objects having spirits); spiritualism (here meaning an appeal to gods or communion with ancestor spirits); shamanism (the vesting of an individual with mystic powers); and divination (the supposed obtaining of truth by magic means), played a major role.
The practice of medicine developed gradually, and separately, in Ancient Egypt, Ancient India, Ancient China, Ancient Greece, Ancient Persia and elsewhere. Medicine as it is practiced now developed largely in the late eighteenth century and early nineteenth century in England (William Harvey, seventeenth century), Germany (Rudolf Virchow) and France (Jean-Martin Charcot, Claude Bernard and others). The new, "scientific" medicine (where results are testable and repeatable) replaced early Western traditions of medicine, based on herbalism, the Greek "four humours" and other pre-modern theories. The focal points of development of clinical medicine shifted to the United Kingdom and the USA by the early 1900s (Canadian-born) Sir William Osler, Harvey Cushing). Possibly the major shift in medical thinking was the gradual rejection in the 1400s during the Black Death of what may be called the 'traditional authority' approach to science and medicine. This was the notion that because some prominent person in the past said something must be so, then that was the way it was, and anything one observed to the contrary was an anomaly (which was paralleled by a similar shift in European society in general - see Copernicus's rejection of Ptolemy's theories on astronomy). People like Vesalius led the way in improving upon or indeed rejecting the theories of great authorities from the past such as Galen, Hippocrates, and Avicenna/Ibn Sina, all of whose theories were in time almost totally discredited. Such new attitudes were also only made possible by the weakening of the Roman Catholic church's power in society, especially in the Republic of Venice.
Evidence-based medicine is a recent movement to establish the most effective algorithms of practice (ways of doing things) through the use of the scientific method and modern global information science by collating all the evidence and developing standard protocols which are then disseminated to healthcare providers. One problem with this 'best practice' approach is that it could be seen to stifle novel approaches to treatment.
Genomics and knowledge of human genetics is already having some influence on medicine, as the causative genes of most monogenic genetic disorders have now been identified, and the development of techniques in molecular biology and genetics are influencing medical practice and decision-making.
Pharmacology has developed from herbalism and many drugs are still derived from plants (atropine, ephedrine, warfarin, aspirin, digoxin, vinca alkaloids, taxol, hyoscine, etc). The modern era began with Robert Koch's discoveries around 1880 of the transmission of disease by bacteria, and then the discovery of antibiotics shortly thereafter around 1900. The first of these was arsphenamine / Salvarsan discovered by Paul Ehrlich in 1908 after he observed that bacteria took up toxic dyes that human cells did not. The first major class of antibiotics was the sulfa drugs, derived by French chemists originally from azo dyes. Throughout the twentieth century, major advances in the treatment of infectious diseases were observable in (Western) societies. The medical establishment is now developing drugs targeted towards one particular disease process. Thus drugs are being developed to minimise the side effects of prescribed drugs, to treat cancer, geriatric problems, long-term problems (such as high cholesterol), chronic diseases type 2 diabetes, lifestyle and degenerative diseases such as arthritis and Alzheimer's disease.
# Practice of medicine
The practice of medicine combines both science as the evidence base and art in the application of this medical knowledge in combination with intuition and clinical judgment to determine the treatment plan for each patient.
Central to medicine is the patient-physician relationship established when a person with a health concern seeks a physician's help; the 'medical encounter'. Other health professionals similarly establish a relationship with a patient and may perform various interventions, e.g. nurses, radiographers and therapists.
As part of the medical encounter, the healthcare provider needs to:
- develop a relationship with the patient
- gather data (medical history, systems enquiry, and physical examination, combined with laboratory or imaging studies (investigations))
- analyze and synthesize that data (assessment and/or differential diagnoses), and then:
- develop a treatment plan (further testing, therapy, watchful observation, referral and follow-up)
- treat the patient accordingly
- assess the progress of treatment and alter the plan as necessary (management).
The medical encounter is documented in a medical record, which is a legal document in many jurisdictions.[3]
## Health care delivery systems
Medicine is practiced within the medical system, which is a legal, credentialing and financing framework, established by a particular culture or government. The characteristics of a health care system have significant effect on the way medical care is delivered.
Financing has a great influence as it defines who pays the costs. Aside from tribal cultures, the most significant divide in developed countries is between universal health care and market-based health care (such as practiced in the U.S.). Universal health care might allow or ban a parallel private market. The latter is described as single-payer system.
Transparency of information is another factor defining a delivery system. Access to information on conditions, treatments, quality and pricing greatly affects the choice by patients / consumers and therefore the incentives of medical professionals. While US health care system has come under fire for lack of openness, new legislation may encourage greater openness. There is a perceived tension between the need for transparency on the one hand and such issues as patient confidentiality and the possible exploitation of information for commercial gain on the other.
## Health care delivery
Medical care delivery is classified into primary, secondary and tertiary care.
Primary care medical services are provided by physicians or other health professionals who have first contact with a patient seeking medical treatment or care. These occur in physician offices, clinics, nursing homes, schools, home visits and other places close to patients. About 90% of medical visits can be treated by the primary care provider. These include treatment of acute and chronic illnesses, preventive care and health education for all ages and both sexes.
Secondary care medical services are provided by medical specialists in their offices or clinics or at local community hospitals for a patient referred by a primary care provider who first diagnosed or treated the patient. Referrals are made for those patients who required the expertise or procedures performed by specialists. These include both ambulatory care and inpatient services, emergency rooms, intensive care medicine, surgery services, physical therapy, labor and delivery, endoscopy units, diagnostic laboratory and medical imaging services, hospice centers, etc. Some primary care providers may also take care of hospitalized patients and deliver babies in a secondary care setting.
Tertiary care medical services are provided by specialist hospitals or regional centers equipped with diagnostic and treatment facilities not generally available at local hospitals. These include trauma centers, burn treatment centers, advanced neonatology unit services, organ transplants, high-risk pregnancy, radiation oncology, etc.
Modern medical care also depends on information - still delivered in many health care settings on paper records, but increasingly nowadays by electronic means.
## Patient-physician-relationship
This kind of relationship and interaction is a central process in the practice of medicine. There are many perspectives from which to understand and describe it.
An idealized physician's perspective, such as is taught in medical school, sees the core aspects of the process as the physician learning the patient's symptoms, concerns and values; in response the physician examines the patient, interprets the symptoms, and formulates a diagnosis to explain the symptoms and their cause to the patient and to propose a treatment. The job of a physician is similar to a human biologist: that is, to know the human frame and situation in terms of normality. Once the physician knows what is normal and can measure the patient against those norms, he or she can then determine the particular departure from the normal and the degree of departure. This is called the diagnosis.
The four great cornerstones of diagnostic medicine are anatomy (structure: what is there), physiology (how the structure/s work), pathology (what goes wrong with the anatomy and physiology) and psychology (mind and behavior). In addition, the physician should consider the patient in their 'well' context rather than simply as a walking medical condition. This means the socio-political context of the patient (family, work, stress, beliefs) should be assessed as it often offers vital clues to the patient's condition and further management. In more detail, the patient presents a set of complaints (the symptoms) to the physician, who then obtains further information about the patient's symptoms, previous state of health, living conditions, and so forth. The physician then makes a review of systems (ROS) or systems inquiry, which is a set of ordered questions about each major body system in order: general (such as weight loss), endocrine, cardio-respiratory, etc. Next comes the actual physical examination; the findings are recorded, leading to a list of possible diagnoses. These will be in order of probability. The next task is to enlist the patient's agreement to a management plan, which will include treatment as well as plans for follow-up. Importantly, during this process the healthcare provider educates the patient about the causes, progression, outcomes, and possible treatments of his ailments, as well as often providing advice for maintaining health. This teaching relationship is the basis of calling the physician doctor, which originally meant "teacher" in Latin. The patient-physician relationship is additionally complicated by the patient's suffering (patient derives from the Latin patior, "suffer") and limited ability to relieve it on his/her own. The physician's expertise comes from his knowledge of what is healthy and normal contrasted with knowledge and experience of other people who have suffered similar symptoms (unhealthy and abnormal), and the proven ability to relieve it with medicines (pharmacology) or other therapies about which the patient may initially have little knowledge.
The physician-patient relationship can be analyzed from the perspective of ethical concerns, in terms of how well the goals of non-maleficence, beneficence, autonomy, and justice are achieved. Many other values and ethical issues can be added to these. In different societies, periods, and cultures, different values may be assigned different priorities. For example, in the last 30 years medical care in the Western World has increasingly emphasized patient autonomy in decision making.
The relationship and process can also be analyzed in terms of social power relationships (e.g., by Michel Foucault), or economic transactions. Physicians have been accorded gradually higher status and respect over the last century, and they have been entrusted with control of access to prescription medicines as a public health measure. This represents a concentration of power and carries both advantages and disadvantages to particular kinds of patients with particular kinds of conditions. A further twist has occurred in the last 25 years as costs of medical care have risen, and a third party (an insurance company or government agency) now often insists upon a share of decision-making power for a variety of reasons, reducing freedom of choice of healthcare providers and patients in many ways.
The quality of the patient-physician relationship is important to both parties. The better the relationship in terms of mutual respect, knowledge, trust, shared values and perspectives about disease and life, and time available, the better will be the amount and quality of information about the patient's disease transferred in both directions, enhancing accuracy of diagnosis and increasing the patient's knowledge about the disease. Where such a relationship is poor the physician's ability to make a full assessment is compromised and the patient is more likely to distrust the diagnosis and proposed treatment. In these circumstances and also in cases where there is genuine divergence of medical opinions, a second opinion from another physician may be sought.
In some settings, e.g. the hospital ward, the patient-physician relationship is much more complex, and many other people are involved when somebody is ill: relatives, neighbors, rescue specialists, nurses, technical personnel, social workers and others.
## Clinical skills
A complete medical evaluation includes a medical history, a systems enquiry, a physical examination, appropriate laboratory or imaging studies, analysis of data and medical decision making to obtain diagnoses, and a treatment plan.[4]
The components of the medical history are:
- Chief complaint (CC): the reason for the current medical visit. These are the 'symptoms.' They are in the patient's own words and are recorded along with the duration of each one. Also called 'presenting complaint.'
- History of present illness / complaint (HPI): the chronological order of events of symptoms and further clarification of each symptom.
- Current activity: occupation, hobbies, what the patient actually does.
- Medications (DHx): what drugs the patient takes including prescribed, over-the-counter, and home remedies, as well as alternative and herbal medicines/herbal remedies such as St John's wort. Allergies are also recorded.
- Past medical history (PMH/PMHx): concurrent medical problems, past hospitalizations and operations, injuries, past infectious diseases and/or vaccinations, history of known allergies.
- Social history (SH): birthplace, residences, marital history, social and economic status, habits (including diet, medications, tobacco, alcohol).
- Family history (FH): listing of diseases in the family that may impact the patient. A family tree is sometimes used.
- Review of systems (ROS) or systems inquiry: a set of additional questions to ask which may be missed on HPI: a general enquiry (have you noticed any weight loss, fevers, lumps and bumps? etc), followed by questions on the body's main organ systems (heart, lungs, digestive tract, urinary tract, etc).
The physical examination is the examination of the patient looking for signs of disease ('Symptoms' are what the patient volunteers, 'Signs' are what the healthcare provider detects by examination). The healthcare provider uses the senses of sight, hearing, touch, and sometimes smell (taste has been made redundant by the availability of modern lab tests). Four chief methods are used: inspection, palpation (feel), percussion (tap to determine resonance characteristics), and auscultation (listen); smelling may be useful (e.g. infection, uremia, diabetic ketoacidosis). The clinical examination involves study of:
- Vital signs including height, weight, body temperature, blood pressure, pulse, respiration rate, hemoglobin oxygen saturation
- General appearance of the patient and specific indicators of disease (nutritional status, presence of jaundice, pallor or clubbing)
- Skin
- Head, eye, ear, nose, and throat (HEENT)
- Cardiovascular (heart and blood vessels)
- Respiratory (large airways and lungs)
- Abdomen and rectum
- Genitalia (and pregnancy if the patient is or could be pregnant)
- Musculoskeletal (spine and extremities)
- Neurological (consciousness, awareness, brain, cranial nerves, spinal cord and peripheral nerves)
- Psychiatric (orientation, mental state, evidence of abnormal perception or thought)
Laboratory and imaging studies results may be obtained, if necessary.
The medical decision-making (MDM) process involves analysis and synthesis of all the above data to come up with a list of possible diagnoses (the differential diagnoses), along with an idea of what needs to be done to obtain a definitive diagnosis that would explain the patient's problem.
The treatment plan may include ordering additional laboratory tests and studies, starting therapy, referral to a specialist, or watchful observation. Follow-up may be advised.
This process is used by primary care providers as well as specialists. It may take only a few minutes if the problem is simple and straightforward. On the other hand, it may take weeks in a patient who has been hospitalized with bizarre symptoms or multi-system problems, with involvement by several specialists.
On subsequent visits, the process may be repeated in an abbreviated manner to obtain any new history, symptoms, physical findings, and lab or imaging results or specialist consultations.
# Branches of medicine
Working together as an interdisciplinary team, many highly trained health profession also besides medical practitioners are involved in the delivery of modern health care. Some examples include: nurse(s) emergency medical technicians and paramedics, laboratory scientists, (pharmacy, pharmacists), (physiotherapy,physiotherapists), respiratory therapists, speech therapists, occupational therapists, radiographers, dietitians and bioengineers.
The scope and sciences underpinning human medicine overlap many other fields. Dentistry and psychology, while separate disciplines from medicine, are considered medical fields.
Physicians have many specializations and subspecializations which are listed below. There are variations from country to country regarding which specialties certain subspecialities are in.
## Diagnostic specialties
- Clinical laboratory sciences are the clinical diagnostic services which apply laboratory techniques to diagnosis and management of patients. In the United States these services are supervised by a pathologist. The personnel that work in these medical laboratory departments are technically trained staff, each of whom usually hold a medical technology degree, who actually perform the tests, assays, and procedures needed for providing the specific services.
- Pathology is the branch of medicine that deals with the study of diseases and the morphologic, physiologic changes produced by them. As a diagnostic specialty, pathology can be considered the basis of modern scientific medical knowledge and plays a large role in evidence-based medicine. Many modern molecular tests such as flow cytometry, polymerase chain reaction (PCR), immunohistochemistry, cytogenetics, gene rearragements studies and fluorescent in situ hybridization (FISH) fall within the territory of pathology.
- Radiology is concerned with imaging of the human body, e.g. by x-rays, x-ray computed tomography, ultrasonography, and nuclear magnetic resonance tomography.
## Clinical disciplines
- Anesthesiology (AE) or anaesthesia (BE) is the clinical discipline concerned with providing anesthesia. Pain medicine is often practiced by specialised anesthesiologists/anesthetists.
- Dermatology is concerned with the skin and its diseases. In the UK, dermatology is a subspeciality of general medicine.
- Emergency medicine is concerned with the diagnosis and treatment of acute or life-threatening conditions, including trauma, surgical, medical, pediatric, and psychiatric emergencies.
- Gender-based medicine studies the biological and physiological differences between the human sexes and how that affects differences in disease.
- General practice, family practice, family medicine or primary care is, in many countries, the first port-of-call for patients with non-emergency medical problems. Family practitioners are usually able to treat over 90% of all complaints without referring to specialists.
- Geriatrics focuses on health promotion and the prevention and treatment of disease and disability in later life.
- Hospital medicine is the general medical care of hospitalized patients. Physicians whose primary professional focus is hospital medicine are called hospitalists in the USA.
- Internal medicine is concerned with systemic diseases of adults, i.e. those diseases that affect the body as a whole (restrictive, current meaning), or with all adult non-operative somatic medicine (traditional, inclusive meaning), thus excluding pediatrics, surgery, gynaecology and obstetrics, and psychiatry. There are several subdisciplines of internal medicine:
- Cardiology
Critical Care
Endocrinology
Gastroenterology
Hematology
Infectious Diseases
Intensive care medicine
Nephrology
Oncology
Pulmonology
Rheumatology
Urology
- Cardiology
- Critical Care
- Endocrinology
- Gastroenterology
- Hematology
- Infectious Diseases
- Intensive care medicine
- Nephrology
- Oncology
- Pulmonology
- Rheumatology
- Urology
- Neurology is concerned with the diagnosis and treatment of nervous system diseases. It is a subspeciality of general medicine in the UK.
- Obstetrics and gynaecology (often abbreviated as Ob/Gyn) are concerned respectively with childbirth and the female reproductive and associated organs. Reproductive medicine and fertility medicine are generally practiced by gynecological specialists.
- Palliative care is a relatively modern branch of clinical medicine that deals with pain and symptom relief and emotional support in patients with terminal illnesses including cancer and heart failure.
- Pediatrics (AE) or paediatrics (BE) is devoted to the care of infants, children, and adolescents. Like internal medicine, there are many pediatric subspecialities for specific age ranges, organ systems, disease classes, and sites of care delivery. Most subspecialities of adult medicine have a pediatric equivalent such as pediatric cardiology, pediatric endocrinology, pediatric gastroenterology, pediatric hematology, pediatric oncology, pediatric ophthalmology, and neonatology.
- Physical medicine and rehabilitation (or physiatry) is concerned with functional improvement after injury, illness, or congenital disorders.
- Preventive medicine is the branch of medicine concerned with preventing disease.
- Psychiatry is the branch of medicine concerned with the bio-psycho-social study of the etiology, diagnosis, treatment and prevention of cognitive, perceptual, emotional and behavioral disorders. Related non-medical fields include psychotherapy and clinical psychology.
- Radiation therapy is concerned with the therapeutic use of ionizing radiation and high energy elementary particle beams in patient treatment.
- Radiology is concerned with the interpretation of imaging modalities including x-rays, ultrasound, radioisotopes, and MRI (Magnetic Resonance Imaging). A newer branch of radiology, interventional radiology, is concerned with using medical devices to access areas of the body with minimally invasive techniques.
- Surgical specialties employ operative treatment. These include Orthopedics, Urology, Ophthalmology, Neurosurgery, Plastic Surgery, Otolaryngology and various subspecialties such as transplant and cardiothoracic. Some disciplines are highly specialized and are often not considered subdisciplines of surgery, although their naming might suggest so.
- Urgent care focuses on delivery of unscheduled, walk-in care outside of the hospital emergency department for injuries and illnesses that are not severe enough to require care in an emergency department.
## Interdisciplinary fields
Interdisciplinary sub-specialties of medicine are:
- Aerospace medicine deals with medical problems related to flying and space travel.
- Bioethics is a field of study which concerns the relationship between biology, science, medicine and ethics, philosophy and theology.
- Biomedical Engineering is a field dealing with the application of engineering principles to medical practice.
- Clinical pharmacology is concerned with how systems of therapeutics interact with patients.
- Conservation medicine studies the relationship between human and animal health, and environmental conditions. Also known as ecological medicine, environmental medicine, or medical geology.
- Disaster medicine deals with medical aspects of emergency preparedness, disaster mitigation and management.
- Diving medicine (or hyperbaric medicine) is the prevention and treatment of diving-related problems.
- Evolutionary medicine is a perspective on medicine derived through applying evolutionary theory.
- Forensic medicine deals with medical questions in legal context, such as determination of the time and cause of death.
- Keraunomedicine is the medical study of lightning casualties.
- Medical humanities includes the humanities (literature, philosophy, ethics, history and religion), social science (anthropology, cultural studies, psychology, sociology), and the arts (literature, theater, film, and visual arts) and their application to medical education and practice.
- Medical informatics, medical computer science, medical information and eHealth are relatively recent fields that deal with the application of computers and information technology to medicine.
- Naturopathic medicine is concerned with primary care, natural remedies, patient education and disease prevention.
- Nosology is the classification of diseases for various purposes.
- Occupational Medicine deals with medical problems related to work and the working environment.
- Osteopathic medicine claims that much disease results from problems with bones and joints.
- Pharmacogenomics is a form of individualized medicine.
- Sports medicine deals with the treatment and preventive care of athletes, amateur and professional. The team includes specialty physicians and surgeons, athletic trainers, physical therapists, coaches, other personnel, and, of course, the athlete.
- Therapeutics is the field, more commonly referenced in earlier periods of history, of the various remedies that can be used to treat disease and promote health [2].
- Travel medicine or emporiatrics deals with health problems of international travelers or travelers across highly different environments.
# Medical education
Medical education is education connected to the practice of being a medical practitioner, either the initial training to become a physician or further training thereafter.
Medical education and training varies considerably across the world, however typically involves entry level education at a university medical school, followed by a period of supervised practice (Internship and/or Residency) and possibly postgraduate vocational training. Continuing medical education is a requirement of many regulatory authorities.
Various teaching methodologies have been utilised in medical education, which is an active area of educational research.
Presently, in England, a typical medicine course at university is 5 years (4 if the student already holds a degree). Amongst some institutions and for some students, it may be 6 years (including the selection of an intercalated BSc - taking one year - at some point after the pre-clinical studies). This is followed by 2 Foundation years afterwards, namely F1 and F2. Students register with the UK General Medical Council at the end of F1. At the end of F2, they may pursue further years of study.
In the USA, a potential medical student must first complete an undergraduate degree (Typically a BSc with a major in biology, biochemistry or medical science), before applying to a graduate medical school to pursue the M.D.
In Australia, students have two options. They can choose to take a six-year undergraduate Bachelor of Medicine/Bachelor of Surgery (MBBS) straight from high school, or complete a undergraduate degree and and then a four year Bachelor of Medicine/Bachelor of Surgery (BMBS) program.
# Legal restrictions
In most countries, it is a legal requirement for medical doctors to be licensed or registered. In general, this entails a medical degree from a university and accreditation by a medical board or an equivalent national organization, which may ask the applicant to pass exams. This restricts the considerable legal authority of the medical profession to physicians that are trained and qualified by national standards. It is also intended as an assurance to patients and as a safeguard against charlatans that practice inadequate medicine for personal gain. While the laws generally require medical doctors to be trained in "evidence based", Western, or Hippocratic Medicine, they are not intended to discourage different paradigms of health.
# Criticism
Criticism of medicine has a long history. In the Middle Ages, some people did not consider it a profession suitable for Christians, as disease was often considered God-sent. God was considered to be the 'divine physician' who sent illness or healing depending on his will. However many monastic orders, particularly the Benedictines, considered the care of the sick as their chief work of mercy. Barber-surgeons generally had a bad reputation that was not to improve until the development of academic surgery as a speciality of medicine, rather than an accessory field.
Through the course of the twentieth century, healthcare providers focused increasingly on the technology that was enabling them to make dramatic improvements in patients' health. The ensuing development of a more mechanistic, detached practice, with the perception of an attendant loss of patient-focused care, known as the medical model of health, led to further criticisms. This issue started to reach collective professional consciousness in the 1970s and the profession had begun to respond by the 1980s and 1990s.
The noted anarchist Ivan Illich heavily criticized modern medicine. In his 1976 work Medical Nemesis, Illich stated that modern medicine only medicalises disease and causes loss of health and wellness, while generally failing to restore health by eliminating disease. This medicalisation of disease forces the human to become a lifelong patient.[5]Other less radical philosophers have voiced similar views, but none were as virulent as Illich. Another example can be found in Technopoly: The Surrender of Culture to Technology by Neil Postman, 1992, which criticises overreliance on technological means in medicine.
Criticism of modern medicine has led to some improvements in the curricula of medical schools, which now teach students systematically on medical ethics, holistic approaches to medicine, the biopsychosocial model and similar concepts.
The inability of modern medicine to properly address some common complaints continues to prompt many people to seek support from alternative medicine. Although most alternative approaches lack scientific validation, some may be effective in individual cases. Some physicians combine alternative medicine with orthodox approaches.
Medical errors and overmedication are also the focus of many complaints and negative coverage. Practitioners of human factors engineering believe that there is much that medicine may usefully gain by emulating concepts in aviation safety, where it was long ago realized that it is dangerous to place too much responsibility on one "superhuman" individual and expect him or her not to make errors. Reporting systems and checking mechanisms are becoming more common in identifying sources of error and improving practice. | https://www.wikidoc.org/index.php/Clinical_medicine | |
fe59341001651a52d8947fb220304d7aa9764eeb | wikidoc | Sulindac | Sulindac
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# Black Box Warning
# Overview
Sulindac is a non-steroidal anti-inflammatory drug that is FDA approved for the {{{indicationType}}} of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis), acute gouty arthritis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema, pruritus, rash, abdominal cramps, abdominal pain, constipation, diarrhea, flatulence, indigestion, loss of appetite, nausea, vomiting, dizziness, headache, and tinnitus.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended starting dosage is 150 mg twice a day. The dosage may be lowered or raised depending on the response.
- The recommended starting dosage is 150 mg twice a day. The dosage may be lowered or raised depending on the response.
- The recommended starting dosage is 150 mg twice a day. The dosage may be lowered or raised depending on the response.
- The recommended dosage is 200 mg twice a day. After a satisfactory response has been achieved, the dosage may be reduced according to the response. In acute painful shoulder, therapy for 7-14 days is usually adequate.
- The recommended dosage is 200 mg twice a day. After a satisfactory response has been achieved, the dosage may be reduced according to the response. In acute gouty arthritis, therapy for 7 days is usually adequate.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sulindac in adult patients.
### Non–Guideline-Supported Use
- Sulindac was given twice daily, started as 75 milligrams per dose in patients weighing up to 44 kg; heavier patients began with 150 mg twice daily.
- 4-year regimen of oral sulindac.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Sulindac in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sulindac in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sulindac in pediatric patients.
# Contraindications
- Sulindac is contraindicated in patients with known hypersensitivity to sulindac or the excipients.
- Sulindac should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic/anaphylactoid reactions to NSAIDs have been reported in such patients.
- Sulindac is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.
# Warnings
- Cardiovascular Thrombotic Events
- Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
- There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events.
- Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.
- Hypertension
- NSAIDs, including sulindac, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including sulindac, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
- Congestive Heart Failure and Edema
- Fluid retention and edema have been observed in some patients taking NSAIDs. Sulindac should be used with caution in patients with fluid retention or heart failure.
- NSAIDs, including sulindac, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
- NSAIDs should be prescribed with extreme caution in those with prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.
- To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
- In addition to hypersensitivity reactions involving the liver, in some patients the findings are consistent with those of cholestatic hepatitis. As with other non-steroidal anti-inflammatory drugs, borderline elevations of one or more liver tests without any other signs and symptoms may occur in up to 15% of patients taking NSAIDs including sulindac. These laboratory abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction. Meaningful (3 times the upper limit of normal) elevations of SGPT or SGOT (AST) occurred in controlled clinical trials in less than 1% of patients. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
- A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with sulindac. Although such reactions as described above are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), sulindac should be discontinued.
- In clinical trials with sulindac, the use of doses of 600 mg/day has been associated with an increased incidence of mild liver test abnormalities.
- Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a non-steroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, patients who are volume-depleted, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
- Advanced Renal Disease
- No information is available from controlled clinical studies regarding the use of sulindac in patients with advanced renal disease. Therefore, treatment with sulindac is not recommended in these patients with advanced renal disease. If sulindac therapy must be initiated, close monitoring of the patient’s renal function is advisable.
- As with other NSAIDs, anaphylactic/anaphylactoid reactions may occur in patients without known prior exposure to sulindac. Sulindac should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. Emergency help should be sought in cases where an anaphylactic/anaphylactoid reaction occurs.
- Skin Reactions
- NSAIDs, including sulindac, can cause serious adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
- Hypersensitivity
- Rarely, fever and other evidence of hypersensitivity including abnormalities in one or more liver function tests and severe skin reactions have occurred during therapy with sulindac. Fatalities have occurred in these patients. Hepatitis, jaundice, or both, with or without fever, may occur usually within the first one to three months of therapy. Determinations of liver function should be considered whenever a patient on therapy with sulindac develops unexplained fever, rash or other dermatologic reactions or constitutional symptoms. If unexplained fever or other evidence of hypersensitivity occurs, therapy with sulindac should be discontinued. The elevated temperature and abnormalities in liver function caused by sulindac characteristically have reverted to normal after discontinuation of therapy. Administration of sulindac should not be reinstituted in such patients.
- In late pregnancy, as with other NSAIDs, sulindac should be avoided because it may cause premature closure of the ductus arteriosus.
### Precautions
- General
- Sulindac cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
- The pharmacological activity of sulindac in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
- Hematological Effects
- Anemia is sometimes seen in patients receiving NSAIDs, including sulindac. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including sulindac, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
- NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving sulindac who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
- Preexisting Asthma
- Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, sulindac should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
- Renal Calculi
- Sulindac metabolites have been reported rarely as the major or a minor component in renal stones in association with other calculus components. Sulindac should be used with caution in patients with a history of renal lithiasis, and they should be kept well hydrated while receiving sulindac.
- Pancreatitis
- Pancreatitis has been reported in patients receiving sulindac. Should pancreatitis be suspected, the drug should be discontinued and not restarted, supportive medical therapy instituted, and the patient monitored closely with appropriate laboratory studies (e.g., serum and urine amylase, amylase/creatinine clearance ratio, electrolytes, serum calcium, glucose, lipase, etc.). A search for other causes of pancreatitis as well as those conditions which mimic pancreatitis should be conducted.
- Ocular Effects
- Because of reports of adverse eye findings with non-steroidal anti-inflammatory agents, it is recommended that patients who develop eye complaints during treatment with sulindac have ophthalmologic studies.
- Hepatic Insufficiency
- In patients with poor liver function, delayed, elevated and prolonged circulating levels of the sulfide and sulfone metabolites may occur. Such patients should be monitored closely; a reduction of daily dosage may be required.
- SLE and Mixed Connective Tissue Disease
- In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease, there may be an increased risk of aseptic meningitis.
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions were reported in clinical trials or have been reported since the drug was marketed. The probability exists of a causal relationship between sulindac and these adverse reactions. The adverse reactions which have been observed in clinical trials encompass observations in 1,865 patients, including 232 observed for at least 48 weeks.
- Incidence Greater Than 1%
The most frequent types of adverse reactions occurring with sulindac are gastrointestinal; these include gastrointestinal pain (10%), dyspepsia*, nausea* with or without vomiting, diarrhea*, constipation*, flatulence, anorexia and gastrointestinal cramps.
Rash*, pruritus
Dizziness*, headache*, nervousness.
Tinnitus.
Edema.
- Incidence Less Than 1 in 100
Gastritis, gastroenteritis or colitis. Peptic ulcer and gastrointestinal bleeding have been reported. GI perforation and intestinal strictures (diaphragms) have been reported rarely.
Liver function abnormalities; jaundice, sometimes with fever; cholestasis; hepatitis; hepatic failure.
There have been rare reports of sulindac metabolites in common bile duct “sludge” and in biliary calculi in patients with symptoms of cholecystitis who underwent a cholecystectomy.
Pancreatitis.
Ageusia; glossitis.
Stomatitis, sore or dry mucous membranes, alopecia, photosensitivity.
Erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, and exfoliative dermatitis have been reported.
Congestive heart failure, especially in patients with marginal cardiac function; palpitation; hypertension.
Thrombocytopenia; ecchymosis, purpura, leukopenia, agranulocytosis, neutropenia, bone marrow depression, including aplastic anemia; hemolytic anemia, increased prothrombin time in patients on oral anticoagulants.
Urine discoloration; dysuria; vaginal bleeding, hematuria; proteinuria; crystalluria; renal impairment, including renal failure; interstitial nephritis; nephrotic syndrome.
Renal calculi containing sulindac metabolites have been observed rarely.
Hyperkalemia.
Muscle weakness.
Depression; psychic disturbances including acute psychosis.
Vertigo; insomnia; somnolence; paresthesia; convulsions; syncope; aseptic meningitis (especially in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease).
Blurred vision; visual disturbances; decreased hearing; metallic or bitter taste.
Epistaxis.
Anaphylaxis; angioneurotic edema; urticaria; bronchial spasm; dyspnea.
Hypersensitivity vasculitis.
A potentially fatal apparent hypersensitivity syndrome has been reported. This syndrome may include constitutional symptoms (fever, chills, diaphoresis, flushing), cutaneous findings (rash or other dermatologic reactions – see above), conjunctivitis, involvement of major organs (changes in liver function including hepatic failure, jaundice, pancreatitis, pneumonitis with or without pleural effusion, leukopenia, leukocytosis, eosinophilia, disseminated intravascular coagulation, anemia, renal impairment, including renal failure), and other less specific findings (adenitis, arthralgia, arthritis, myalgia, fatigue, malaise, hypotension, chest pain, tachycardia).
- Causal Relationship Unknown
- A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group A β-hemolytic streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents, sometimes with fatal outcome.
- Other reactions have been reported in clinical trials or since the drug was marketed, but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, that possibility cannot be excluded. Therefore, these observations are listed to serve as alerting information to physicians.
Arrhythmia.
Hyperglycemia.
Neuritis.
Disturbances of the retina and its vasculature.
Gynecomastia.
.*Incidence between 3% and 9%. Those reactions occurring in 1% to 3% of patients are not marked with an asterisk.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Sulindac in the drug label.
# Drug Interactions
- Ace Inhibitors and Angiotensin II Antagonists
- Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors and angiotensin II antagonists. These interactions should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors or angiotensin II antagonists. In some patients with compromised renal function (e.g. elderly patients or patients who are volume-depleted, including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory drugs, the co-administration of an NSAID and an ACE-inhibitor or an angiotensin II antagonist may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, monitor renal function periodically in patients receiving ACEIs or AIIAs and NSAIDs in combination therapy.
- Acetaminophen
- Acetaminophen had no effect on the plasma levels of sulindac or its sulfide metabolite.
- Aspirin
- The concomitant administration of aspirin with sulindac significantly depressed the plasma levels of the active sulfide metabolite. A double-blind study compared the safety and efficacy of sulindac 300 or 400 mg daily given alone or with aspirin 2.4 g/day for the treatment of osteoarthritis. The addition of aspirin did not alter the types of clinical or laboratory adverse experiences for sulindac; however, the combination showed an increase in the incidence of gastrointestinal adverse experiences. Since the addition of aspirin did not have a favorable effect on the therapeutic response to sulindac, the combination is not recommended.
- Cyclosporine
- Administration of non-steroidal anti-inflammatory drugs concomitantly with cyclosporine has been associated with an increase in cyclosporine-induced toxicity, possibly due to decreased synthesis of renal prostacyclin. NSAIDs should be used with caution in patients taking cyclosporine, and renal function should be carefully monitored.
- Diflunisal
- The concomitant administration of sulindac and diflunisal in normal volunteers resulted in lowering of the plasma levels of the active sulindac sulfide metabolite by approximately one-third.
- Diuretics
- Clinical studies, as well as post marketing observations, have shown that sulindac can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure, as well as to assure diuretic efficacy.
- DMSO
- DMSO should not be used with sulindac. Concomitant administration has been reported to reduce the plasma levels of the active sulfide metabolite and potentially reduce efficacy. In addition, this combination has been reported to cause peripheral neuropathy.
- Lithium
- NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.
- Methotrexate
- NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.
- NSAIDs
- The concomitant use of sulindac with other NSAIDs is not recommended due to the increased possibility of gastrointestinal toxicity, with little or no increase in efficacy.
- Oral anticoagulants
- Although sulindac and its sulfide metabolite are highly bound to protein, studies in which sulindac was given at a dose of 400 mg daily have shown no clinically significant interaction with oral anticoagulants. However, patients should be monitored carefully until it is certain that no change in their anticoagulant dosage is required. Special attention should be paid to patients taking higher doses than those recommended and to patients with renal impairment or other metabolic defects that might increase sulindac blood levels. The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.
- Oral hypoglycemic agents
- Although sulindac and its sulfide metabolite are highly bound to protein, studies in which sulindac was given at a dose of 400 mg daily, have shown no clinically significant interaction with oral hypoglycemic agents. However, patients should be monitored carefully until it is certain that no change in their hypoglycemic dosage is required. Special attention should be paid to patients taking higher doses than those recommended and to patients with renal impairment or other metabolic defects that might increase sulindac blood levels.
- Probenecid
- Probenecid given concomitantly with sulindac had only a slight effect on plasma sulfide levels, while plasma levels of sulindac and sulfone were increased. Sulindac was shown to produce a modest reduction in the uricosuric action of probenecid, which probably is not significant under most circumstances.
- Propoxyphene hydrochloride
- Propoxyphene hydrochloride had no effect on the plasma levels of sulindac or its sulfide metabolite.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Teratogenic Effects
- Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. Sulindac should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Nonteratogenic Effects
- Because of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.
- The known effects of drugs of this class on the human fetus during the third trimester of pregnancy include: constriction of the ductus arteriosus prenatally, tricuspid incompetence, and pulmonary hypertension; non-closure of the ductus arteriosus postnatally which may be resistant to medical management; myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or failure, renal injury/dysgenesis which may result in prolonged or permanent renal failure, oligohydramnios, gastrointestinal bleeding or perforation, and increased risk of necrotizing enterocolitis.
- In reproduction studies in the rat, a decrease in average fetal weight and an increase in numbers of dead pups were observed on the first day of the postpartum period at dosage levels of 20 and 40 mg/kg/day (2½ and 5 times the usual maximum daily dose in humans), although there was no adverse effect on the survival and growth during the remainder of the postpartum period. Sulindac prolongs the duration of gestation in rats, as do other compounds of this class. Visceral and skeletal malformations observed in low incidence among rabbits in some teratology studies did not occur at the same dosage levels in repeat studies, nor at a higher dosage level in the same species.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sulindac in women who are pregnant.
### Labor and Delivery
- In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of sulindac on labor and delivery in pregnant women are unknown.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk; however, it is secreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from sulindac, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- As with any NSAID, caution should be exercised in treating the elderly (65 years and older) since advancing age appears to increase the possibility of adverse reactions. Elderly patients seem to tolerate ulceration or bleeding less well than other individuals and many spontaneous reports of fatal GI events are in this population.
- Sulindac is known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Sulindac with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Sulindac with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Sulindac in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Sulindac in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sulindac in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sulindac in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Sulindac in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Sulindac in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Cases of overdosage have been reported and rarely, deaths have occurred. The following signs and symptoms may be observed following overdosage; stupor, coma, diminished urine output and hypotension.
### Management
- In the event of overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment.
- Animal studies show that absorption is decreased by the prompt administration of activated charcoal and excretion is enhanced by alkalinization of the urine.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Sulindac in the drug label.
# Pharmacology
## Mechanism of Action
- Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic activities in animal models. The mechanism of action, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.
## Structure
- Sulindac is a non-steroidal, anti-inflammatory indene derivative designated chemically as (Z)-5-fluoro-2-methyl-1-methylene]-1H-indene-3-acetic acid. It is not a salicylate, pyrazolone or propionic acid derivative. Its empirical formula is C20H17FO3S, with a molecular weight of 356.42. Sulindac, a yellow crystalline compound, is a weak organic acid practically insoluble in water below pH 4.5, but very soluble as the sodium salt or in buffers of pH 6 or higher.
- Sulindac is available in 150 and 200 mg tablets for oral administration. Each tablet contains the following inactive ingredients: magnesium stearate, microcrystalline cellulose, plasdone and sodium starch glycolate.
- Following absorption, sulindac undergoes two major biotransformations - reversible reduction to the sulfide metabolite, and irreversible oxidation to the sulfone metabolite. Available evidence indicates that the biological activity resides with the sulfide metabolite.
- The structural formulas of sulindac and its metabolites are:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Sulindac in the drug label.
## Pharmacokinetics
- Absorption
- The extent of sulindac absorption from sulindac tablets, USP is similar as compared to sulindac solution.
- There is no information regarding food effect on sulindac absorption. Antacids containing magnesium hydroxide 200 mg and aluminum hydroxide 225 mg per 5 mL have been shown not to significantly decrease the extent of sulindac absorption.
- Distribution
- Sulindac, and its sulfone and sulfide metabolites, are 93.1, 95.4, and 97.9% bound to plasma proteins, predominantly to albumin. Plasma protein binding measured over a concentration range (0.5-2.0 µg/mL) was constant. Following an oral, radiolabeled dose of sulindac in rats, concentrations of radiolabel in red blood cells were about 10% of those in plasma. Sulindac penetrates the blood-brain and placental barriers. Concentrations in brain did not exceed 4% of those in plasma. Plasma concentrations in the placenta and in the fetus were less than 25% and 5% respectively, of systemic plasma concentrations. Sulindac is excreted in rat milk; concentrations in milk were 10 to 20% of those levels in plasma. It is not known if sulindac is excreted in human milk.
- Metabolism
- Sulindac undergoes two major biotransformations of its sulfoxide moiety: oxidation to the inactive sulfone and reduction to the pharmacologically active sulfide. The latter is readily reversible in animals and in man. These metabolites are present as unchanged compounds in plasma and principally as glucuronide conjugates in human urine and bile. A dihydroxydihydro analog has also been identified as a minor metabolite in human urine.
- With the twice-a-day dosage regimen, plasma concentrations of sulindac and its two metabolites accumulate: mean concentration over a dosage interval at steady state relative to the first dose averages 1.5 and 2.5 times higher, respectively, for sulindac and its active sulfide metabolite.
- Sulindac and its sulfone metabolite undergo extensive enterohepatic circulation relative to the sulfide metabolite in animals. Studies in man have also demonstrated that recirculation of the parent drug sulindac and its sulfone metabolite is more extensive than that of the active sulfide metabolite. The active sulfide metabolite accounts for less than six percent of the total intestinal exposure to sulindac and its metabolites.
- Biochemical as well as pharmacological evidence indicates that the activity of sulindac resides in its sulfide metabolite. An in-vitro assay for inhibition of cyclooxygenase activity exhibited an EC50 of 0.02µM for sulindac sulfide. In-vivo models of inflammation indicate that activity is more highly correlated with concentrations of the metabolite than with parent drug concentrations.
- Elimination
- Approximately 50% of the administered dose of sulindac is excreted in the urine with the conjugated sulfone metabolite accounting for the major portion. Less than 1% of the administered dose of sulindac appears in the urine as the sulfide metabolite. Approximately 25% is found in the feces, primarily as the sulfone and sulfide metabolites.
- The mean effective half life (T1/2) is 7.8 and 16.4 hours, respectively, for sulindac and its active sulfide metabolite.
- Because sulindac is excreted in the urine primarily as biologically inactive forms, it may possibly affect renal function to a lesser extent than other non-steroidal anti-inflammatory drugs; however, renal adverse experiences have been reported with sulindac.
- In a study of patients with chronic glomerular disease treated with therapeutic doses of sulindac, no effect was demonstrated on renal blood flow, glomerular filtration rate, or urinary excretion of prostaglandin E2 and the primary metabolite of prostacyclin, 6-keto-PGF1α. However, in other studies in healthy volunteers and patients with liver disease, sulindac was found to blunt the renal responses to intravenous furosemide, i.e., the diuresis, natriuresis, increments in plasma renin activity and urinary excretion of prostaglandins. These observations may represent a differentiation of the effects of sulindac on renal functions based on differences in pathogenesis of the renal prostaglandin dependence associated with differing dose-response relationships of different NSAIDs to the various renal functions influenced by prostaglandins.
- In healthy men, the average fecal blood loss, measured over a two-week period during administration of 400 mg per day of sulindac, was similar to that for placebo, and was statistically significantly less than that resulting from 4800 mg per day of aspirin.
- Special Populations
- Pediatrics
- The pharmacokinetics of sulindac have not been investigated in pediatric patients.
- Race
- Pharmacokinetic differences due to race have not been identified.
- Hepatic Insufficiency
- Patients with acute and chronic hepatic disease may require reduced doses of sulindac compared to patients with normal hepatic function since hepatic metabolism is an important elimination pathway.
- Following a single dose, plasma concentrations of the active sulfide metabolite have been reported to be higher in patients with alcoholic liver disease compared to healthy normal subjects.
- Renal Insufficiency
- Sulindac pharmacokinetics have been investigated in patients with renal insufficiency. The disposition of sulindac was studied in end-stage renal disease patients requiring hemodialysis. Plasma concentrations of sulindac and its sulfone metabolite were comparable to those of normal healthy volunteers whereas concentrations of the active sulfide metabolite were significantly reduced. Plasma protein binding was reduced and the AUC of the unbound sulfide metabolite was about half that in healthy subjects.
- Sulindac and its metabolites are not significantly removed from the blood in patients undergoing hemodialysis.
- Since sulindac is eliminated primarily by the kidneys, patients with significantly impaired renal function should be closely monitored.
- A lower daily dosage should be anticipated to avoid excessive drug accumulation.
- In controlled clinical studies sulindac was evaluated in the following five conditions:
- In patients with osteoarthritis of the hip and knee, the anti-inflammatory and analgesic activity of sulindac was demonstrated by clinical measurements that included: assessments by both patient and investigator of overall response; decrease in disease activity as assessed by both patient and investigator; improvement in ARA Functional Class; relief of night pain; improvement in overall evaluation of pain, including pain on weight bearing and pain on active and passive motion; improvement in joint mobility, range of motion, and functional activities; decreased swelling and tenderness; and decreased duration of stiffness following prolonged inactivity.
- In clinical studies in which dosages were adjusted according to patient needs, sulindac, 200 to 400 mg daily was shown to be comparable in effectiveness to aspirin 2400 to 4800 mg daily. Sulindac was generally well tolerated, and patients on it had a lower overall incidence of total adverse effects, of milder gastrointestinal reactions, and of tinnitus than did patients on aspirin.
- In patients with rheumatoid arthritis, the anti-inflammatory and analgesic activity of sulindac was demonstrated by clinical measurements that included: assessments by both patient and investigator of overall response; decrease in disease activity as assessed by both patient and investigator; reduction in overall joint pain; reduction in duration and severity of morning stiffness; reduction in day and night pain; decrease in time required to walk 50 feet; decrease in general pain as measured on a visual analog scale; improvement in the Ritchie articular index; decrease in proximal interphalangeal joint size; improvement in ARA Functional Class; increase in grip strength; reduction in painful joint count and score; reduction in swollen joint count and score; and increased flexion and extension of the wrist.
- In clinical studies in which dosages were adjusted according to patient needs, sulindac 300 to 400 mg daily was shown to be comparable in effectiveness to aspirin 3600 to 4800 mg daily. Sulindac was generally well tolerated, and patients on it had a lower overall incidence of total adverse effects, of milder gastrointestinal reactions, and of tinnitus than did patients on aspirin. (See ADVERSE REACTIONS)
- In patients with rheumatoid arthritis, sulindac may be used in combination with gold salts at usual dosage levels. In clinical studies, sulindac added to the regimen of gold salts usually resulted in additional symptomatic relief but did not alter the course of the underlying disease.
- In patients with ankylosing spondylitis, the anti-inflammatory and analgesic activity of sulindac was demonstrated by clinical measurements that included: assessments by both patient and investigator of overall response; decrease in disease activity as assessed by both patient and investigator; improvement in ARA Functional Class; improvement in patient and investigator evaluation of spinal pain, tenderness and/or spasm; reduction in the duration of morning stiffness; increase in the time to onset of fatigue; relief of night pain; increase in chest expansion; and increase in spinal mobility evaluated by fingers-to-floor distance, occiput to wall distance, the Schober Test, and the Wright Modification of the Schober Test. In a clinical study in which dosages were adjusted according to patient need, sulindac 200 to 400 mg daily was as effective as indomethacin 75 to 150 mg daily. In a second study, sulindac 300 to 400 mg daily was comparable in effectiveness to phenylbutazone 400 to 600 mg daily. Sulindac was better tolerated than phenylbutazone.
- In patients with acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis), the anti-inflammatory and analgesic activity of sulindac was demonstrated by clinical measurements that included: assessments by both patient and investigator of overall response; relief of night pain, spontaneous pain, and pain on active motion; decrease in local tenderness; and improvement in range of motion measured by abduction, and internal and external rotation. In clinical studies in acute painful shoulder, sulindac 300 to 400 mg daily and oxyphenbutazone 400 to 600 mg daily were shown to be equally effective and well tolerated.
- In patients with acute gouty arthritis, the anti-inflammatory and analgesic activity of sulindac was demonstrated by clinical measurements that included: assessments by both the patient and investigator of overall response; relief of weight-bearing pain; relief of pain at rest and on active and passive motion; decrease in tenderness; reduction in warmth and swelling; increase in range of motion; and improvement in ability to function. In clinical studies, sulindac at 400 mg daily and phenylbutazone at 600 mg daily were shown to be equally effective. In these short-term studies in which reduction of dosage was permitted according to response, both drugs were equally well tolerated.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Sulindac in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Sulindac in the drug label.
# How Supplied
- Sulindac Tablets USP, 150 mg are yellow, round tablets, bisected and debossed with “Є” to the left of bisect and “10” to the right of bisect on one side, and plain on the other side, available in bottles of 100, 500 and 1000.
- Sulindac Tablets USP, 200 mg are yellow, oval-shaped tablets, bisected and debossed with “Є” to the left of bisect and “11” to the right of bisect on one side, and plain on the other side, available in bottles of 100, 500 and 1000.
- Storage
- Store in a well-closed container at 20º to 25ºC (68 to 77ºF).
## Storage
There is limited information regarding Sulindac Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
- Sulindac, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up.
- Sulindac, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).
- Sulindac, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
- Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
- Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
- Patients should be informed of the signs of an anaphylactic/anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help.
- In late pregnancy, as with other NSAIDs, sulindac should be avoided because it may cause premature closure of the ductus arteriosus.
# Precautions with Alcohol
- Alcohol-Sulindac interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- SULINDAC®
# Look-Alike Drug Names
- Clinoril® — Clozaril®
# Drug Shortage Status
# Price | Sulindac
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Black Box Warning
# Overview
Sulindac is a non-steroidal anti-inflammatory drug that is FDA approved for the {{{indicationType}}} of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis), acute gouty arthritis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema, pruritus, rash, abdominal cramps, abdominal pain, constipation, diarrhea, flatulence, indigestion, loss of appetite, nausea, vomiting, dizziness, headache, and tinnitus.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended starting dosage is 150 mg twice a day. The dosage may be lowered or raised depending on the response.
- The recommended starting dosage is 150 mg twice a day. The dosage may be lowered or raised depending on the response.
- The recommended starting dosage is 150 mg twice a day. The dosage may be lowered or raised depending on the response.
- The recommended dosage is 200 mg twice a day. After a satisfactory response has been achieved, the dosage may be reduced according to the response. In acute painful shoulder, therapy for 7-14 days is usually adequate.
- The recommended dosage is 200 mg twice a day. After a satisfactory response has been achieved, the dosage may be reduced according to the response. In acute gouty arthritis, therapy for 7 days is usually adequate.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sulindac in adult patients.
### Non–Guideline-Supported Use
- Sulindac was given twice daily, started as 75 milligrams per dose in patients weighing up to 44 kg; heavier patients began with 150 mg twice daily.
- 4-year regimen of oral sulindac.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Sulindac in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sulindac in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sulindac in pediatric patients.
# Contraindications
- Sulindac is contraindicated in patients with known hypersensitivity to sulindac or the excipients.
- Sulindac should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic/anaphylactoid reactions to NSAIDs have been reported in such patients.
- Sulindac is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.
# Warnings
- Cardiovascular Thrombotic Events
- Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
- There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events.
- Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.
- Hypertension
- NSAIDs, including sulindac, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including sulindac, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
- Congestive Heart Failure and Edema
- Fluid retention and edema have been observed in some patients taking NSAIDs. Sulindac should be used with caution in patients with fluid retention or heart failure.
- NSAIDs, including sulindac, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
- NSAIDs should be prescribed with extreme caution in those with prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.
- To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
- In addition to hypersensitivity reactions involving the liver, in some patients the findings are consistent with those of cholestatic hepatitis. As with other non-steroidal anti-inflammatory drugs, borderline elevations of one or more liver tests without any other signs and symptoms may occur in up to 15% of patients taking NSAIDs including sulindac. These laboratory abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction. Meaningful (3 times the upper limit of normal) elevations of SGPT or SGOT (AST) occurred in controlled clinical trials in less than 1% of patients. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
- A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with sulindac. Although such reactions as described above are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), sulindac should be discontinued.
- In clinical trials with sulindac, the use of doses of 600 mg/day has been associated with an increased incidence of mild liver test abnormalities.
- Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a non-steroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, patients who are volume-depleted, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
- Advanced Renal Disease
- No information is available from controlled clinical studies regarding the use of sulindac in patients with advanced renal disease. Therefore, treatment with sulindac is not recommended in these patients with advanced renal disease. If sulindac therapy must be initiated, close monitoring of the patient’s renal function is advisable.
- As with other NSAIDs, anaphylactic/anaphylactoid reactions may occur in patients without known prior exposure to sulindac. Sulindac should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. Emergency help should be sought in cases where an anaphylactic/anaphylactoid reaction occurs.
- Skin Reactions
- NSAIDs, including sulindac, can cause serious adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
- Hypersensitivity
- Rarely, fever and other evidence of hypersensitivity including abnormalities in one or more liver function tests and severe skin reactions have occurred during therapy with sulindac. Fatalities have occurred in these patients. Hepatitis, jaundice, or both, with or without fever, may occur usually within the first one to three months of therapy. Determinations of liver function should be considered whenever a patient on therapy with sulindac develops unexplained fever, rash or other dermatologic reactions or constitutional symptoms. If unexplained fever or other evidence of hypersensitivity occurs, therapy with sulindac should be discontinued. The elevated temperature and abnormalities in liver function caused by sulindac characteristically have reverted to normal after discontinuation of therapy. Administration of sulindac should not be reinstituted in such patients.
- In late pregnancy, as with other NSAIDs, sulindac should be avoided because it may cause premature closure of the ductus arteriosus.
### Precautions
- General
- Sulindac cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
- The pharmacological activity of sulindac in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
- Hematological Effects
- Anemia is sometimes seen in patients receiving NSAIDs, including sulindac. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including sulindac, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
- NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving sulindac who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
- Preexisting Asthma
- Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, sulindac should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
- Renal Calculi
- Sulindac metabolites have been reported rarely as the major or a minor component in renal stones in association with other calculus components. Sulindac should be used with caution in patients with a history of renal lithiasis, and they should be kept well hydrated while receiving sulindac.
- Pancreatitis
- Pancreatitis has been reported in patients receiving sulindac. Should pancreatitis be suspected, the drug should be discontinued and not restarted, supportive medical therapy instituted, and the patient monitored closely with appropriate laboratory studies (e.g., serum and urine amylase, amylase/creatinine clearance ratio, electrolytes, serum calcium, glucose, lipase, etc.). A search for other causes of pancreatitis as well as those conditions which mimic pancreatitis should be conducted.
- Ocular Effects
- Because of reports of adverse eye findings with non-steroidal anti-inflammatory agents, it is recommended that patients who develop eye complaints during treatment with sulindac have ophthalmologic studies.
- Hepatic Insufficiency
- In patients with poor liver function, delayed, elevated and prolonged circulating levels of the sulfide and sulfone metabolites may occur. Such patients should be monitored closely; a reduction of daily dosage may be required.
- SLE and Mixed Connective Tissue Disease
- In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease, there may be an increased risk of aseptic meningitis.
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions were reported in clinical trials or have been reported since the drug was marketed. The probability exists of a causal relationship between sulindac and these adverse reactions. The adverse reactions which have been observed in clinical trials encompass observations in 1,865 patients, including 232 observed for at least 48 weeks.
- Incidence Greater Than 1%
The most frequent types of adverse reactions occurring with sulindac are gastrointestinal; these include gastrointestinal pain (10%), dyspepsia***, nausea*** with or without vomiting, diarrhea***, constipation***, flatulence, anorexia and gastrointestinal cramps.
Rash***, pruritus
Dizziness***, headache***, nervousness.
Tinnitus.
Edema.
- Incidence Less Than 1 in 100
Gastritis, gastroenteritis or colitis. Peptic ulcer and gastrointestinal bleeding have been reported. GI perforation and intestinal strictures (diaphragms) have been reported rarely.
Liver function abnormalities; jaundice, sometimes with fever; cholestasis; hepatitis; hepatic failure.
There have been rare reports of sulindac metabolites in common bile duct “sludge” and in biliary calculi in patients with symptoms of cholecystitis who underwent a cholecystectomy.
Pancreatitis.
Ageusia; glossitis.
Stomatitis, sore or dry mucous membranes, alopecia, photosensitivity.
Erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, and exfoliative dermatitis have been reported.
Congestive heart failure, especially in patients with marginal cardiac function; palpitation; hypertension.
Thrombocytopenia; ecchymosis, purpura, leukopenia, agranulocytosis, neutropenia, bone marrow depression, including aplastic anemia; hemolytic anemia, increased prothrombin time in patients on oral anticoagulants.
Urine discoloration; dysuria; vaginal bleeding, hematuria; proteinuria; crystalluria; renal impairment, including renal failure; interstitial nephritis; nephrotic syndrome.
Renal calculi containing sulindac metabolites have been observed rarely.
Hyperkalemia.
Muscle weakness.
Depression; psychic disturbances including acute psychosis.
Vertigo; insomnia; somnolence; paresthesia; convulsions; syncope; aseptic meningitis (especially in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease).
Blurred vision; visual disturbances; decreased hearing; metallic or bitter taste.
Epistaxis.
Anaphylaxis; angioneurotic edema; urticaria; bronchial spasm; dyspnea.
Hypersensitivity vasculitis.
A potentially fatal apparent hypersensitivity syndrome has been reported. This syndrome may include constitutional symptoms (fever, chills, diaphoresis, flushing), cutaneous findings (rash or other dermatologic reactions – see above), conjunctivitis, involvement of major organs (changes in liver function including hepatic failure, jaundice, pancreatitis, pneumonitis with or without pleural effusion, leukopenia, leukocytosis, eosinophilia, disseminated intravascular coagulation, anemia, renal impairment, including renal failure), and other less specific findings (adenitis, arthralgia, arthritis, myalgia, fatigue, malaise, hypotension, chest pain, tachycardia).
- Causal Relationship Unknown
- A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group A β-hemolytic streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents, sometimes with fatal outcome.
- Other reactions have been reported in clinical trials or since the drug was marketed, but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, that possibility cannot be excluded. Therefore, these observations are listed to serve as alerting information to physicians.
Arrhythmia.
Hyperglycemia.
Neuritis.
Disturbances of the retina and its vasculature.
Gynecomastia.
.***Incidence between 3% and 9%. Those reactions occurring in 1% to 3% of patients are not marked with an asterisk.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Sulindac in the drug label.
# Drug Interactions
- Ace Inhibitors and Angiotensin II Antagonists
- Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors and angiotensin II antagonists. These interactions should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors or angiotensin II antagonists. In some patients with compromised renal function (e.g. elderly patients or patients who are volume-depleted, including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory drugs, the co-administration of an NSAID and an ACE-inhibitor or an angiotensin II antagonist may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, monitor renal function periodically in patients receiving ACEIs or AIIAs and NSAIDs in combination therapy.
- Acetaminophen
- Acetaminophen had no effect on the plasma levels of sulindac or its sulfide metabolite.
- Aspirin
- The concomitant administration of aspirin with sulindac significantly depressed the plasma levels of the active sulfide metabolite. A double-blind study compared the safety and efficacy of sulindac 300 or 400 mg daily given alone or with aspirin 2.4 g/day for the treatment of osteoarthritis. The addition of aspirin did not alter the types of clinical or laboratory adverse experiences for sulindac; however, the combination showed an increase in the incidence of gastrointestinal adverse experiences. Since the addition of aspirin did not have a favorable effect on the therapeutic response to sulindac, the combination is not recommended.
- Cyclosporine
- Administration of non-steroidal anti-inflammatory drugs concomitantly with cyclosporine has been associated with an increase in cyclosporine-induced toxicity, possibly due to decreased synthesis of renal prostacyclin. NSAIDs should be used with caution in patients taking cyclosporine, and renal function should be carefully monitored.
- Diflunisal
- The concomitant administration of sulindac and diflunisal in normal volunteers resulted in lowering of the plasma levels of the active sulindac sulfide metabolite by approximately one-third.
- Diuretics
- Clinical studies, as well as post marketing observations, have shown that sulindac can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure, as well as to assure diuretic efficacy.
- DMSO
- DMSO should not be used with sulindac. Concomitant administration has been reported to reduce the plasma levels of the active sulfide metabolite and potentially reduce efficacy. In addition, this combination has been reported to cause peripheral neuropathy.
- Lithium
- NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.
- Methotrexate
- NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.
- NSAIDs
- The concomitant use of sulindac with other NSAIDs is not recommended due to the increased possibility of gastrointestinal toxicity, with little or no increase in efficacy.
- Oral anticoagulants
- Although sulindac and its sulfide metabolite are highly bound to protein, studies in which sulindac was given at a dose of 400 mg daily have shown no clinically significant interaction with oral anticoagulants. However, patients should be monitored carefully until it is certain that no change in their anticoagulant dosage is required. Special attention should be paid to patients taking higher doses than those recommended and to patients with renal impairment or other metabolic defects that might increase sulindac blood levels. The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.
- Oral hypoglycemic agents
- Although sulindac and its sulfide metabolite are highly bound to protein, studies in which sulindac was given at a dose of 400 mg daily, have shown no clinically significant interaction with oral hypoglycemic agents. However, patients should be monitored carefully until it is certain that no change in their hypoglycemic dosage is required. Special attention should be paid to patients taking higher doses than those recommended and to patients with renal impairment or other metabolic defects that might increase sulindac blood levels.
- Probenecid
- Probenecid given concomitantly with sulindac had only a slight effect on plasma sulfide levels, while plasma levels of sulindac and sulfone were increased. Sulindac was shown to produce a modest reduction in the uricosuric action of probenecid, which probably is not significant under most circumstances.
- Propoxyphene hydrochloride
- Propoxyphene hydrochloride had no effect on the plasma levels of sulindac or its sulfide metabolite.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Teratogenic Effects
- Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. Sulindac should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Nonteratogenic Effects
- Because of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.
- The known effects of drugs of this class on the human fetus during the third trimester of pregnancy include: constriction of the ductus arteriosus prenatally, tricuspid incompetence, and pulmonary hypertension; non-closure of the ductus arteriosus postnatally which may be resistant to medical management; myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or failure, renal injury/dysgenesis which may result in prolonged or permanent renal failure, oligohydramnios, gastrointestinal bleeding or perforation, and increased risk of necrotizing enterocolitis.
- In reproduction studies in the rat, a decrease in average fetal weight and an increase in numbers of dead pups were observed on the first day of the postpartum period at dosage levels of 20 and 40 mg/kg/day (2½ and 5 times the usual maximum daily dose in humans), although there was no adverse effect on the survival and growth during the remainder of the postpartum period. Sulindac prolongs the duration of gestation in rats, as do other compounds of this class. Visceral and skeletal malformations observed in low incidence among rabbits in some teratology studies did not occur at the same dosage levels in repeat studies, nor at a higher dosage level in the same species.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sulindac in women who are pregnant.
### Labor and Delivery
- In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of sulindac on labor and delivery in pregnant women are unknown.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk; however, it is secreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from sulindac, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- As with any NSAID, caution should be exercised in treating the elderly (65 years and older) since advancing age appears to increase the possibility of adverse reactions. Elderly patients seem to tolerate ulceration or bleeding less well than other individuals and many spontaneous reports of fatal GI events are in this population.
- Sulindac is known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Sulindac with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Sulindac with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Sulindac in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Sulindac in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sulindac in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sulindac in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Sulindac in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Sulindac in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Cases of overdosage have been reported and rarely, deaths have occurred. The following signs and symptoms may be observed following overdosage; stupor, coma, diminished urine output and hypotension.
### Management
- In the event of overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment.
- Animal studies show that absorption is decreased by the prompt administration of activated charcoal and excretion is enhanced by alkalinization of the urine.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Sulindac in the drug label.
# Pharmacology
## Mechanism of Action
- Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic activities in animal models. The mechanism of action, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.
## Structure
- Sulindac is a non-steroidal, anti-inflammatory indene derivative designated chemically as (Z)-5-fluoro-2-methyl-1-[ρ-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetic acid. It is not a salicylate, pyrazolone or propionic acid derivative. Its empirical formula is C20H17FO3S, with a molecular weight of 356.42. Sulindac, a yellow crystalline compound, is a weak organic acid practically insoluble in water below pH 4.5, but very soluble as the sodium salt or in buffers of pH 6 or higher.
- Sulindac is available in 150 and 200 mg tablets for oral administration. Each tablet contains the following inactive ingredients: magnesium stearate, microcrystalline cellulose, plasdone and sodium starch glycolate.
- Following absorption, sulindac undergoes two major biotransformations - reversible reduction to the sulfide metabolite, and irreversible oxidation to the sulfone metabolite. Available evidence indicates that the biological activity resides with the sulfide metabolite.
- The structural formulas of sulindac and its metabolites are:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Sulindac in the drug label.
## Pharmacokinetics
- Absorption
- The extent of sulindac absorption from sulindac tablets, USP is similar as compared to sulindac solution.
- There is no information regarding food effect on sulindac absorption. Antacids containing magnesium hydroxide 200 mg and aluminum hydroxide 225 mg per 5 mL have been shown not to significantly decrease the extent of sulindac absorption.
- Distribution
- Sulindac, and its sulfone and sulfide metabolites, are 93.1, 95.4, and 97.9% bound to plasma proteins, predominantly to albumin. Plasma protein binding measured over a concentration range (0.5-2.0 µg/mL) was constant. Following an oral, radiolabeled dose of sulindac in rats, concentrations of radiolabel in red blood cells were about 10% of those in plasma. Sulindac penetrates the blood-brain and placental barriers. Concentrations in brain did not exceed 4% of those in plasma. Plasma concentrations in the placenta and in the fetus were less than 25% and 5% respectively, of systemic plasma concentrations. Sulindac is excreted in rat milk; concentrations in milk were 10 to 20% of those levels in plasma. It is not known if sulindac is excreted in human milk.
- Metabolism
- Sulindac undergoes two major biotransformations of its sulfoxide moiety: oxidation to the inactive sulfone and reduction to the pharmacologically active sulfide. The latter is readily reversible in animals and in man. These metabolites are present as unchanged compounds in plasma and principally as glucuronide conjugates in human urine and bile. A dihydroxydihydro analog has also been identified as a minor metabolite in human urine.
- With the twice-a-day dosage regimen, plasma concentrations of sulindac and its two metabolites accumulate: mean concentration over a dosage interval at steady state relative to the first dose averages 1.5 and 2.5 times higher, respectively, for sulindac and its active sulfide metabolite.
- Sulindac and its sulfone metabolite undergo extensive enterohepatic circulation relative to the sulfide metabolite in animals. Studies in man have also demonstrated that recirculation of the parent drug sulindac and its sulfone metabolite is more extensive than that of the active sulfide metabolite. The active sulfide metabolite accounts for less than six percent of the total intestinal exposure to sulindac and its metabolites.
- Biochemical as well as pharmacological evidence indicates that the activity of sulindac resides in its sulfide metabolite. An in-vitro assay for inhibition of cyclooxygenase activity exhibited an EC50 of 0.02µM for sulindac sulfide. In-vivo models of inflammation indicate that activity is more highly correlated with concentrations of the metabolite than with parent drug concentrations.
- Elimination
- Approximately 50% of the administered dose of sulindac is excreted in the urine with the conjugated sulfone metabolite accounting for the major portion. Less than 1% of the administered dose of sulindac appears in the urine as the sulfide metabolite. Approximately 25% is found in the feces, primarily as the sulfone and sulfide metabolites.
- The mean effective half life (T1/2) is 7.8 and 16.4 hours, respectively, for sulindac and its active sulfide metabolite.
- Because sulindac is excreted in the urine primarily as biologically inactive forms, it may possibly affect renal function to a lesser extent than other non-steroidal anti-inflammatory drugs; however, renal adverse experiences have been reported with sulindac.
- In a study of patients with chronic glomerular disease treated with therapeutic doses of sulindac, no effect was demonstrated on renal blood flow, glomerular filtration rate, or urinary excretion of prostaglandin E2 and the primary metabolite of prostacyclin, 6-keto-PGF1α. However, in other studies in healthy volunteers and patients with liver disease, sulindac was found to blunt the renal responses to intravenous furosemide, i.e., the diuresis, natriuresis, increments in plasma renin activity and urinary excretion of prostaglandins. These observations may represent a differentiation of the effects of sulindac on renal functions based on differences in pathogenesis of the renal prostaglandin dependence associated with differing dose-response relationships of different NSAIDs to the various renal functions influenced by prostaglandins.
- In healthy men, the average fecal blood loss, measured over a two-week period during administration of 400 mg per day of sulindac, was similar to that for placebo, and was statistically significantly less than that resulting from 4800 mg per day of aspirin.
- Special Populations
- Pediatrics
- The pharmacokinetics of sulindac have not been investigated in pediatric patients.
- Race
- Pharmacokinetic differences due to race have not been identified.
- Hepatic Insufficiency
- Patients with acute and chronic hepatic disease may require reduced doses of sulindac compared to patients with normal hepatic function since hepatic metabolism is an important elimination pathway.
- Following a single dose, plasma concentrations of the active sulfide metabolite have been reported to be higher in patients with alcoholic liver disease compared to healthy normal subjects.
- Renal Insufficiency
- Sulindac pharmacokinetics have been investigated in patients with renal insufficiency. The disposition of sulindac was studied in end-stage renal disease patients requiring hemodialysis. Plasma concentrations of sulindac and its sulfone metabolite were comparable to those of normal healthy volunteers whereas concentrations of the active sulfide metabolite were significantly reduced. Plasma protein binding was reduced and the AUC of the unbound sulfide metabolite was about half that in healthy subjects.
- Sulindac and its metabolites are not significantly removed from the blood in patients undergoing hemodialysis.
- Since sulindac is eliminated primarily by the kidneys, patients with significantly impaired renal function should be closely monitored.
- A lower daily dosage should be anticipated to avoid excessive drug accumulation.
- In controlled clinical studies sulindac was evaluated in the following five conditions:
- In patients with osteoarthritis of the hip and knee, the anti-inflammatory and analgesic activity of sulindac was demonstrated by clinical measurements that included: assessments by both patient and investigator of overall response; decrease in disease activity as assessed by both patient and investigator; improvement in ARA Functional Class; relief of night pain; improvement in overall evaluation of pain, including pain on weight bearing and pain on active and passive motion; improvement in joint mobility, range of motion, and functional activities; decreased swelling and tenderness; and decreased duration of stiffness following prolonged inactivity.
- In clinical studies in which dosages were adjusted according to patient needs, sulindac, 200 to 400 mg daily was shown to be comparable in effectiveness to aspirin 2400 to 4800 mg daily. Sulindac was generally well tolerated, and patients on it had a lower overall incidence of total adverse effects, of milder gastrointestinal reactions, and of tinnitus than did patients on aspirin.
- In patients with rheumatoid arthritis, the anti-inflammatory and analgesic activity of sulindac was demonstrated by clinical measurements that included: assessments by both patient and investigator of overall response; decrease in disease activity as assessed by both patient and investigator; reduction in overall joint pain; reduction in duration and severity of morning stiffness; reduction in day and night pain; decrease in time required to walk 50 feet; decrease in general pain as measured on a visual analog scale; improvement in the Ritchie articular index; decrease in proximal interphalangeal joint size; improvement in ARA Functional Class; increase in grip strength; reduction in painful joint count and score; reduction in swollen joint count and score; and increased flexion and extension of the wrist.
- In clinical studies in which dosages were adjusted according to patient needs, sulindac 300 to 400 mg daily was shown to be comparable in effectiveness to aspirin 3600 to 4800 mg daily. Sulindac was generally well tolerated, and patients on it had a lower overall incidence of total adverse effects, of milder gastrointestinal reactions, and of tinnitus than did patients on aspirin. (See ADVERSE REACTIONS)
- In patients with rheumatoid arthritis, sulindac may be used in combination with gold salts at usual dosage levels. In clinical studies, sulindac added to the regimen of gold salts usually resulted in additional symptomatic relief but did not alter the course of the underlying disease.
- In patients with ankylosing spondylitis, the anti-inflammatory and analgesic activity of sulindac was demonstrated by clinical measurements that included: assessments by both patient and investigator of overall response; decrease in disease activity as assessed by both patient and investigator; improvement in ARA Functional Class; improvement in patient and investigator evaluation of spinal pain, tenderness and/or spasm; reduction in the duration of morning stiffness; increase in the time to onset of fatigue; relief of night pain; increase in chest expansion; and increase in spinal mobility evaluated by fingers-to-floor distance, occiput to wall distance, the Schober Test, and the Wright Modification of the Schober Test. In a clinical study in which dosages were adjusted according to patient need, sulindac 200 to 400 mg daily was as effective as indomethacin 75 to 150 mg daily. In a second study, sulindac 300 to 400 mg daily was comparable in effectiveness to phenylbutazone 400 to 600 mg daily. Sulindac was better tolerated than phenylbutazone.
- In patients with acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis), the anti-inflammatory and analgesic activity of sulindac was demonstrated by clinical measurements that included: assessments by both patient and investigator of overall response; relief of night pain, spontaneous pain, and pain on active motion; decrease in local tenderness; and improvement in range of motion measured by abduction, and internal and external rotation. In clinical studies in acute painful shoulder, sulindac 300 to 400 mg daily and oxyphenbutazone 400 to 600 mg daily were shown to be equally effective and well tolerated.
- In patients with acute gouty arthritis, the anti-inflammatory and analgesic activity of sulindac was demonstrated by clinical measurements that included: assessments by both the patient and investigator of overall response; relief of weight-bearing pain; relief of pain at rest and on active and passive motion; decrease in tenderness; reduction in warmth and swelling; increase in range of motion; and improvement in ability to function. In clinical studies, sulindac at 400 mg daily and phenylbutazone at 600 mg daily were shown to be equally effective. In these short-term studies in which reduction of dosage was permitted according to response, both drugs were equally well tolerated.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Sulindac in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Sulindac in the drug label.
# How Supplied
- Sulindac Tablets USP, 150 mg are yellow, round tablets, bisected and debossed with “Є” to the left of bisect and “10” to the right of bisect on one side, and plain on the other side, available in bottles of 100, 500 and 1000.
- Sulindac Tablets USP, 200 mg are yellow, oval-shaped tablets, bisected and debossed with “Є” to the left of bisect and “11” to the right of bisect on one side, and plain on the other side, available in bottles of 100, 500 and 1000.
- Storage
- Store in a well-closed container at 20º to 25ºC (68 to 77ºF).
## Storage
There is limited information regarding Sulindac Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
- Sulindac, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up.
- Sulindac, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).
- Sulindac, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
- Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
- Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
- Patients should be informed of the signs of an anaphylactic/anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help.
- In late pregnancy, as with other NSAIDs, sulindac should be avoided because it may cause premature closure of the ductus arteriosus.
# Precautions with Alcohol
- Alcohol-Sulindac interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- SULINDAC®[1]
# Look-Alike Drug Names
- Clinoril® — Clozaril®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Clinoril | |
0926d5da7d19a8727409c5a219782dca669e6b07 | wikidoc | Clitoris | Clitoris
# Overview
The clitoris is a sexual organ that is present only in female mammals. In humans, the visible button-like portion is located near the anterior junction of the labia minora, above the opening of the urethra and vagina. Unlike the penis, which is homologous to the clitoris, the clitoris does not contain the distal portion of the urethra and functions solely to induce sexual pleasure. The only known exception to this is in the Spotted Hyena. In this species, the urogenital system is unique in that the female urinates, mates and gives birth via an enlarged, erectile clitoris, known as a pseudo-penis.
# Pronunciation and etymology
The word is Template:PronEng Template:Noprint) or Template:IPA Template:Noprint). The plural forms are clitorises in English and clitorides in Latin. In slang, it is sometimes abbreviated as clit, which originated in the 1960s. The Oxford English Dictionary suggests that the pronunciation Template:IPA) is also used in the UK, and gives the likely etymology as coming from the Greek Template:Polytonic, perhaps derived from the verb Template:Polytonic, to shut. The Online Etymology Dictionary maintains that the etymology of this diminutive is still uncertain noting that many sources take kleitoris “Template:Polytonic” literally from the Greek "little hill”. Other etymological candidates are key or latch, to touch or titillate lasciviously, to tickle, to be inclined (toward pleasure) and slope, from the same root as climax. It has been noted in German as der Kitzler meaning "the tickler". Its Latin genitive is clitoridis, as in "glans clitoridis".
# Development and formation
At the time of development of the urinary and reproductive organs in embryogenesis the previously undifferentiated genital tubercle develops into the clitoris or the penis, along with all other major organ systems, making them homologous.
# Form
The head or glans of the clitoris is a simple bundle of 8000 nerve fibers, estimated to be twice the number found in the penis, making it particularly well-suited for sexual stimulation.
The clitoris is a complex structure that includes external and internal components. Projecting at the front of the vaginal commissure where the edges of the outer lips (labia majora) meet at the base of the pubic mound is the clitoral hood (prepuce), which in full or part covers the head (clitoral glans) -- commonly about the size and shape of a shirt-button. Following from the head back and up along the shaft, it is found that this extends up to several centimeters before reversing direction, branched resulting in a shaped like an inverted "V", and extending as a pair of "legs" known as the clitoral crura formed of the corpora cavernosa, which are concealed behind the labia minora, and terminating attached to the pubic arch, according to some , or following interior to the labia minora to meet at the fourchette, according to others.
Associated are the urethral sponge, clitoral/vestibular bulbs, perineal sponge, a network of nerves and blood vessels, suspensory ligaments, muscles and pelvic diaphragm.
There is considerable variation with regard to how much of the clitoris protrudes from the hood and how much is covered by it, ranging from complete, covered invisibility to full, protruding visibility. An article published in the Journal of Obstetrics and Gynecology in July 1992 states that the average width of the clitoral glans lies within the range of 2.5 – 4.5 mm (0.10-0.18 in) indicating that the average size is smaller than a pencil eraser. There is no identified correlation between the size of a clitoris and the person's age, neither to being post-menopausal, nor to height, weight or use of oral contraceptives. Those who have given birth do tend to have slightly larger measurements.
Masters and Johnson were the first to determine that the clitoral structures surround and extend along the vagina, determining that all orgasms are of clitoral origin. More recently, Australian urologist Dr. Helen O'Connell using MRI technology noted a direct relationship between the legs or roots of the clitoris and the erectile tissue of the clitoral bulbs and corpora, and the distal urethra and vagina. She asserts that this interconnected relationship is the physiological explanation for the conjectured G-spot and experience of vaginal orgasm taking into account the stimulation of the internal parts of the clitoris during vaginal penetration. Some individuals who experience orgasm from both direct clitoral stimulation of the glans and vaginal access to the internal bodies may distinguish between them in terms of both the physical and general sensations associated with each.
During sexual arousal and during orgasm, the clitoris and the whole of the genitalia engorge and change color as these erectile tissues fill with blood, and the individual experiences vaginal contractions. Masters and Johnson documented the sexual response cycle, which has four phases and is still the clinically accepted definition of the human orgasm. More recent research has determined that some can experience a sustained intense orgasm through stimulation of the clitoris and remain in the orgasmic phase for much longer than the original studies indicate, evidenced by genital engorgement and color changes, and vaginal contractions.
# Development
The clitoris is formed from the same tissues that would become the glans and upper shaft of a penis if the embryo had been exposed to “male” hormones. Changes in appearance of male and female embryos begin roughly eight weeks after conception. By birth, the genital structures have developed into the female reproductive system.
Embryo sex based on external genitalia is apparent to a doctor at the end of the 14th menstrual week, and the sex can usually be identified by an ultrasound after 16 to 18 menstrual weeks.
# Recognition of existence
Over a period of more than 2,500 years, some have considered the clitoris and the penis equivalent in all respects except their arrangement. Medical literature first recognized the existence of the clitoris in the 16th century. This is the subject of some dispute: Realdo Colombo (also known as Matteo Renaldo Colombo) was a lecturer in surgery at the University of Padua, Italy, and in 1559 he published a book called De re anatomica in which he described the "seat of woman's delight". Colombo concluded, "Since no one has discerned these projections and their workings, if it is permissible to give names to things discovered by me, it should be called the love or sweetness of Venus."
Colombo's claim was disputed by his successor at Padua, Gabriele Falloppio who discovered the fallopian tube), who claimed that he was the first to discover the clitoris. Caspar Bartholin, a 17th century Danish anatomist, dismissed both claims, arguing that the clitoris had been widely known to medical science since the 2nd century. Indeed, Hippocrates used the term columella (little pillar). Avicenna named the clitoris the albatra or virga (rod). Albucasis, an Arabic medical authority, named it tentigo (tension). It was also known to the Romans, who named it landica. (The Latin Sexual Vocabulary by J.N. Adams Baltimore: The Johns Hopkins University Press, 1982. pp. 95-6.)
This cycle of suppression and discovery continued, notably in the work of De Graaf (Tractatus de Virorum Organis Generationi Inservientibus, De Mulierub Organis Generationi Inservientibus Tractatus Novus) in the 17th century and Kobelt (Die männlichen und weiblichen Wollustorgane des Menschen und einiger Säugetiere) in the 19th.
The full extent of the clitoris was alluded to by Masters and Johnson in 1966, but in such a muddled fashion that the significance of their description became obscured. That same year, feminist psychiatrist Mary Jane Sherfey published an article on female sexuality that described in detail the extensive nature of the internal anatomy of the clitoris and in 1981, the Federation of Feminist Women's Health Clinics (FFWHC) continued this process with anatomically precise illustrations. Today, MRI complements these efforts, as it is both a live and multiplanar method of examination .
# Female genital modification
The external part of the clitoris may be partially or totally removed during female genital cutting, also known as a clitoridectomy, female circumcision, or female genital mutilation (FGM); this may be a voluntary or involuntary procedure. The topic is highly controversial with many countries condemning the traditions that give rise to involuntary procedures, and with some countries outlawing even voluntary procedures. Amnesty International estimates that over 2 million involuntary female circumcisions are being performed every year, mainly in African countries.
In various cultures, the clitoris is sometimes pierced directly. In U.S. body modification culture, it is actually extremely rare for the clitoral shaft itself to be pierced, as of the already few people who desire the piercing, only a small percentage are anatomically suited for it; furthermore, most piercing artists are understandably reluctant to attempt such a delicate procedure. Some styles, such as the Isabella and the Nefertiti, do pass through the clitoris but are placed deep at the base, where they provide unique stimulation; they still require the proper genital build, but are more common than shaft piercings. Additionally, what is (erroneously) referred to as a "clit piercing" is almost always the much more common (and much less complicated) clitoral hood piercing.
Enlargement may be intentional or unintentional. Those taking hormones and/or other medications as part of female-to-male transition usually experience dramatic clitoral growth; individual desires (and the difficulties of surgical phalloplasty) often result in the retention of the original genitalia, the enlarged clitoris analogous to a penis as part of the transition. On the other hand, use of anabolic steroids by bodybuilders and other athletes can result in significant enlargement of the clitoris in concert with other masculinizing effects on their bodies. Temporary engorgement results from suction pumping, practiced to enhance sexual pleasure or for aesthetic purposes.
# Intersex and transgender people
Transgender people who undergo sex reassignment surgery (male-to-female) may choose to have their surgeon design a clitoris, using their existing genital tissue. The new clitoris may be referred to as a neoclitoris.
# Additional images
- Outer anatomy of clitoris.
- Muscles of the perineum.
- Sagittal section of the lower part of the trunk, right segment. | Clitoris
Template:Infobox Anatomy
# Overview
The clitoris is a sexual organ that is present only in female mammals. In humans, the visible button-like portion is located near the anterior junction of the labia minora, above the opening of the urethra and vagina. Unlike the penis, which is homologous to the clitoris, the clitoris does not contain the distal portion of the urethra and functions solely to induce sexual pleasure. The only known exception to this is in the Spotted Hyena. In this species, the urogenital system is unique in that the female urinates, mates and gives birth via an enlarged, erectile clitoris, known as a pseudo-penis.[1]
# Pronunciation and etymology
The word is Template:PronEng Template:Noprint) or Template:IPA Template:Noprint). The plural forms are clitorises in English and clitorides in Latin. In slang, it is sometimes abbreviated as clit, which originated in the 1960s. The Oxford English Dictionary suggests that the pronunciation Template:IPA) is also used in the UK, and gives the likely etymology as coming from the Greek Template:Polytonic, perhaps derived from the verb Template:Polytonic, to shut. The Online Etymology Dictionary maintains that the etymology of this diminutive is still uncertain noting that many sources take kleitoris “Template:Polytonic” literally from the Greek "little hill”. Other etymological candidates are key or latch, to touch or titillate lasciviously, to tickle, to be inclined (toward pleasure) and slope, from the same root as climax. It has been noted in German as der Kitzler meaning "the tickler". Its Latin genitive is clitoridis, as in "glans clitoridis".
# Development and formation
At the time of development of the urinary and reproductive organs in embryogenesis the previously undifferentiated genital tubercle develops into the clitoris or the penis, along with all other major organ systems, making them homologous. [2]
# Form
The head or glans of the clitoris is a simple bundle of 8000 nerve fibers, estimated to be twice the number found in the penis, [3]making it particularly well-suited for sexual stimulation.
Template:Infobox Anatomy
The clitoris is a complex structure that includes external and internal components. Projecting at the front of the vaginal commissure where the edges of the outer lips (labia majora) meet at the base of the pubic mound is the clitoral hood (prepuce), which in full or part covers the head (clitoral glans) -- commonly about the size and shape of a shirt-button. Following from the head back and up along the shaft, it is found that this extends up to several centimeters before reversing direction, branched resulting in a shaped like an inverted "V", and extending as a pair of "legs" known as the clitoral crura formed of the corpora cavernosa, which are concealed behind the labia minora, and terminating attached to the pubic arch, according to some [1], or following interior to the labia minora to meet at the fourchette, according to others.[4]
Associated are the urethral sponge, clitoral/vestibular bulbs, perineal sponge, a network of nerves and blood vessels, suspensory ligaments, muscles and pelvic diaphragm.[2]
There is considerable variation with regard to how much of the clitoris protrudes from the hood and how much is covered by it, ranging from complete, covered invisibility to full, protruding visibility. An article published in the Journal of Obstetrics and Gynecology in July 1992 states that the average width of the clitoral glans lies within the range of 2.5 – 4.5 mm (0.10-0.18 in) indicating that the average size is smaller than a pencil eraser. There is no identified correlation between the size of a clitoris and the person's age, neither to being post-menopausal, nor to height, weight or use of oral contraceptives. Those who have given birth do tend to have slightly larger measurements.
Masters and Johnson were the first to determine that the clitoral structures surround and extend along the vagina, determining that all orgasms are of clitoral origin. [5] More recently, Australian urologist Dr. Helen O'Connell using MRI technology noted a direct relationship between the legs or roots of the clitoris and the erectile tissue of the clitoral bulbs and corpora, and the distal urethra and vagina. [6]She asserts that this interconnected relationship is the physiological explanation for the conjectured G-spot and experience of vaginal orgasm taking into account the stimulation of the internal parts of the clitoris during vaginal penetration. [7] Some individuals who experience orgasm from both direct clitoral stimulation of the glans and vaginal access to the internal bodies may distinguish between them in terms of both the physical and general sensations associated with each.
During sexual arousal and during orgasm, the clitoris and the whole of the genitalia engorge and change color as these erectile tissues fill with blood, and the individual experiences vaginal contractions. Masters and Johnson documented the sexual response cycle, which has four phases and is still the clinically accepted definition of the human orgasm. More recent research has determined that some can experience a sustained intense orgasm through stimulation of the clitoris and remain in the orgasmic phase for much longer than the original studies indicate, evidenced by genital engorgement and color changes, and vaginal contractions. [8]
# Development
The clitoris is formed from the same tissues that would become the glans and upper shaft of a penis if the embryo had been exposed to “male” hormones. Changes in appearance of male and female embryos begin roughly eight weeks after conception. By birth, the genital structures have developed into the female reproductive system. [9]
Embryo sex based on external genitalia is apparent to a doctor at the end of the 14th menstrual week, and the sex can usually be identified by an ultrasound after 16 to 18 menstrual weeks. [10]
# Recognition of existence
Over a period of more than 2,500 years, some have considered the clitoris and the penis equivalent in all respects except their arrangement.[4] Medical literature first recognized the existence of the clitoris in the 16th century. This is the subject of some dispute: Realdo Colombo (also known as Matteo Renaldo Colombo) was a lecturer in surgery at the University of Padua, Italy, and in 1559 he published a book called De re anatomica in which he described the "seat of woman's delight". Colombo concluded, "Since no one has discerned these projections and their workings, if it is permissible to give names to things discovered by me, it should be called the love or sweetness of Venus."
Colombo's claim was disputed by his successor at Padua, Gabriele Falloppio who discovered the fallopian tube), who claimed that he was the first to discover the clitoris. Caspar Bartholin, a 17th century Danish anatomist, dismissed both claims, arguing that the clitoris had been widely known to medical science since the 2nd century. Indeed, Hippocrates used the term columella (little pillar). Avicenna named the clitoris the albatra or virga (rod). Albucasis, an Arabic medical authority, named it tentigo (tension). It was also known to the Romans, who named it landica. (The Latin Sexual Vocabulary by J.N. Adams Baltimore: The Johns Hopkins University Press, 1982. pp. 95-6.)
This cycle of suppression and discovery continued, notably in the work of De Graaf (Tractatus de Virorum Organis Generationi Inservientibus, De Mulierub Organis Generationi Inservientibus Tractatus Novus) in the 17th century and Kobelt (Die männlichen und weiblichen Wollustorgane des Menschen und einiger Säugetiere) in the 19th.
The full extent of the clitoris was alluded to by Masters and Johnson in 1966, but in such a muddled fashion that the significance of their description became obscured. That same year, feminist psychiatrist Mary Jane Sherfey published an article on female sexuality that described in detail the extensive nature of the internal anatomy of the clitoris and in 1981, the Federation of Feminist Women's Health Clinics (FFWHC) continued this process with anatomically precise illustrations. [4] Today, MRI complements these efforts, as it is both a live and multiplanar method of examination [11].
# Female genital modification
The external part of the clitoris may be partially or totally removed during female genital cutting, also known as a clitoridectomy, female circumcision, or female genital mutilation (FGM); this may be a voluntary or involuntary procedure. The topic is highly controversial with many countries condemning the traditions that give rise to involuntary procedures, and with some countries outlawing even voluntary procedures. Amnesty International estimates that over 2 million involuntary female circumcisions are being performed every year, mainly in African countries.
In various cultures, the clitoris is sometimes pierced directly. In U.S. body modification culture, it is actually extremely rare for the clitoral shaft itself to be pierced, as of the already few people who desire the piercing, only a small percentage are anatomically suited for it; furthermore, most piercing artists are understandably reluctant to attempt such a delicate procedure. Some styles, such as the Isabella and the Nefertiti, do pass through the clitoris but are placed deep at the base, where they provide unique stimulation; they still require the proper genital build, but are more common than shaft piercings. Additionally, what is (erroneously) referred to as a "clit piercing" is almost always the much more common (and much less complicated) clitoral hood piercing.
Enlargement may be intentional or unintentional. Those taking hormones and/or other medications as part of female-to-male transition usually experience dramatic clitoral growth; individual desires (and the difficulties of surgical phalloplasty) often result in the retention of the original genitalia, the enlarged clitoris analogous to a penis as part of the transition. On the other hand, use of anabolic steroids by bodybuilders and other athletes can result in significant enlargement of the clitoris in concert with other masculinizing effects on their bodies. Temporary engorgement results from suction pumping, practiced to enhance sexual pleasure or for aesthetic purposes.
# Intersex and transgender people
Transgender people who undergo sex reassignment surgery (male-to-female) may choose to have their surgeon design a clitoris, using their existing genital tissue. The new clitoris may be referred to as a neoclitoris.
# Additional images
- Outer anatomy of clitoris.
- Muscles of the perineum.
- Sagittal section of the lower part of the trunk, right segment. | https://www.wikidoc.org/index.php/Clitoris | |
94ba0cc1ba2f2d5c59870be84a6221da2ab76c78 | wikidoc | Clobazam | Clobazam
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# Overview
Clobazam is a Benzodiazepine that is FDA approved for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older. Common adverse reactions include constipation, somnolence or sedation, pyrexia, lethargy, and drooling.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Seizures associated with Lennox-Gastaut syndrome (LGS)
- A daily dose of clobazam greater than 5 mg should be administered in divided doses twice daily
- 5 mg daily dose can be administered as a single dose.
- Dose patients according to body weight.
- Do not proceed with dose escalation more rapidly than weekly, because serum concentrations of clobazam and its active metabolite require 5 and 9 days, respectively, to reach steady-state.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Clobazam in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Clobazam in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Seizures associated with Lennox-Gastaut syndrome (LGS) (2 years of age or older)
- A daily dose of clobazam greater than 5 mg should be administered in divided doses twice daily
- 5 mg daily dose can be administered as a single dose.
- Dose patients according to body weight.
- Do not proceed with dose escalation more rapidly than weekly, because serum concentrations of clobazam and its active metabolite require 5 and 9 days, respectively, to reach steady-state.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Clobazam in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Clobazam in pediatric patients.
# Contraindications
- Clobazam is contraindicated in patients with a history of hypersensitivity to the drug or its ingredients.
- Hypersensitivity reactions have included serious dermatological reactions.
# Warnings
### Somnolence or Sedation
- Clobazam causes somnolence and sedation.
- In clinical trials, somnolence or sedation was reported at all effective doses and was dose-related.
- In general, somnolence and sedation begin within the first month of treatment and may diminish with continued treatment.
- Prescribers should monitor patients for somnolence and sedation, particularly with concomitant use of other central nervous system depressants.
- Prescribers should caution patients against engaging in hazardous activities requiring mental alertness, such as operating dangerous machinery or motor vehicles, until the effect of clobazam is known.
### Potentiation of Sedation from Concomitant Use with Central Nervous System Depressants
- Since clobazam has a central nervous system (CNS) depressant effect, patients or their caregivers should be cautioned against simultaneous use with other CNS depressant drugs or alcohol, and cautioned that the effects of other CNS depressant drugs or alcohol may be potentiated.
### Withdrawal Symptoms
- Abrupt discontinuation of clobazam should be avoided.
- Clobazam should be tapered by decreasing the dose every week by 5-10 mg/day until discontinuation.
- Withdrawal symptoms (Benzodiazepine withdrawal syndrome) occurred following abrupt discontinuation of clobazam; the risk of withdrawal symptoms is greater with higher doses.
- As with all antiepileptic drugs, clobazam should be withdrawn gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus.
- Withdrawal symptoms (e.g., convulsions, psychosis, hallucinations, behavioral disorder, tremor, and anxiety) have been reported following abrupt discontinuance of benzodiazepines.
- The more severe withdrawal symptoms have usually been limited to patients who received excessive doses over an extended period of time, followed by an abrupt discontinuation.
- Generally milder withdrawal symptoms (e.g., dysphoria, anxiety, and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic doses for several months.
### Serious Dermatological Reactions
- Serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported with clobazam in both children and adults during the post-marketing period.
- Patients should be closely monitored for signs or symptoms of SJS/TEN, especially during the first 8 weeks of treatment initiation or when re-introducing therapy.
- Clobazam should be discontinued at the first sign of rash, unless the rash is clearly not drug-related.
- If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.
### Physical and Psychological Dependence
- Patients with a history of substance abuse should be under careful surveillance when receiving clobazam or other psychotropic agents because of the predisposition of such patients to habituation and dependence.
### Suicidal Behavior and Ideation
- Antiepileptic drugs (AEDs), including clobazam, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.
- Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% cclobazamdence interval : 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED treated patients was 0.43%, compared to 0.24% among 16,029 placebo treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated.
- There were four suicides in drug treated patients in the trials and none in placebo treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed.
- Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.
- The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
- Anyone considering prescribing clobazam or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.
- Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.
- Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
- Behaviors of concern should be reported immediately to healthcare providers.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- During its development for the adjunctive treatment of seizures associated with LGS, clobazam was administered to 333 healthy volunteers and 300 patients with a current or prior diagnosis of LGS, including 197 patients treated for 12 months or more.
- The conditions and duration of exposure varied greatly and included single- and multiple-dose clinical pharmacology studies in healthy volunteers and two double-blind studies in patients with LGS (Study 1 and 2). Only Study 1 included a placebo group, allowing comparison of adverse reaction rates on clobazam at several doses to placebo.
Adverse Reactions Leading to Discontinuation in an LGS Placebo Controlled Clinical Trial (Study 1)
- The adverse reactions associated with clobazam treatment discontinuation in ≥1% of patients in decreasing order of frequency included lethargy, somnolence, ataxia, aggression, fatigue, and insomnia.
Most Common Adverse Reactions in an LGS Placebo Controlled Clinical Trial (Study 1)
Table 3 lists the adverse reactions that occurred in ≥5% of clobazam treated patients (at any dose), and at a rate greater than placebo treated patients, in the randomized, double-blind, placebo-controlled, parallel group clinical study of adjunctive AED therapy for 15 weeks (Study 1).
## Postmarketing Experience
These reactions are reported voluntarily from a population of uncertain size; therefore, it is not possible to estimate their frequency or establish a causal relationship to drug exposure.
Adverse reactions are categorized by system organ class.
### Blood Disorders
- Anemia
- Eosinophilia
- Leukopenia
- Thrombocytopenia
### Eye Disorders
- Diplopia
- Vision blurred
### Gastrointestinal Disorders
- Abdominal distention
### General Disorders and Administration Site Conditions
- Hypothermia
### Investigations
- Hepatic enzyme increased
### Musculoskeletal
- Muscle spasms
### Psychiatric Disorders
- Agitation
- Anxiety
- Apathy
- Confusional state
- Depression
- Delirium
- Delusion
- Hallucination
### Renal and Urinary Disorders
- Urinary retention
### Respiratory Disorders
- Aspiration
- Respiratory depression
### Skin and Subcutaneous Tissue Disorders
- Rash
- Urticaria
- Angioedema
- Facial and lip edema
# Drug Interactions
### Effect of clobazam on Other Drugs
- Clobazam is a weak CYP3A4 inducer.
- As some hormonal contraceptives are metabolized by CYP3A4, their effectiveness may be diminished when given with clobazam.
- Additional non-hormonal forms of contraception are recommended when using clobazam.
- Clobazam inhibits CYP2D6.
- Dose adjustment of drugs metabolized by CYP2D6 may be necessary.
- Strong and moderate inhibitors of CYP2C19
- Strong and moderate inhibitors of CYP2C19 may result in increased exposure to N-desmethylclobazam, the active metabolite of clobazam.
- This may increase the risk of dose-related adverse reactions.
- Dosage adjustment of clobazam may be necessary when co-administered with strong CYP2C19 inhibitors (e.g., fluconazole, fluvoxamine, ticlopidine) or moderate CYP2C19 inhibitors (e.g., omeprazole).
### CNS Depressants and Alcohol
- Concomitant use of clobazam with other CNS depressants may increase the risk of sedation and somnolence.
- Alcohol, as a CNS depressant, will interact with clobazam in a similar way and also increases clobazam's maximum plasma exposure by approximately 50%. Therefore, caution patients or their caregivers against simultaneous use with other CNS depressant drugs or alcohol, and caution that the effects of other CNS depressant drugs or alcohol may be potentiated.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies of clobazam in pregnant women.
- In animal studies, administration of clobazam during pregnancy resulted in developmental toxicity, including increased incidences of fetal malformations, at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those expected at therapeutic doses in patients. Clobazam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Available human data on the risk of teratogenicity associated with benzodiazepines are inconclusive.
- There is insufficient evidence in humans to assess the effect of benzodiazepine exposure during pregnancy on neurodevelopment.
- Administration of benzodiazepines immediately prior to or during childbirth can result in a syndrome of hypothermia, hypotonia, respiratory depression, and difficulty feeding.
- In addition, infants born to mothers who have taken benzodiazepines during the later stages of pregnancy can develop dependence, and subsequently withdrawal, during the postnatal period.
- Data for other benzodiazepines suggest the possibility of adverse developmental effects (including long-term effects on neurobehavioral and immunological function) in animals following prenatal exposure to benzodiazepines at clinically relevant doses.
- In a study in which clobazam (150, 450, or 750 mg/kg/day) was orally administered to pregnant rats throughout the period of organogenesis, embryofetal mortality and incidences of fetal skeletal variations were increased at all doses.
- The low effect dose for embryofetal developmental toxicity in rats (150 mg/kg/day) was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, lower than those in humans at the maximum recommended human dose (MRHD) of 40 mg/day.
- Oral administration of clobazam (10, 30, or 75 mg/kg/day) to pregnant rabbits throughout the period of organogenesis resulted in decreased fetal body weights, and increased incidences of fetal malformations (visceral and skeletal) at the mid and high doses, and an increase in embryofetal mortality at the high dose.
- Incidences of fetal variations were increased at all doses.
- The highest dose tested was associated with maternal toxicity (ataxia and decreased activity).
- The low effect dose for embryofetal developmental toxicity in rabbits (10 mg/kg/day) was associated with plasma exposures for clobazam and N-desmethylclobazam lower than those in humans at the MRHD.
- Oral administration of clobazam (50, 350, or 750 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased embryofetal mortality at the high dose, decreased pup survival at the mid and high doses and alterations in offspring behavior (locomotor activity) at all doses. The low effect dose for adverse effects on pre- and postnatal development in rats (50 mg/kg/day) was associated with plasma exposures for clobazam and N-desmethylclobazam lower than those in humans at the MRHD.
Pregnancy Category (AUS): C
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clobazam in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Clobazam during labor and delivery.
### Nursing Mothers
- Clobazam is excreted in human milk.
- Because of the potential for serious adverse reactions in nursing infants from clobazam, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in patients less than 2 years of age have not been established.
- In a study in which clobazam (4, 36, or 120 mg/kg/day) was orally administered to rats during the juvenile period of development (postnatal days 14 to 48), adverse effects on growth (decreased bone density and bone length) and behavior (altered motor activity and auditory startle response; learning deficit) were observed at the high dose.
- The effect on bone density, but not on behavior, was reversible when drug was discontinued.
- The no-effect level for juvenile toxicity (36 mg/kg/day) was associated with plasma exposures (AUC) to clobazam and its major active metabolite, N-desmethylclobazam, less than those expected at therapeutic doses in pediatric patients.
### Geriatic Use
- Plasma concentrations at any given dose are generally higher in the elderly: proceed slowly with dose escalation.
- The starting dose should be 5 mg/day for all elderly patients.
- Then titrate elderly patients according to weight, but to half the dose presented in Table 1, as tolerated.
- If necessary and based upon clinical response, an additional titration to the maximum dose (20 mg/day or 40 mg/day, depending on weight) may be started on day 21.
- Clinical studies of clobazam did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, elderly subjects appear to eliminate clobazam more slowly than younger subjects based on population pharmacokinetic analysis. For these reasons, the initial dose in elderly patients should be 5 mg/day.
### Gender
- Population pharmacokinetic analyses showed no difference in the clearance of clobazam between women and men.
### Race
- Population pharmacokinetic analyses including Caucasian (75%), African American (15%), and Asian (9%) subjects showed that there is no evidence of clinically significant effect of race on the clearance of clobazam.
### Renal Impairment
- No dose adjustment is required for patients with mild and moderate renal impairment.
- There is no experience with clobazam in patients with severe renal impairment or end stage renal disease (ESRD).
- It is not known if clobazam or its active metabolite, N-desmethylclobazam, is dialyzable.
### Hepatic Impairment
- Clobazam is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of clobazam. *For this reason, proceed slowly with dosing escalations.
- For patients with mild to moderate hepatic impairment (Child-Pugh score 5-9), the starting dose should be 5 mg/day in both weight groups.
- Then titrate patients according to weight, but to half the dose presented in Table 1, as tolerated.
- If necessary and based upon clinical response, start an additional titration on day 21 to the maximum dose (20 mg/day or 40 mg/day, depending on the weight group).
- There is inadequate information about metabolism of clobazam in patients with severe hepatic impairment.
- Therefore no dosing recommendation in those patients can be given.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Clobazam in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Clobazam in patients who are immunocompromised.
### Dosage Adjustments in CYP2C19 Poor Metabolizers
- In CYP2C19 poor metabolizers, levels of N-desmethylclobazam, clobazam's active metabolite, will be increased. Therefore, in patients known to be CYP2C19 poor metabolizers, the starting dose should be 5 mg/day and dose titration should proceed slowly according to weight, but to half the dose presented in Table 1, as tolerated.
- If necessary and based upon clinical response, an additional titration to the maximum dose (20 mg/day or 40 mg/day, depending on the weight group) may be started on day 21.
# Administration and Monitoring
### Administration
- Oral
- Instruct patients to read the "Instructions for Use" carefully for complete directions on how to properly dose and administer clobazam oral suspension.
### clobazam Tablet Oral Administration
- Clobazam tablets can be taken with or without food.
- Clobazam tablets can be administered whole, broken in half along the score, or crushed and mixed in applesauce.
### Clobazam Oral Suspension Oral Administration
- Clobazam oral suspension can be taken with or without food.
- Shake clobazam Oral Suspension well before every administration.
- When administering the oral suspension, use only the oral dosing syringe provided with the product.
- Each carton includes two syringes, but only one syringe should be used for dosing.
- The second oral syringe is reserved as a replacement in case the first syringe is damaged or lost.
- Insert the provided adapter firmly into the neck of the bottle before first use and keep the adapter in place for the duration of the usage of the bottle. *To withdraw the dose, insert the dosing syringe into the adapter and invert the bottle then slowly pull back the plunger to prescribed dose.
- After removing the syringe from the bottle adapter, slowly squirt clobazam Oral Suspension into the corner of the patient's mouth.
- Replace the cap after each use.
- The cap fits over the adapter when the adapter is properly placed.
### Monitoring
- Monitor for central nervous system (CNS) depression.
- Monitor patients with a history of substance abuse for signs of habituation and dependence.
- Monitor for suicidal thoughts or behaviors.
- Monitored for signs or symptoms of SJS/TEN, especially during the first 8 weeks of treatment initiation or when re-introducing therapy.
# IV Compatibility
There is limited information regarding the compatibility of Clobazam and IV administrations.
# Overdosage
### Signs and Symptoms of Overdosage
- Overdose and intoxication with benzodiazepines, including clobazam, may lead to CNS depression, associated with drowsiness, confusion and lethargy, possibly progressing to ataxia, respiratory depression, hypotension, and, rarely, coma or death.
- The risk of a fatal outcome is increased in cases of combined poisoning with other CNS depressants, including alcohol.
### Management of Overdosage
- The management of clobazam overdose may include gastric lavage and/or administration of activated charcoal, intravenous fluid replenishment, early control of airway and general supportive measures, in addition to monitoring level of consciousness and vital signs.
- Hypotension can be treated by replenishment with plasma substitutes and, if necessary, with sympathomimetic agents.
- The efficacy of supplementary administration of physostigmine (a cholinergic agent) or of flumazenil (a benzodiazepine antagonist) in clobazam overdose has not been assessed.
- The administration of flumazenil in cases of benzodiazepine overdose can lead to withdrawal and adverse reactions. Its use in patients with epilepsy is typically not recommended.
# Pharmacology
## Mechanism of Action
- The exact mechanism of action for clobazam, a 1,5-benzodiazepine, is not fully understood but is thought to involve potentiation of GABAergic neurotransmission resulting from binding at the benzodiazepine site of the GABAA receptor.
## Structure
- Clobazam is a white or almost white, crystalline powder with a slightly bitter taste; is slightly soluble in water, sparingly soluble in ethanol, and freely soluble in methylene chloride.
- The melting range of clobazam is from 182ºC to 185ºC.
- The molecular formula is C16H13O2N2Cl and the molecular weight is 300.7.
## Pharmacodynamics
### Effects on Electrocardiogram
- The effect of clobazam 20 mg and 80 mg administered twice daily on QTc interval was evaluated in a randomized, evaluator blinded, placebo-, and active-controlled (moxifloxacin 400 mg) parallel thorough QT study in 280 healthy subjects.
- In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% cclobazamdence interval for the largest placebo adjusted, baseline-corrected QTc based on the Fridericia correction method was below 10 ms, the threshold for regulatory concern.
- Thus, at a dose two times the maximum recommended dose, clobazam did not prolong the QTc interval to any clinically relevant extent.
## Pharmacokinetics
- The peak plasma levels (Cmax) and the area under the curve (AUC) of clobazam are dose-proportional over the dose range of 10-80 mg following single- or multiple-dose administration of clobazam.
- Based on a population pharmacokinetic analysis, the pharmacokinetics of clobazam are linear from 5-160 mg/day.
- Clobazam is converted to N-desmethylclobazam which has about 1/5 the activity of clobazam.
- The estimated mean elimination half-lives (t1/2) of clobazam and N-desmethylclobazam were 36-42 hours and 71-82 hours, respectively.
### Absorption
- Clobazam is rapidly and extensively absorbed following oral administration. *The time to peak concentrations (Tmax) of clobazam tablets under fasted conditions ranged from 0.5 to 4 hours after single- or multiple-dose administrations.
- The relative bioavailability of clobazam tablets compared to an oral solution is approximately 100%.
- After single dose administration of the oral suspension under fasted conditions, the Tmax ranged from 0.5 to 2 hours.
- Based on exposure (Cmax and AUC) of clobazam, clobazam tablets and suspension were shown to have similar bioavailability under fasted conditions.
- The administration of clobazam tablets with food or when crushed in applesauce does not affect absorption.
- Although not studied, the oral bioavailability of the oral suspension is unlikely to be affected under fed conditions.
### Distribution
- Clobazam is lipophilic and distributes rapidly throughout the body.
- The apparent volume of distribution at steady state was approximately 100 L. *The in vitro plasma protein binding of clobazam and N-desmethylclobazam is approximately 80-90% and 70%, respectively.
### Metabolism and Excretion
- Clobazam is extensively metabolized in the liver, with approximately 2% of the dose recovered in urine and 1% in feces as unchanged drug.
- The major metabolic pathway of clobazam involves N-demethylation, primarily by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6.
- N-desmethylclobazam, an active metabolite, is the major circulating metabolite in humans, and at therapeutic doses, plasma concentrations are 3-5 times higher than those of the parent compound.
- Based on animal and in vitro receptor binding data, estimates of the relative potency of N-desmethylclobazam compared to parent compound range from 1/5 to equal potency.
- N-desmethylclobazam is extensively metabolized, mainly by CYP2C19.
- N-desmethylclobazam and its metabolites comprise ~94% of the total drug-related components in urine.
- Following a single oral dose of radiolabeled drug, approximately 11% of the dose was excreted in the feces and approximately 82% was excreted in the urine.
- The polymorphic CYP2C19 is the major contributor to the metabolism of the pharmacologically active N-desmethylclobazam.
- In CYP2C19 poor metabolizers, levels of N-desmethylclobazam were 5-fold higher in plasma and 2- to 3-fold higher in the urine than in CYP2C19 extensive metabolizers.
### Pharmacokinetics in Specific Populations
- Population pharmacokinetic analyses showed that the clearance of clobazam is lower in elderly subjects compared to other age groups (ages 2 to 64).
- Dosing should be adjusted in the elderly.
- Population pharmacokinetic analyses showed no difference in the clearance of clobazam between women and men.
- Population pharmacokinetic analyses including Caucasian (75%), African American (15%), and Asian (9%) subjects showed that there is no evidence of clinically significant effect of race on the clearance of clobazam.
- The effect of renal impairment on the pharmacokinetics of clobazam was evaluated in patients with mild (creatinine clearance >50 to 80 mL/min; N=6) and moderate (CLCR=30 to 50 mL/min; N=6) renal dysfunction, with matching healthy controls (N=6), following administration of multiple doses of clobazam 20 mg/day.
- There were insignificant changes in Cmax (3-24%) and AUC (≤13%) for clobazam or N-desmethylclobazam in patients with mild or moderate renal impairment compared to patients with normal renal function.
- Patients with severe renal impairment or ESRD were not included in this study.
- There are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of clobazam.
- In a small study, the pharmacokinetics of a 20 mg single oral dose of clobazam in 9 patients with liver impairment were compared to healthy controls (N=6).
- The Cmax and the mean plasma clearance of clobazam, as well as the Cmax of N-desmethylclobazam, showed no significant change compared to the healthy controls.
- The AUC values of N-desmethylclobazam in these patients were not available. Adjust dosage in patients with hepatic impairment.
### Drug Interaction Studies
- Clobazam did not inhibit: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A1, UGT1A4, UGT1A6, or UGT2B4 in vitro.
- N-desmethylclobazam showed weak inhibition of: CYP2C9, UGT1A4, UGT1A6 and UGT2B4.
- Clobazam and N-desmethylclobazam did not significantly increase CYP1A2 or CYP2C19 activities, but did induce CYP3A4 activity in a concentration-dependent manner.
- Clobazam and N-desmethylclobazam also increased UGT1A1 mRNA but at concentrations much higher than therapeutic levels.
- The potential for clobazam or N-desmethylclobazam to induce CYP2B6and CYP2C8 has not been evaluated.
- Clobazam and N-desmethylclobazam do not inhibit P-glycoprotein (P-gp), but are P-gp substrates.
Potential for clobazam to Affect Other Drugs
- The effect of repeated 40 mg once-daily doses of clobazam on the pharmacokinetic profiles of single-dose dextromethorphan (CYP2D6 substrate), midazolam (CYP3A4 substrate), caffeine (CYP1A2 substrate), and tolbutamide (CYP2C9 substrate), was studied when these probe substrates were given as a drug cocktail (N=18).
- Clobazam increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively, reflecting its inhibition of CYP2D6 in vivo.
- Drugs metabolized by CYP2D6 may require dose adjustment when used with clobazam.
- Clobazam decreased the AUC and Cmax of midazolam by 27% and 24%, respectively, and increased the AUC and Cmax of the metabolite 1-hydroxymidazolam by 4-fold and 2-fold, respectively.
- This level of induction does not call for dosage adjustment of drugs that are primarily metabolized by CYP3A4 when used concomitantly with clobazam.
- Some hormonal contraceptives are metabolized by CYP3A4 and their effectiveness may be diminished when given with clobazam. Repeated clobazam doses had no effect on caffeine and tolbutamide.
- A population pharmacokinetic analysis indicated clobazam did not affect the exposure of valproic acid (a CYP2C9/2C19 substrate) or lamotrigine (a UGT substrate).
Potential for Other Drugs to Affect clobazam
- Co-administration of ketoconazole (a strong CYP3A4 inhibitor) 400 mg once-daily for 5 days increased clobazam AUC by 54%, with an insignificant effect on clobazam Cmax.
- There was no significant change in AUC and Cmax of N-desmethylclobazam (N=18).
- Strong (e.g., fluconazole, fluvoxamine, ticlopidine) and moderate (e.g., omeprazole) inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam, the active metabolite of clobazam, based on extrapolation from pharmacogenomic data.
- Dosage adjustment of clobazam may be necessary when co-administered with strong or moderate CYP2C19 inhibitors.
- The effects of concomitant antiepileptic drugs that are CYP3A4 inducers (phenobarbital, phenytoin, and carbamazepine), CYP2C9 inducers (valproic acid, phenobarbital, phenytoin, and carbamazepine), and CYP2C9 inhibitors (felbamate and oxcarbazepine) were evaluated using data from clinical trials.
- Results of population pharmacokinetic analysis show that these concomitant antiepileptic drugs did not significantly alter the pharmacokinetics of clobazam or N-desmethylclobazam at steady-state.
- Alcohol has been reported to increase the maximum plasma exposure of clobazam by approximately 50%. Alcohol may have additive CNS depressant effects when taken with clobazam.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- The carcinogenic potential of clobazam has not been adequately assessed.
- In a limited study in rats, oral administration of clobazam (4, 20, and 100 mg/kg/day) for 2 years resulted in an increased incidence of thyroid follicular cell adenomas in males at the high dose.
- Clobazam and the major active metabolite, N-desmethylclobazam, were negative for genotoxicity, based on data from a battery of in vitro (bacteria reverse mutation, mammalian clastogenicity) and in vivo (mouse micronucleus) assays.
- In a study in which clobazam (50, 350, or 750 mg/kg/day) was orally administered to male and female rats prior to and during mating and continuing in females to gestation day 6, increases in abnormal sperm and pre-implantation loss were observed at the highest dose tested.
- The no effect level for fertility and early embryonic development in rats was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, less than those in humans at the maximum recommended human dose of 40 mg/day.
# Clinical Studies
The effectiveness of clobazam for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome was established in two multicenter controlled studies (Study 1 and Study 2). Both studies were similar in terms of disease characteristics and concomitant AED treatments. The most common concomitant AED treatments at baseline included: valproate, lamotrigine, levetiracetam, and topiramate.
### Study 1
Study 1 (N=238) was a randomized, double-blind, placebo-controlled study consisting of a 4-week baseline period followed by a 3-week titration period and 12-week maintenance period. Patients age 2-54 years with a current or prior diagnosis of LGS were stratified into 2 weight groups (12.5 kg to ≤30 kg or >30 kg) and then randomized to placebo or one of three target maintenance doses of clobazam according to Table 5.
Doses above 5 mg/day were administered in two divided doses.
The primary efficacy measure was the percent reduction in the weekly frequency of drop seizures (atonic, tonic, or myoclonic), also known as drop attacks, from the 4-week baseline period to 12-week maintenance period.
The pre-dosing baseline mean weekly drop seizure frequency was 98, 100, 61, and 105 for the placebo, low-, medium-, and high-dose groups, respectively. Figure 1 presents the mean percent reduction in weekly drop seizures from this baseline. All dose groups of clobazam were statistically superior (p≤0.05) to the placebo group. This effect appeared to be dose dependent.
Figure 2 shows changes from baseline in weekly drop seizure frequency by category for patients treated with clobazam and placebo in Study 1. Patients in whom the seizure frequency increased are shown at left as "worse." Patients in whom the seizure frequency decreased are shown in five categories.
There was no evidence that tolerance to the therapeutic effect of clobazam developed during the 3-month maintenance period.
### Study 2
Study 2 (N=68) was a randomized, double-blind comparison study of high- and low-dose clobazam, consisting of a 4-week baseline period followed by a 3-week titration period and 4-week maintenance period. Patients age 2-25 years with a current or prior diagnosis of LGS were stratified by weight, then randomized to either a low or high dose of clobazam, and then entered a 3-week titration period.
The primary efficacy measure was the percent reduction in the weekly frequency of drop seizures (atonic, tonic, or myoclonic), also known as drop attacks, from the 4-week baseline period to the 4-week maintenance period.
A statistically significantly greater reduction in seizure frequency was observed in the high-dose group compared to the low-dose group (median percent reduction of 93% vs 29%; p<0.05).
# How Supplied
### Clobazam- Tablets
Each clobazam tablet contains 10 mg or 20 mg of clobazam.
- It is a white to off-white, oval tablet with a functional score on one side and either a "1" and "0" or a "2" and "0" debossed on the other side.
NDC 67386-314-01: 10 mg scored tablet, Bottles of 100
NDC 67386-315-01: 20 mg scored tablet, Bottles of 100
- NDC 67386-314-01: 10 mg scored tablet, Bottles of 100
- NDC 67386-315-01: 20 mg scored tablet, Bottles of 100
### Clobazam- Oral suspension
- Clobazam oral suspension is a berry flavored off-white liquid supplied in a bottle with child-resistant closure.
- The oral suspension is packaged with a dispenser set which contains two calibrated oral dosing syringes and a bottle adapter.
NDC 67386-313-21: 2.5 mg/mL supplied in a bottle containing 120 mL of suspension.
- NDC 67386-313-21: 2.5 mg/mL supplied in a bottle containing 120 mL of suspension.
## Storage
### Clobazam Tablets
- Store tablets and oral suspension at 20°C to 25°C (68°F to 77°F). See USP controlled room temperature.
### Clobazam Oral suspension
- Store and dispense clobazam oral suspension in its original bottle in an upright position.
- Use within 90 days of first opening the bottle, then discard any remainder
- Store tablets and oral suspension at 20°C to 25°C (68°F to 77°F). See USP controlled room temperature.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### Hypersensitivity
Inform patients or caregivers that clobazam is contraindicated in patients with a history of hypersensitivity to the drug or its ingredients.
### Somnolence or Sedation
Advise patients or caregivers to check with their healthcare provider before clobazam is taken with other CNS depressants such as other benzodiazepines, opioids, tricyclic antidepressants, sedating antihistamines, or alcohol.
If applicable, caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that clobazam does not affect them adversely (e.g., impair judgment, thinking or motor skills).
### Increasing or Decreasing the clobazam Dose
Inform patients or caregivers to consult their healthcare provider before increasing the clobazam dose or abruptly discontinuing clobazam. Advise patients or caregivers that abrupt withdrawal of AEDs may increase their risk of seizure.
### Interactions with Hormonal Contraceptives
Counsel women to also use non-hormonal methods of contraception when clobazam is used with hormonal contraceptives and to continue these alternative methods for 28 days after discontinuing clobazam to ensure contraceptive reliability.
### Serious Dermatological Reactions
Advise patients or caregivers that serious skin reactions have been reported in patients taking clobazam. Serious skin reactions, including SJS/TEN, may need to be treated in a hospital and may be life-threatening. If a skin reaction occurs while taking clobazam, patients or caregivers should consult with healthcare providers immediately.
### Suicidal Thinking and Behavior
Counsel patients, their caregivers, and their families that AEDs, including clobazam, may increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm. Patients should report behaviors of concern immediately to healthcare providers.
### Use in Pregnancy
Instruct patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy.
### Use in Nursing
Instruct patients to notify their physician if they are breast feeding or intend to breast feed during therapy.
# Precautions with Alcohol
- Since clobazam has a central nervous system (CNS) depressant effect, patients or their caregivers should be cautioned against simultaneous use with other CNS depressant drugs or alcohol, and cautioned that the effects of other CNS depressant drugs or alcohol may be potentiated.
# Brand Names
- ONFI
# Look-Alike Drug Names
There is limited information regarding Clobazam Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Clobazam
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Stefano Giannoni [2]
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# Overview
Clobazam is a Benzodiazepine that is FDA approved for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older. Common adverse reactions include constipation, somnolence or sedation, pyrexia, lethargy, and drooling.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Seizures associated with Lennox-Gastaut syndrome (LGS)
- A daily dose of clobazam greater than 5 mg should be administered in divided doses twice daily
- 5 mg daily dose can be administered as a single dose.
- Dose patients according to body weight.
- Do not proceed with dose escalation more rapidly than weekly, because serum concentrations of clobazam and its active metabolite require 5 and 9 days, respectively, to reach steady-state.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Clobazam in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Clobazam in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Seizures associated with Lennox-Gastaut syndrome (LGS) (2 years of age or older)
- A daily dose of clobazam greater than 5 mg should be administered in divided doses twice daily
- 5 mg daily dose can be administered as a single dose.
- Dose patients according to body weight.
- Do not proceed with dose escalation more rapidly than weekly, because serum concentrations of clobazam and its active metabolite require 5 and 9 days, respectively, to reach steady-state.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Clobazam in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Clobazam in pediatric patients.
# Contraindications
- Clobazam is contraindicated in patients with a history of hypersensitivity to the drug or its ingredients.
- Hypersensitivity reactions have included serious dermatological reactions.
# Warnings
### Somnolence or Sedation
- Clobazam causes somnolence and sedation.
- In clinical trials, somnolence or sedation was reported at all effective doses and was dose-related.
- In general, somnolence and sedation begin within the first month of treatment and may diminish with continued treatment.
- Prescribers should monitor patients for somnolence and sedation, particularly with concomitant use of other central nervous system depressants.
- Prescribers should caution patients against engaging in hazardous activities requiring mental alertness, such as operating dangerous machinery or motor vehicles, until the effect of clobazam is known.
### Potentiation of Sedation from Concomitant Use with Central Nervous System Depressants
- Since clobazam has a central nervous system (CNS) depressant effect, patients or their caregivers should be cautioned against simultaneous use with other CNS depressant drugs or alcohol, and cautioned that the effects of other CNS depressant drugs or alcohol may be potentiated.
### Withdrawal Symptoms
- Abrupt discontinuation of clobazam should be avoided.
- Clobazam should be tapered by decreasing the dose every week by 5-10 mg/day until discontinuation.
- Withdrawal symptoms (Benzodiazepine withdrawal syndrome) occurred following abrupt discontinuation of clobazam; the risk of withdrawal symptoms is greater with higher doses.
- As with all antiepileptic drugs, clobazam should be withdrawn gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus.
- Withdrawal symptoms (e.g., convulsions, psychosis, hallucinations, behavioral disorder, tremor, and anxiety) have been reported following abrupt discontinuance of benzodiazepines.
- The more severe withdrawal symptoms have usually been limited to patients who received excessive doses over an extended period of time, followed by an abrupt discontinuation.
- Generally milder withdrawal symptoms (e.g., dysphoria, anxiety, and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic doses for several months.
### Serious Dermatological Reactions
- Serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported with clobazam in both children and adults during the post-marketing period.
- Patients should be closely monitored for signs or symptoms of SJS/TEN, especially during the first 8 weeks of treatment initiation or when re-introducing therapy.
- Clobazam should be discontinued at the first sign of rash, unless the rash is clearly not drug-related.
- If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.
### Physical and Psychological Dependence
- Patients with a history of substance abuse should be under careful surveillance when receiving clobazam or other psychotropic agents because of the predisposition of such patients to habituation and dependence.
### Suicidal Behavior and Ideation
- Antiepileptic drugs (AEDs), including clobazam, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.
- Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% cclobazamdence interval [CI]: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED treated patients was 0.43%, compared to 0.24% among 16,029 placebo treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated.
- There were four suicides in drug treated patients in the trials and none in placebo treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed.
- Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.
- The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
- Anyone considering prescribing clobazam or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.
- Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.
- Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
- Behaviors of concern should be reported immediately to healthcare providers.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- During its development for the adjunctive treatment of seizures associated with LGS, clobazam was administered to 333 healthy volunteers and 300 patients with a current or prior diagnosis of LGS, including 197 patients treated for 12 months or more.
- The conditions and duration of exposure varied greatly and included single- and multiple-dose clinical pharmacology studies in healthy volunteers and two double-blind studies in patients with LGS (Study 1 and 2). Only Study 1 included a placebo group, allowing comparison of adverse reaction rates on clobazam at several doses to placebo.
Adverse Reactions Leading to Discontinuation in an LGS Placebo Controlled Clinical Trial (Study 1)
- The adverse reactions associated with clobazam treatment discontinuation in ≥1% of patients in decreasing order of frequency included lethargy, somnolence, ataxia, aggression, fatigue, and insomnia.
Most Common Adverse Reactions in an LGS Placebo Controlled Clinical Trial (Study 1)
Table 3 lists the adverse reactions that occurred in ≥5% of clobazam treated patients (at any dose), and at a rate greater than placebo treated patients, in the randomized, double-blind, placebo-controlled, parallel group clinical study of adjunctive AED therapy for 15 weeks (Study 1).
## Postmarketing Experience
These reactions are reported voluntarily from a population of uncertain size; therefore, it is not possible to estimate their frequency or establish a causal relationship to drug exposure.
Adverse reactions are categorized by system organ class.
### Blood Disorders
- Anemia
- Eosinophilia
- Leukopenia
- Thrombocytopenia
### Eye Disorders
- Diplopia
- Vision blurred
### Gastrointestinal Disorders
- Abdominal distention
### General Disorders and Administration Site Conditions
- Hypothermia
### Investigations
- Hepatic enzyme increased
### Musculoskeletal
- Muscle spasms
### Psychiatric Disorders
- Agitation
- Anxiety
- Apathy
- Confusional state
- Depression
- Delirium
- Delusion
- Hallucination
### Renal and Urinary Disorders
- Urinary retention
### Respiratory Disorders
- Aspiration
- Respiratory depression
### Skin and Subcutaneous Tissue Disorders
- Rash
- Urticaria
- Angioedema
- Facial and lip edema
# Drug Interactions
### Effect of clobazam on Other Drugs
- Clobazam is a weak CYP3A4 inducer.
- As some hormonal contraceptives are metabolized by CYP3A4, their effectiveness may be diminished when given with clobazam.
- Additional non-hormonal forms of contraception are recommended when using clobazam.
- Clobazam inhibits CYP2D6.
- Dose adjustment of drugs metabolized by CYP2D6 may be necessary.
- Strong and moderate inhibitors of CYP2C19
- Strong and moderate inhibitors of CYP2C19 may result in increased exposure to N-desmethylclobazam, the active metabolite of clobazam.
- This may increase the risk of dose-related adverse reactions.
- Dosage adjustment of clobazam may be necessary when co-administered with strong CYP2C19 inhibitors (e.g., fluconazole, fluvoxamine, ticlopidine) or moderate CYP2C19 inhibitors (e.g., omeprazole).
### CNS Depressants and Alcohol
- Concomitant use of clobazam with other CNS depressants may increase the risk of sedation and somnolence.
- Alcohol, as a CNS depressant, will interact with clobazam in a similar way and also increases clobazam's maximum plasma exposure by approximately 50%. Therefore, caution patients or their caregivers against simultaneous use with other CNS depressant drugs or alcohol, and caution that the effects of other CNS depressant drugs or alcohol may be potentiated.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies of clobazam in pregnant women.
- In animal studies, administration of clobazam during pregnancy resulted in developmental toxicity, including increased incidences of fetal malformations, at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those expected at therapeutic doses in patients. Clobazam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Available human data on the risk of teratogenicity associated with benzodiazepines are inconclusive.
- There is insufficient evidence in humans to assess the effect of benzodiazepine exposure during pregnancy on neurodevelopment.
- Administration of benzodiazepines immediately prior to or during childbirth can result in a syndrome of hypothermia, hypotonia, respiratory depression, and difficulty feeding.
- In addition, infants born to mothers who have taken benzodiazepines during the later stages of pregnancy can develop dependence, and subsequently withdrawal, during the postnatal period.
- Data for other benzodiazepines suggest the possibility of adverse developmental effects (including long-term effects on neurobehavioral and immunological function) in animals following prenatal exposure to benzodiazepines at clinically relevant doses.
- In a study in which clobazam (150, 450, or 750 mg/kg/day) was orally administered to pregnant rats throughout the period of organogenesis, embryofetal mortality and incidences of fetal skeletal variations were increased at all doses.
- The low effect dose for embryofetal developmental toxicity in rats (150 mg/kg/day) was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, lower than those in humans at the maximum recommended human dose (MRHD) of 40 mg/day.
- Oral administration of clobazam (10, 30, or 75 mg/kg/day) to pregnant rabbits throughout the period of organogenesis resulted in decreased fetal body weights, and increased incidences of fetal malformations (visceral and skeletal) at the mid and high doses, and an increase in embryofetal mortality at the high dose.
- Incidences of fetal variations were increased at all doses.
- The highest dose tested was associated with maternal toxicity (ataxia and decreased activity).
- The low effect dose for embryofetal developmental toxicity in rabbits (10 mg/kg/day) was associated with plasma exposures for clobazam and N-desmethylclobazam lower than those in humans at the MRHD.
- Oral administration of clobazam (50, 350, or 750 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased embryofetal mortality at the high dose, decreased pup survival at the mid and high doses and alterations in offspring behavior (locomotor activity) at all doses. The low effect dose for adverse effects on pre- and postnatal development in rats (50 mg/kg/day) was associated with plasma exposures for clobazam and N-desmethylclobazam lower than those in humans at the MRHD.
Pregnancy Category (AUS): C
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clobazam in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Clobazam during labor and delivery.
### Nursing Mothers
- Clobazam is excreted in human milk.
- Because of the potential for serious adverse reactions in nursing infants from clobazam, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in patients less than 2 years of age have not been established.
- In a study in which clobazam (4, 36, or 120 mg/kg/day) was orally administered to rats during the juvenile period of development (postnatal days 14 to 48), adverse effects on growth (decreased bone density and bone length) and behavior (altered motor activity and auditory startle response; learning deficit) were observed at the high dose.
- The effect on bone density, but not on behavior, was reversible when drug was discontinued.
- The no-effect level for juvenile toxicity (36 mg/kg/day) was associated with plasma exposures (AUC) to clobazam and its major active metabolite, N-desmethylclobazam, less than those expected at therapeutic doses in pediatric patients.
### Geriatic Use
- Plasma concentrations at any given dose are generally higher in the elderly: proceed slowly with dose escalation.
- The starting dose should be 5 mg/day for all elderly patients.
- Then titrate elderly patients according to weight, but to half the dose presented in Table 1, as tolerated.
- If necessary and based upon clinical response, an additional titration to the maximum dose (20 mg/day or 40 mg/day, depending on weight) may be started on day 21.
- Clinical studies of clobazam did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, elderly subjects appear to eliminate clobazam more slowly than younger subjects based on population pharmacokinetic analysis. For these reasons, the initial dose in elderly patients should be 5 mg/day.
### Gender
- Population pharmacokinetic analyses showed no difference in the clearance of clobazam between women and men.
### Race
- Population pharmacokinetic analyses including Caucasian (75%), African American (15%), and Asian (9%) subjects showed that there is no evidence of clinically significant effect of race on the clearance of clobazam.
### Renal Impairment
- No dose adjustment is required for patients with mild and moderate renal impairment.
- There is no experience with clobazam in patients with severe renal impairment or end stage renal disease (ESRD).
- It is not known if clobazam or its active metabolite, N-desmethylclobazam, is dialyzable.
### Hepatic Impairment
- Clobazam is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of clobazam. *For this reason, proceed slowly with dosing escalations.
- For patients with mild to moderate hepatic impairment (Child-Pugh score 5-9), the starting dose should be 5 mg/day in both weight groups.
- Then titrate patients according to weight, but to half the dose presented in Table 1, as tolerated.
- If necessary and based upon clinical response, start an additional titration on day 21 to the maximum dose (20 mg/day or 40 mg/day, depending on the weight group).
- There is inadequate information about metabolism of clobazam in patients with severe hepatic impairment.
- Therefore no dosing recommendation in those patients can be given.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Clobazam in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Clobazam in patients who are immunocompromised.
### Dosage Adjustments in CYP2C19 Poor Metabolizers
- In CYP2C19 poor metabolizers, levels of N-desmethylclobazam, clobazam's active metabolite, will be increased. Therefore, in patients known to be CYP2C19 poor metabolizers, the starting dose should be 5 mg/day and dose titration should proceed slowly according to weight, but to half the dose presented in Table 1, as tolerated.
- If necessary and based upon clinical response, an additional titration to the maximum dose (20 mg/day or 40 mg/day, depending on the weight group) may be started on day 21.
# Administration and Monitoring
### Administration
- Oral
- Instruct patients to read the "Instructions for Use" carefully for complete directions on how to properly dose and administer clobazam oral suspension.
### clobazam Tablet Oral Administration
- Clobazam tablets can be taken with or without food.
- Clobazam tablets can be administered whole, broken in half along the score, or crushed and mixed in applesauce.
### Clobazam Oral Suspension Oral Administration
- Clobazam oral suspension can be taken with or without food.
- Shake clobazam Oral Suspension well before every administration.
- When administering the oral suspension, use only the oral dosing syringe provided with the product.
- Each carton includes two syringes, but only one syringe should be used for dosing.
- The second oral syringe is reserved as a replacement in case the first syringe is damaged or lost.
- Insert the provided adapter firmly into the neck of the bottle before first use and keep the adapter in place for the duration of the usage of the bottle. *To withdraw the dose, insert the dosing syringe into the adapter and invert the bottle then slowly pull back the plunger to prescribed dose.
- After removing the syringe from the bottle adapter, slowly squirt clobazam Oral Suspension into the corner of the patient's mouth.
- Replace the cap after each use.
- The cap fits over the adapter when the adapter is properly placed.
### Monitoring
- Monitor for central nervous system (CNS) depression.
- Monitor patients with a history of substance abuse for signs of habituation and dependence.
- Monitor for suicidal thoughts or behaviors.
- Monitored for signs or symptoms of SJS/TEN, especially during the first 8 weeks of treatment initiation or when re-introducing therapy.
# IV Compatibility
There is limited information regarding the compatibility of Clobazam and IV administrations.
# Overdosage
### Signs and Symptoms of Overdosage
- Overdose and intoxication with benzodiazepines, including clobazam, may lead to CNS depression, associated with drowsiness, confusion and lethargy, possibly progressing to ataxia, respiratory depression, hypotension, and, rarely, coma or death.
- The risk of a fatal outcome is increased in cases of combined poisoning with other CNS depressants, including alcohol.
### Management of Overdosage
- The management of clobazam overdose may include gastric lavage and/or administration of activated charcoal, intravenous fluid replenishment, early control of airway and general supportive measures, in addition to monitoring level of consciousness and vital signs.
- Hypotension can be treated by replenishment with plasma substitutes and, if necessary, with sympathomimetic agents.
- The efficacy of supplementary administration of physostigmine (a cholinergic agent) or of flumazenil (a benzodiazepine antagonist) in clobazam overdose has not been assessed.
- The administration of flumazenil in cases of benzodiazepine overdose can lead to withdrawal and adverse reactions. Its use in patients with epilepsy is typically not recommended.
# Pharmacology
## Mechanism of Action
- The exact mechanism of action for clobazam, a 1,5-benzodiazepine, is not fully understood but is thought to involve potentiation of GABAergic neurotransmission resulting from binding at the benzodiazepine site of the GABAA receptor.
## Structure
- Clobazam is a white or almost white, crystalline powder with a slightly bitter taste; is slightly soluble in water, sparingly soluble in ethanol, and freely soluble in methylene chloride.
- The melting range of clobazam is from 182ºC to 185ºC.
- The molecular formula is C16H13O2N2Cl and the molecular weight is 300.7.
## Pharmacodynamics
### Effects on Electrocardiogram
- The effect of clobazam 20 mg and 80 mg administered twice daily on QTc interval was evaluated in a randomized, evaluator blinded, placebo-, and active-controlled (moxifloxacin 400 mg) parallel thorough QT study in 280 healthy subjects.
- In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% cclobazamdence interval for the largest placebo adjusted, baseline-corrected QTc based on the Fridericia correction method was below 10 ms, the threshold for regulatory concern.
- Thus, at a dose two times the maximum recommended dose, clobazam did not prolong the QTc interval to any clinically relevant extent.
## Pharmacokinetics
- The peak plasma levels (Cmax) and the area under the curve (AUC) of clobazam are dose-proportional over the dose range of 10-80 mg following single- or multiple-dose administration of clobazam.
- Based on a population pharmacokinetic analysis, the pharmacokinetics of clobazam are linear from 5-160 mg/day.
- Clobazam is converted to N-desmethylclobazam which has about 1/5 the activity of clobazam.
- The estimated mean elimination half-lives (t1/2) of clobazam and N-desmethylclobazam were 36-42 hours and 71-82 hours, respectively.
### Absorption
- Clobazam is rapidly and extensively absorbed following oral administration. *The time to peak concentrations (Tmax) of clobazam tablets under fasted conditions ranged from 0.5 to 4 hours after single- or multiple-dose administrations.
- The relative bioavailability of clobazam tablets compared to an oral solution is approximately 100%.
- After single dose administration of the oral suspension under fasted conditions, the Tmax ranged from 0.5 to 2 hours.
- Based on exposure (Cmax and AUC) of clobazam, clobazam tablets and suspension were shown to have similar bioavailability under fasted conditions.
- The administration of clobazam tablets with food or when crushed in applesauce does not affect absorption.
- Although not studied, the oral bioavailability of the oral suspension is unlikely to be affected under fed conditions.
### Distribution
- Clobazam is lipophilic and distributes rapidly throughout the body.
- The apparent volume of distribution at steady state was approximately 100 L. *The in vitro plasma protein binding of clobazam and N-desmethylclobazam is approximately 80-90% and 70%, respectively.
### Metabolism and Excretion
- Clobazam is extensively metabolized in the liver, with approximately 2% of the dose recovered in urine and 1% in feces as unchanged drug.
- The major metabolic pathway of clobazam involves N-demethylation, primarily by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6.
- N-desmethylclobazam, an active metabolite, is the major circulating metabolite in humans, and at therapeutic doses, plasma concentrations are 3-5 times higher than those of the parent compound.
- Based on animal and in vitro receptor binding data, estimates of the relative potency of N-desmethylclobazam compared to parent compound range from 1/5 to equal potency.
- N-desmethylclobazam is extensively metabolized, mainly by CYP2C19.
- N-desmethylclobazam and its metabolites comprise ~94% of the total drug-related components in urine.
- Following a single oral dose of radiolabeled drug, approximately 11% of the dose was excreted in the feces and approximately 82% was excreted in the urine.
- The polymorphic CYP2C19 is the major contributor to the metabolism of the pharmacologically active N-desmethylclobazam.
- In CYP2C19 poor metabolizers, levels of N-desmethylclobazam were 5-fold higher in plasma and 2- to 3-fold higher in the urine than in CYP2C19 extensive metabolizers.
### Pharmacokinetics in Specific Populations
- Population pharmacokinetic analyses showed that the clearance of clobazam is lower in elderly subjects compared to other age groups (ages 2 to 64).
- Dosing should be adjusted in the elderly.
- Population pharmacokinetic analyses showed no difference in the clearance of clobazam between women and men.
- Population pharmacokinetic analyses including Caucasian (75%), African American (15%), and Asian (9%) subjects showed that there is no evidence of clinically significant effect of race on the clearance of clobazam.
- The effect of renal impairment on the pharmacokinetics of clobazam was evaluated in patients with mild (creatinine clearance [CLCR] >50 to 80 mL/min; N=6) and moderate (CLCR=30 to 50 mL/min; N=6) renal dysfunction, with matching healthy controls (N=6), following administration of multiple doses of clobazam 20 mg/day.
- There were insignificant changes in Cmax (3-24%) and AUC (≤13%) for clobazam or N-desmethylclobazam in patients with mild or moderate renal impairment compared to patients with normal renal function.
- Patients with severe renal impairment or ESRD were not included in this study.
- There are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of clobazam.
- In a small study, the pharmacokinetics of a 20 mg single oral dose of clobazam in 9 patients with liver impairment were compared to healthy controls (N=6).
- The Cmax and the mean plasma clearance of clobazam, as well as the Cmax of N-desmethylclobazam, showed no significant change compared to the healthy controls.
- The AUC values of N-desmethylclobazam in these patients were not available. Adjust dosage in patients with hepatic impairment.
### Drug Interaction Studies
- Clobazam did not inhibit: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A1, UGT1A4, UGT1A6, or UGT2B4 in vitro.
- N-desmethylclobazam showed weak inhibition of: CYP2C9, UGT1A4, UGT1A6 and UGT2B4.
- Clobazam and N-desmethylclobazam did not significantly increase CYP1A2 or CYP2C19 activities, but did induce CYP3A4 activity in a concentration-dependent manner.
- Clobazam and N-desmethylclobazam also increased UGT1A1 mRNA but at concentrations much higher than therapeutic levels.
- The potential for clobazam or N-desmethylclobazam to induce CYP2B6and CYP2C8 has not been evaluated.
- Clobazam and N-desmethylclobazam do not inhibit P-glycoprotein (P-gp), but are P-gp substrates.
Potential for clobazam to Affect Other Drugs
- The effect of repeated 40 mg once-daily doses of clobazam on the pharmacokinetic profiles of single-dose dextromethorphan (CYP2D6 substrate), midazolam (CYP3A4 substrate), caffeine (CYP1A2 substrate), and tolbutamide (CYP2C9 substrate), was studied when these probe substrates were given as a drug cocktail (N=18).
- Clobazam increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively, reflecting its inhibition of CYP2D6 in vivo.
- Drugs metabolized by CYP2D6 may require dose adjustment when used with clobazam.
- Clobazam decreased the AUC and Cmax of midazolam by 27% and 24%, respectively, and increased the AUC and Cmax of the metabolite 1-hydroxymidazolam by 4-fold and 2-fold, respectively.
- This level of induction does not call for dosage adjustment of drugs that are primarily metabolized by CYP3A4 when used concomitantly with clobazam.
- Some hormonal contraceptives are metabolized by CYP3A4 and their effectiveness may be diminished when given with clobazam. Repeated clobazam doses had no effect on caffeine and tolbutamide.
- A population pharmacokinetic analysis indicated clobazam did not affect the exposure of valproic acid (a CYP2C9/2C19 substrate) or lamotrigine (a UGT substrate).
Potential for Other Drugs to Affect clobazam
- Co-administration of ketoconazole (a strong CYP3A4 inhibitor) 400 mg once-daily for 5 days increased clobazam AUC by 54%, with an insignificant effect on clobazam Cmax.
- There was no significant change in AUC and Cmax of N-desmethylclobazam (N=18).
- Strong (e.g., fluconazole, fluvoxamine, ticlopidine) and moderate (e.g., omeprazole) inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam, the active metabolite of clobazam, based on extrapolation from pharmacogenomic data.
- Dosage adjustment of clobazam may be necessary when co-administered with strong or moderate CYP2C19 inhibitors.
- The effects of concomitant antiepileptic drugs that are CYP3A4 inducers (phenobarbital, phenytoin, and carbamazepine), CYP2C9 inducers (valproic acid, phenobarbital, phenytoin, and carbamazepine), and CYP2C9 inhibitors (felbamate and oxcarbazepine) were evaluated using data from clinical trials.
- Results of population pharmacokinetic analysis show that these concomitant antiepileptic drugs did not significantly alter the pharmacokinetics of clobazam or N-desmethylclobazam at steady-state.
- Alcohol has been reported to increase the maximum plasma exposure of clobazam by approximately 50%. Alcohol may have additive CNS depressant effects when taken with clobazam.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- The carcinogenic potential of clobazam has not been adequately assessed.
- In a limited study in rats, oral administration of clobazam (4, 20, and 100 mg/kg/day) for 2 years resulted in an increased incidence of thyroid follicular cell adenomas in males at the high dose.
- Clobazam and the major active metabolite, N-desmethylclobazam, were negative for genotoxicity, based on data from a battery of in vitro (bacteria reverse mutation, mammalian clastogenicity) and in vivo (mouse micronucleus) assays.
- In a study in which clobazam (50, 350, or 750 mg/kg/day) was orally administered to male and female rats prior to and during mating and continuing in females to gestation day 6, increases in abnormal sperm and pre-implantation loss were observed at the highest dose tested.
- The no effect level for fertility and early embryonic development in rats was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, less than those in humans at the maximum recommended human dose of 40 mg/day.
# Clinical Studies
The effectiveness of clobazam for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome was established in two multicenter controlled studies (Study 1 and Study 2). Both studies were similar in terms of disease characteristics and concomitant AED treatments. The most common concomitant AED treatments at baseline included: valproate, lamotrigine, levetiracetam, and topiramate.
### Study 1
Study 1 (N=238) was a randomized, double-blind, placebo-controlled study consisting of a 4-week baseline period followed by a 3-week titration period and 12-week maintenance period. Patients age 2-54 years with a current or prior diagnosis of LGS were stratified into 2 weight groups (12.5 kg to ≤30 kg or >30 kg) and then randomized to placebo or one of three target maintenance doses of clobazam according to Table 5.
Doses above 5 mg/day were administered in two divided doses.
The primary efficacy measure was the percent reduction in the weekly frequency of drop seizures (atonic, tonic, or myoclonic), also known as drop attacks, from the 4-week baseline period to 12-week maintenance period.
The pre-dosing baseline mean weekly drop seizure frequency was 98, 100, 61, and 105 for the placebo, low-, medium-, and high-dose groups, respectively. Figure 1 presents the mean percent reduction in weekly drop seizures from this baseline. All dose groups of clobazam were statistically superior (p≤0.05) to the placebo group. This effect appeared to be dose dependent.
Figure 2 shows changes from baseline in weekly drop seizure frequency by category for patients treated with clobazam and placebo in Study 1. Patients in whom the seizure frequency increased are shown at left as "worse." Patients in whom the seizure frequency decreased are shown in five categories.
There was no evidence that tolerance to the therapeutic effect of clobazam developed during the 3-month maintenance period.
### Study 2
Study 2 (N=68) was a randomized, double-blind comparison study of high- and low-dose clobazam, consisting of a 4-week baseline period followed by a 3-week titration period and 4-week maintenance period. Patients age 2-25 years with a current or prior diagnosis of LGS were stratified by weight, then randomized to either a low or high dose of clobazam, and then entered a 3-week titration period.
The primary efficacy measure was the percent reduction in the weekly frequency of drop seizures (atonic, tonic, or myoclonic), also known as drop attacks, from the 4-week baseline period to the 4-week maintenance period.
A statistically significantly greater reduction in seizure frequency was observed in the high-dose group compared to the low-dose group (median percent reduction of 93% vs 29%; p<0.05).
# How Supplied
### Clobazam- Tablets
Each clobazam tablet contains 10 mg or 20 mg of clobazam.
- It is a white to off-white, oval tablet with a functional score on one side and either a "1" and "0" or a "2" and "0" debossed on the other side.
NDC 67386-314-01: 10 mg scored tablet, Bottles of 100
NDC 67386-315-01: 20 mg scored tablet, Bottles of 100
- NDC 67386-314-01: 10 mg scored tablet, Bottles of 100
- NDC 67386-315-01: 20 mg scored tablet, Bottles of 100
### Clobazam- Oral suspension
- Clobazam oral suspension is a berry flavored off-white liquid supplied in a bottle with child-resistant closure.
- The oral suspension is packaged with a dispenser set which contains two calibrated oral dosing syringes and a bottle adapter.
NDC 67386-313-21: 2.5 mg/mL supplied in a bottle containing 120 mL of suspension.
- NDC 67386-313-21: 2.5 mg/mL supplied in a bottle containing 120 mL of suspension.
## Storage
### Clobazam Tablets
- Store tablets and oral suspension at 20°C to 25°C (68°F to 77°F). See USP controlled room temperature.
### Clobazam Oral suspension
- Store and dispense clobazam oral suspension in its original bottle in an upright position.
- Use within 90 days of first opening the bottle, then discard any remainder
- Store tablets and oral suspension at 20°C to 25°C (68°F to 77°F). See USP controlled room temperature.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### Hypersensitivity
Inform patients or caregivers that clobazam is contraindicated in patients with a history of hypersensitivity to the drug or its ingredients.
### Somnolence or Sedation
Advise patients or caregivers to check with their healthcare provider before clobazam is taken with other CNS depressants such as other benzodiazepines, opioids, tricyclic antidepressants, sedating antihistamines, or alcohol.
If applicable, caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that clobazam does not affect them adversely (e.g., impair judgment, thinking or motor skills).
### Increasing or Decreasing the clobazam Dose
Inform patients or caregivers to consult their healthcare provider before increasing the clobazam dose or abruptly discontinuing clobazam. Advise patients or caregivers that abrupt withdrawal of AEDs may increase their risk of seizure.
### Interactions with Hormonal Contraceptives
Counsel women to also use non-hormonal methods of contraception when clobazam is used with hormonal contraceptives and to continue these alternative methods for 28 days after discontinuing clobazam to ensure contraceptive reliability.
### Serious Dermatological Reactions
Advise patients or caregivers that serious skin reactions have been reported in patients taking clobazam. Serious skin reactions, including SJS/TEN, may need to be treated in a hospital and may be life-threatening. If a skin reaction occurs while taking clobazam, patients or caregivers should consult with healthcare providers immediately.
### Suicidal Thinking and Behavior
Counsel patients, their caregivers, and their families that AEDs, including clobazam, may increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm. Patients should report behaviors of concern immediately to healthcare providers.
### Use in Pregnancy
Instruct patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy.
### Use in Nursing
Instruct patients to notify their physician if they are breast feeding or intend to breast feed during therapy.
# Precautions with Alcohol
- Since clobazam has a central nervous system (CNS) depressant effect, patients or their caregivers should be cautioned against simultaneous use with other CNS depressant drugs or alcohol, and cautioned that the effects of other CNS depressant drugs or alcohol may be potentiated.
# Brand Names
- ONFI[1]
# Look-Alike Drug Names
There is limited information regarding Clobazam Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Clobazam | |
072643bfda6833f41fa00ace7e42a555a6eb9f34 | wikidoc | Coenzyme | Coenzyme
# Overview
Coenzymes are small organic non-protein molecules that carry chemical groups between enzymes. Coenzymes are sometimes referred to as cosubstrates. These molecules are substrates for enzymes and do not form a permanent part of the enzymes' structures. This distinguishes coenzymes from prosthetic groups, which are non-protein components that are bound tightly to enzymes - such as iron-sulfur centers, flavin or haem groups. Both coenzymes and prosthetic groups are types of the broader group of cofactors, which are any non-protein molecules (usually organic molecules or metal ions) that are required by an enzyme for its activity.
In metabolism, coenzymes are involved in both group-transfer reactions, for example coenzyme A and adenosine triphosphate (ATP), and redox reactions, such as coenzyme Q10 and nicotinamide adenine dinucleotide (NAD+). Coenzymes are consumed and recycled continuously in metabolism, with one set of enzymes adding a chemical group to the coenzyme and another set removing it. For example, enzymes such as ATP synthase continuously phosphorylate adenosine diphosphate (ADP), converting it into ATP, while enzymes such as kinases dephosphorylate the ATP and convert it back to ADP.
Coenzymes molecules are often vitamins or are made from vitamins. Many conezymes contain the nucleotide adenosine as part of their structures, such as ATP, coenzyme A and NAD+. This common structure may reflect a common evolutionary origin as part of ribozymes in an ancient RNA world.
# Coenzymes as metabolic intermediates
Metabolism involves a vast array of chemical reactions, but most fall under a few basic types of reactions that involve the transfer of functional groups. This common chemistry allows cells to use a small set of metabolic intermediates to carry chemical groups between different reactions. These group-transfer intermediates are the coenzymes.
Each class of group-transfer reaction is carried out by a particular coenzyme, which is the substrate for a set of enzymes that produce it, and a set of enzymes that consume it. An example of this are the dehydrogenases that use nicotinamide adenine dinucleotide (NADH) as a cofactor. Here, hundreds of separate types of enzymes remove electrons from their substrates and reduce NAD+ to NADH. This reduced coenzyme is then a substrate for any of the reductases in the cell that need to reduce their substrates.
Coenzymes are therefore continuously recycled as part of metabolism. As an example, the total quantity of ATP in the human body is about 0.1 mole. This ATP is constantly being broken down into ADP, and then converted back into ATP. Thus, at any given time, the total amount of ATP + ADP remains fairly constant. The energy used by human cells requires the hydrolysis of 100 to 150 moles of ATP daily which is around 50 to 75 kg. Typically, a human will use up their body weight of ATP over the course of the day. This means that each ATP molecule is recycled 1000 to 1500 times daily.
# Types
Coenzymes are the major role in organisms of vitamins, although vitamins do have other functions in the body. Coenzymes are also commonly made from nucleotides: such as adenosine triphosphate, the biochemical carrier of phosphate groups, or coenzyme A, the coenzyme that carries acyl groups. Most coenzymes are found in a huge variety of species, and some are universal to all forms of life. An exception to this wide distribution is a group of unique coenzymes that evolved in methanogens, which are restricted to this group of archaea.
## Vitamins and derivatives
## Non-vitamins
# Evolution
Coenzymes, such as ATP and NADH, are present in all known forms of life and form a core part of metabolism. Such universal conservation indicates that these molecules evolved very early in the development of living things. At least some of the current set of coenzymes may therefore have been present in the last universal ancestor, which lived about 4 billion years ago.
Coenzymes may have been present even earlier in the history of life on Earth. Interestingly, the nucleotide adenosine is present in coenzymes that catalyse many basic metabolic reactions such as methyl, acyl, and phosphoryl group transfer, as well as redox reactions. This ubiquitous chemical scaffold has therefore been proposed to be a remnant of the RNA world, with early ribozymes evolving to bind a restricted set of nucleotides and related compounds. Adenosine-based coenzymes are thought to have acted as interchangeable adaptors that allowed enzymes and ribozymes to bind new coenzymes through small modifications in existing adenosine-binding domains, which had originally evolved to bind a different cofactor. This process of adapting a pre-evolved structure for a novel use is referred to as exaptation.
# History
The first coenzyme to be discovered was NAD+, which was identified by Arthur Harden and William Youndin 1906. They noticed that adding boiled and filtered yeast extract greatly accelerated alcoholic fermentation in unboiled yeast extracts. They called the unidentified factor responsible for this effect a coferment. Through a long and difficult purification from yeast extracts, this heat-stable factor was identified as a nucleotide sugar phosphate by Hans von Euler-Chelpin. Other coenzymes were identified throughout the early 20th century, with ATP being isolated in 1929 by Karl Lohmann, and coenzyme A being discovered in 1945 by Fritz Albert Lipmann.
The functions of coenzymes were at first mysterious, but in 1936, Otto Heinrich Warburg identified the function of NAD+ in hydride transfer. This discovery was followed in the early 1940s by the work of Herman Kalckar, who established the link between the oxidation of sugars and the generation of ATP. This confirmed the central role of ATP in energy transfer that had been proposed by Fritz Albert Lipmann in 1941. Later, in 1949, Morris Friedkin and Albert L. Lehninger proved that the coenzyme NAD+ linked metabolic pathways such as the citric acid cycle and the synthesis of ATP. | Coenzyme
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Coenzymes are small organic non-protein molecules that carry chemical groups between enzymes.[1] Coenzymes are sometimes referred to as cosubstrates. These molecules are substrates for enzymes and do not form a permanent part of the enzymes' structures. This distinguishes coenzymes from prosthetic groups, which are non-protein components that are bound tightly to enzymes - such as iron-sulfur centers, flavin or haem groups. Both coenzymes and prosthetic groups are types of the broader group of cofactors, which are any non-protein molecules (usually organic molecules or metal ions) that are required by an enzyme for its activity.[2]
In metabolism, coenzymes are involved in both group-transfer reactions, for example coenzyme A and adenosine triphosphate (ATP), and redox reactions, such as coenzyme Q10 and nicotinamide adenine dinucleotide (NAD+). Coenzymes are consumed and recycled continuously in metabolism, with one set of enzymes adding a chemical group to the coenzyme and another set removing it. For example, enzymes such as ATP synthase continuously phosphorylate adenosine diphosphate (ADP), converting it into ATP, while enzymes such as kinases dephosphorylate the ATP and convert it back to ADP.
Coenzymes molecules are often vitamins or are made from vitamins. Many conezymes contain the nucleotide adenosine as part of their structures, such as ATP, coenzyme A and NAD+. This common structure may reflect a common evolutionary origin as part of ribozymes in an ancient RNA world.
# Coenzymes as metabolic intermediates
Metabolism involves a vast array of chemical reactions, but most fall under a few basic types of reactions that involve the transfer of functional groups.[3] This common chemistry allows cells to use a small set of metabolic intermediates to carry chemical groups between different reactions.[4] These group-transfer intermediates are the coenzymes.
Each class of group-transfer reaction is carried out by a particular coenzyme, which is the substrate for a set of enzymes that produce it, and a set of enzymes that consume it. An example of this are the dehydrogenases that use nicotinamide adenine dinucleotide (NADH) as a cofactor. Here, hundreds of separate types of enzymes remove electrons from their substrates and reduce NAD+ to NADH. This reduced coenzyme is then a substrate for any of the reductases in the cell that need to reduce their substrates.[5]
Coenzymes are therefore continuously recycled as part of metabolism. As an example, the total quantity of ATP in the human body is about 0.1 mole. This ATP is constantly being broken down into ADP, and then converted back into ATP. Thus, at any given time, the total amount of ATP + ADP remains fairly constant. The energy used by human cells requires the hydrolysis of 100 to 150 moles of ATP daily which is around 50 to 75 kg. Typically, a human will use up their body weight of ATP over the course of the day.[6] This means that each ATP molecule is recycled 1000 to 1500 times daily.
# Types
Coenzymes are the major role in organisms of vitamins, although vitamins do have other functions in the body.[7] Coenzymes are also commonly made from nucleotides: such as adenosine triphosphate, the biochemical carrier of phosphate groups, or coenzyme A, the coenzyme that carries acyl groups. Most coenzymes are found in a huge variety of species, and some are universal to all forms of life. An exception to this wide distribution is a group of unique coenzymes that evolved in methanogens, which are restricted to this group of archaea.[8]
## Vitamins and derivatives
## Non-vitamins
# Evolution
Coenzymes, such as ATP and NADH, are present in all known forms of life and form a core part of metabolism. Such universal conservation indicates that these molecules evolved very early in the development of living things.[28] At least some of the current set of coenzymes may therefore have been present in the last universal ancestor, which lived about 4 billion years ago.[29][30]
Coenzymes may have been present even earlier in the history of life on Earth.[31] Interestingly, the nucleotide adenosine is present in coenzymes that catalyse many basic metabolic reactions such as methyl, acyl, and phosphoryl group transfer, as well as redox reactions. This ubiquitous chemical scaffold has therefore been proposed to be a remnant of the RNA world, with early ribozymes evolving to bind a restricted set of nucleotides and related compounds.[32][33] Adenosine-based coenzymes are thought to have acted as interchangeable adaptors that allowed enzymes and ribozymes to bind new coenzymes through small modifications in existing adenosine-binding domains, which had originally evolved to bind a different cofactor.[34] This process of adapting a pre-evolved structure for a novel use is referred to as exaptation.
# History
The first coenzyme to be discovered was NAD+, which was identified by Arthur Harden and William Youndin 1906.[35] They noticed that adding boiled and filtered yeast extract greatly accelerated alcoholic fermentation in unboiled yeast extracts. They called the unidentified factor responsible for this effect a coferment. Through a long and difficult purification from yeast extracts, this heat-stable factor was identified as a nucleotide sugar phosphate by Hans von Euler-Chelpin.[36] Other coenzymes were identified throughout the early 20th century, with ATP being isolated in 1929 by Karl Lohmann,[37] and coenzyme A being discovered in 1945 by Fritz Albert Lipmann.[38]
The functions of coenzymes were at first mysterious, but in 1936, Otto Heinrich Warburg identified the function of NAD+ in hydride transfer.[39] This discovery was followed in the early 1940s by the work of Herman Kalckar, who established the link between the oxidation of sugars and the generation of ATP.[40] This confirmed the central role of ATP in energy transfer that had been proposed by Fritz Albert Lipmann in 1941.[41] Later, in 1949, Morris Friedkin and Albert L. Lehninger proved that the coenzyme NAD+ linked metabolic pathways such as the citric acid cycle and the synthesis of ATP.[42] | https://www.wikidoc.org/index.php/Co-enzyme | |
e493ca78ac47ade6b87bf8fd740832e854aeeca2 | wikidoc | Factor X | Factor X
Factor X, also known by the eponym Stuart–Prower factor, is an enzyme (EC 3.4.21.6) of the coagulation cascade. It is a serine endopeptidase (protease group S1, PA clan). Factor X is synthesized in the liver and requires vitamin K for its synthesis.
Factor X is activated, by hydrolysis, into factor Xa by both factor IX (with its cofactor, factor VIII in a complex known as intrinsic Xase) and factor VII with its cofactor, tissue factor (a complex known as extrinsic Xase). It is therefore the first member of the final common pathway or thrombin pathway.
It acts by cleaving prothrombin in two places (an arg-thr and then an arg-ile bond), which yields the active thrombin. This process is optimized when factor Xa is complexed with activated co-factor V in the prothrombinase complex.
Factor Xa is inactivated by protein Z-dependent protease inhibitor (ZPI), a serine protease inhibitor (serpin). The affinity of this protein for factor Xa is increased 1000-fold by the presence of protein Z, while it does not require protein Z for inactivation of factor XI. Defects in protein Z lead to increased factor Xa activity and a propensity for thrombosis.
The half life of factor X is 40–45 hours.
# Structure
The first crystal structure of human factor Xa was deposited in May 1993. To date, 191 crystal structures of factor Xa with various inhibitors have been deposited in the protein data bank. The active site of factor Xa is divided into four sub pockets as S1, S2, S3 and S4. The S1 subpocket determines the major component of selectivity and binding. The S2 sub-pocket is small, shallow and not well defined. It merges with the S4 subpocket. The S3 sub-pocket is located on the rim of the S1 pocket and is quite exposed to solvent. The S4 sub-pocket has three ligand binding domains: the "hydrophobic box", the "cationic hole" and the water site. Factor Xa inhibitors generally bind in an L-shaped conformation, where one group of the ligand occupies the anionic S1 pocket lined by residues Asp189, Ser195, and Tyr228, and another group of the ligand occupies the aromatic S4 pocket lined by residues Tyr99, Phe174, and Trp215. Typically, a fairly rigid linker group bridges these two interaction sites.
# Genetics
The human factor X gene is located on chromosome 13 (13q34).
# Role in disease
Inborn deficiency of factor X is very rare (1:1,000,000), and may present with epistaxis (nosebleeds), hemarthrosis (bleeding into joints) and gastrointestinal blood loss. Apart from congenital deficiency, low factor X levels may occur occasionally in a number of disease states. For example, factor X deficiency may be seen in amyloidosis, where factor X is adsorbed to the amyloid fibrils in the vasculature.
Deficiency of vitamin K or antagonism by warfarin (or similar medication) leads to the production of an inactive factor X. In warfarin therapy, this is desirable to prevent thrombosis. As of late 2007, four out of five emerging anti-coagulation therapeutics targeted this enzyme.
Inhibiting Factor Xa would offer an alternate method for anticoagulation. Direct Xa inhibitors are popular anticoagulants.
# Therapeutic use
Factor X is part of fresh frozen plasma and the prothrombinase complex. There are two commercially available Factor X concentrates: "Factor X P Behring" manufactured by CSL Behring, and high purity Factor X "Coagadex" produced by Bio Products Laboratory and approved for use in the United States by the FDA in October 2015 and in the EU on 16th March 2016 after earlier acceptance by CHMP and COMP.
# Use in biochemistry
The factor Xa protease can be used in biochemistry to cleave off protein tags that improve expression or purification of a protein of interest. Its preferred cleavage site (after the arginine in the sequence Ile-Glu/Asp-Gly-Arg, IEGR or IDGR) can easily be engineered between a tag sequence and the protein of interest. After expression and purification, the tag is then proteolytically removed by factor Xa.
# Factor Xa
Factor Xa is the activated form of the coagulation factor thrombokinase, known eponymously as Stuart-Prower factor. Factor X is an enzyme, a serine endopeptidase, which plays a key role at several stages of the coagulation system. Factor X is synthesized in the liver. The most commonly used anticoagulants in clinical practice, warfarin and the heparin series of anticoagulants and fondaparinux, act to inhibit the action of Factor Xa in various degrees.
Traditional models of coagulation developed in the 1960s envisaged two separate cascades, the extrinsic (tissue factor (TF)) pathway and the intrinsic pathway. These pathways converge to a common point, the formation of the Factor Xa/Va complex which together with calcium and bound on a phospholipids surface generate thrombin (Factor IIa) from prothrombin (Factor II).
A new model, the cell-based model of anticoagulation appears to explain more fully the steps in coagulation. This model has three stages: 1) initiation of coagulation on TF-bearing cells, 2) amplification of the procoagulant signal by thrombin generated on the TF-bearing cell and 3) propagation of thrombin generation on the platelet surface. Factor Xa plays a key role in all three of these stages.
In stage 1, Factor VII binds to the transmembrane protein TF on the surface of cells and is converted to Factor VIIa. The result is a Factor VIIa/TF complex which catalyzes the activation of Factor X and Factor IX. Factor Xa formed on the surface of the TF-bearing cell interacts with Factor Va to form the prothrombinase complex which generates small amounts of thrombin on the surface of TF-bearing cells.
In stage 2, the amplification stage, if enough thrombin has been generated, then activation of platelets and platelet associated cofactors occurs.
In stage 3, thrombin generation, Factor XIa activates free Factor IX on the surface of activated platelets. The activated Factor IXa with Factor VIIIa forms the "tenase" complex. This "tenase" complex activates more Factor X, which in turn forms new prothrombinase complexes with Factor Va. Factor Xa is the prime component of the prothrombinase complex which converts large amounts of prothrombin—the "thrombin burst". Each molecule of Factor Xa can generate 1000 molecules of thrombin. This large burst of thrombin is responsible for fibrin polymerization to form a thrombus.
Inhibition of the synthesis or activity of Factor X is the mechanism of action for many anticoagulants in use today. Warfarin, a synthetic derivative of coumarin, is the most widely used oral anticoagulant in the US. In some European countries, other coumarin derivatives (phenprocoumon and acenocoumarol) are used. These agents known as vitamin K antagonists (VKA), inhibit the vitamin K-dependent carboxylation of Factors II (prothrombin), VII, IX, X in the hepatocyte. This carboxylation after the translation is essential for the physiological activity.
Heparin (unfractionated heparin) and its derivatives low molecular weight heparin (LMWH) bind to a plasma cofactor, antithrombin (AT) to inactivate several coagulation factors IIa, Xa, XIa and XIIa. The affinity of unfractionated heparin and the various LMWHs for Factor Xa varies considerably. The efficacy of heparin-based anticoagulants increases as selectivity for Factor Xa increases. LMWH shows increased inactivation of Factor Xa compared to unfractionated heparin, and fondaparinux, an agent based on the critical pentasacharide sequence of heparin, shows more selectivity than LMWH. This inactivation of Factor Xa by heparins is termed "indirect" since it relies on the presence of AT and not a direct interaction with Factor Xa.
Recently a new series of specific, direct acting inhibitors of Factor Xa has been developed. These include the drugs rivaroxaban, apixaban, betrixaban, LY517717, darexaban (YM150), edoxaban and 813893. These agents have several theoretical advantages over current therapy. They may be given orally. They have rapid onset of action. And they may be more effective against Factor Xa in that they inhibit both free Factor Xa and Factor Xa in the prothrombinase complex.
# History
American and British scientists described deficiency of factor X independently in 1953 and 1956, respectively. As with some other coagulation factors, the factor was initially named after these patients, a Mr Rufus Stuart (1921) and a Miss Audrey Prower (1934).
# Interactions
Factor X has been shown to interact with Tissue factor pathway inhibitor. | Factor X
Factor X, also known by the eponym Stuart–Prower factor, is an enzyme (EC 3.4.21.6) of the coagulation cascade. It is a serine endopeptidase (protease group S1, PA clan). Factor X is synthesized in the liver and requires vitamin K for its synthesis.
Factor X is activated, by hydrolysis, into factor Xa by both factor IX (with its cofactor, factor VIII in a complex known as intrinsic Xase) and factor VII with its cofactor, tissue factor (a complex known as extrinsic Xase). It is therefore the first member of the final common pathway or thrombin pathway.
It acts by cleaving prothrombin in two places (an arg-thr and then an arg-ile bond), which yields the active thrombin. This process is optimized when factor Xa is complexed with activated co-factor V in the prothrombinase complex.
Factor Xa is inactivated by protein Z-dependent protease inhibitor (ZPI), a serine protease inhibitor (serpin). The affinity of this protein for factor Xa is increased 1000-fold by the presence of protein Z, while it does not require protein Z for inactivation of factor XI. Defects in protein Z lead to increased factor Xa activity and a propensity for thrombosis.
The half life of factor X is 40–45 hours.
# Structure
The first crystal structure of human factor Xa was deposited in May 1993. To date, 191 crystal structures of factor Xa with various inhibitors have been deposited in the protein data bank. The active site of factor Xa is divided into four sub pockets as S1, S2, S3 and S4. The S1 subpocket determines the major component of selectivity and binding. The S2 sub-pocket is small, shallow and not well defined. It merges with the S4 subpocket. The S3 sub-pocket is located on the rim of the S1 pocket and is quite exposed to solvent. The S4 sub-pocket has three ligand binding domains: the "hydrophobic box", the "cationic hole" and the water site. Factor Xa inhibitors generally bind in an L-shaped conformation, where one group of the ligand occupies the anionic S1 pocket lined by residues Asp189, Ser195, and Tyr228, and another group of the ligand occupies the aromatic S4 pocket lined by residues Tyr99, Phe174, and Trp215. Typically, a fairly rigid linker group bridges these two interaction sites.[1]
# Genetics
The human factor X gene is located on chromosome 13 (13q34).
# Role in disease
Inborn deficiency of factor X is very rare (1:1,000,000), and may present with epistaxis (nosebleeds), hemarthrosis (bleeding into joints) and gastrointestinal blood loss. Apart from congenital deficiency, low factor X levels may occur occasionally in a number of disease states. For example, factor X deficiency may be seen in amyloidosis, where factor X is adsorbed to the amyloid fibrils in the vasculature.
Deficiency of vitamin K or antagonism by warfarin (or similar medication) leads to the production of an inactive factor X. In warfarin therapy, this is desirable to prevent thrombosis. As of late 2007, four out of five emerging anti-coagulation therapeutics targeted this enzyme.[2]
Inhibiting Factor Xa would offer an alternate method for anticoagulation. Direct Xa inhibitors are popular anticoagulants.
# Therapeutic use
Factor X is part of fresh frozen plasma and the prothrombinase complex. There are two commercially available Factor X concentrates: "Factor X P Behring" manufactured by CSL Behring,[3] and high purity Factor X "Coagadex" produced by Bio Products Laboratory and approved for use in the United States by the FDA in October 2015 and in the EU on 16th March 2016 after earlier acceptance by CHMP and COMP.[4][self-published source][5]
# Use in biochemistry
The factor Xa protease can be used in biochemistry to cleave off protein tags that improve expression or purification of a protein of interest. Its preferred cleavage site (after the arginine in the sequence Ile-Glu/Asp-Gly-Arg, IEGR or IDGR) can easily be engineered between a tag sequence and the protein of interest. After expression and purification, the tag is then proteolytically removed by factor Xa.
# Factor Xa
Factor Xa is the activated form of the coagulation factor thrombokinase, known eponymously as Stuart-Prower factor. Factor X is an enzyme, a serine endopeptidase, which plays a key role at several stages of the coagulation system. Factor X is synthesized in the liver. The most commonly used anticoagulants in clinical practice, warfarin and the heparin series of anticoagulants and fondaparinux, act to inhibit the action of Factor Xa in various degrees.
Traditional models of coagulation developed in the 1960s envisaged two separate cascades, the extrinsic (tissue factor (TF)) pathway and the intrinsic pathway. These pathways converge to a common point, the formation of the Factor Xa/Va complex which together with calcium and bound on a phospholipids surface generate thrombin (Factor IIa) from prothrombin (Factor II).
A new model, the cell-based model of anticoagulation appears to explain more fully the steps in coagulation. This model has three stages: 1) initiation of coagulation on TF-bearing cells, 2) amplification of the procoagulant signal by thrombin generated on the TF-bearing cell and 3) propagation of thrombin generation on the platelet surface. Factor Xa plays a key role in all three of these stages.[6]
In stage 1, Factor VII binds to the transmembrane protein TF on the surface of cells and is converted to Factor VIIa. The result is a Factor VIIa/TF complex which catalyzes the activation of Factor X and Factor IX. Factor Xa formed on the surface of the TF-bearing cell interacts with Factor Va to form the prothrombinase complex which generates small amounts of thrombin on the surface of TF-bearing cells.
In stage 2, the amplification stage, if enough thrombin has been generated, then activation of platelets and platelet associated cofactors occurs.
In stage 3, thrombin generation, Factor XIa activates free Factor IX on the surface of activated platelets. The activated Factor IXa with Factor VIIIa forms the "tenase" complex. This "tenase" complex activates more Factor X, which in turn forms new prothrombinase complexes with Factor Va. Factor Xa is the prime component of the prothrombinase complex which converts large amounts of prothrombin—the "thrombin burst". Each molecule of Factor Xa can generate 1000 molecules of thrombin. This large burst of thrombin is responsible for fibrin polymerization to form a thrombus.
Inhibition of the synthesis or activity of Factor X is the mechanism of action for many anticoagulants in use today. Warfarin, a synthetic derivative of coumarin, is the most widely used oral anticoagulant in the US. In some European countries, other coumarin derivatives (phenprocoumon and acenocoumarol) are used. These agents known as vitamin K antagonists (VKA), inhibit the vitamin K-dependent carboxylation of Factors II (prothrombin), VII, IX, X in the hepatocyte. This carboxylation after the translation is essential for the physiological activity.[7]
Heparin (unfractionated heparin) and its derivatives low molecular weight heparin (LMWH) bind to a plasma cofactor, antithrombin (AT) to inactivate several coagulation factors IIa, Xa, XIa and XIIa. The affinity of unfractionated heparin and the various LMWHs for Factor Xa varies considerably. The efficacy of heparin-based anticoagulants increases as selectivity for Factor Xa increases. LMWH shows increased inactivation of Factor Xa compared to unfractionated heparin, and fondaparinux, an agent based on the critical pentasacharide sequence of heparin, shows more selectivity than LMWH. This inactivation of Factor Xa by heparins is termed "indirect" since it relies on the presence of AT and not a direct interaction with Factor Xa.
Recently a new series of specific, direct acting inhibitors of Factor Xa has been developed. These include the drugs rivaroxaban, apixaban, betrixaban, LY517717, darexaban (YM150), edoxaban and 813893. These agents have several theoretical advantages over current therapy. They may be given orally. They have rapid onset of action. And they may be more effective against Factor Xa in that they inhibit both free Factor Xa and Factor Xa in the prothrombinase complex.[8]
# History
American and British scientists described deficiency of factor X independently in 1953 and 1956, respectively. As with some other coagulation factors, the factor was initially named after these patients, a Mr Rufus Stuart (1921) and a Miss Audrey Prower (1934).
# Interactions
Factor X has been shown to interact with Tissue factor pathway inhibitor.[9] | https://www.wikidoc.org/index.php/Coagulation_factor_Xa | |
6c0232c87ce8c8c943b825562767de0ea37f0452 | wikidoc | Necrosis | Necrosis
Necrosis (in Greek Νεκρός = Dead) is the name given to accidental death of cells and living tissue.
Necrosis is less orderly than apoptosis, which is part of programmed cell death. In contrast apoptosis, cleanup of cell debris by phagocytes of the immune system is generally more difficult, as the disorderly death generally does not send cell signals which tell nearby phagocytes to engulf the dying cell. This lack of signalling makes it harder for the immune system to locate and recycle dead cells which have died through necrosis than if the cell had undergone apoptosis. The release of intracellular content after cellular membrane damage is the cause of inflammation in necrosis.
# Causes
There are many causes of necrosis including prolonged exposure to injury, infection, cancer, infarction, poisons, bites from some spiders such as brown recluses and inflammation. Severe damage to one essential system in the cell leads to secondary damage to other systems, a so-called "cascade of effects". Necrosis can arise from lack of proper care to a wound site. Necrosis is accompanied by the release of special enzymes, that are stored by lysosomes, which are capable of digesting cell components or the entire cell itself. The injuries received by the cell may compromise the lysosome membrane, or may initiate an unorganized chain reaction which causes the release in enzymes. Unlike apoptosis, cells that die by necrosis may release harmful chemicals that damage other cells. In biopsy, necrosis is halted by fixation or freezing.
# Morphologic patterns
There are seven distinctive morphologic patterns of necrosis:
- Coagulative necrosis is typically seen in hypoxic environments (e.g. myocardial infarction, infarct of the spleen). Cell outlines remain after cell death and can be observed by light microscopy.
- Liquefactive necrosis is usually associated with cellular destruction and pus formation (e.g. pneumonia). This is typical of bacterial or, sometimes, fungal infections because of their ability to stimulate an inflammatory reaction. Curiously, ischemia (restriction of blood supply) in the brain produces liquefactive rather than coagulative necrosis.
- Gummatous necrosis is restricted to necrosis involving spirochaetal infections (e.g. syphilis).
- Haemorrhagic necrosis is due to blockage of the venous drainage of an organ or tissue (e.g. in testicular torsion).
- Caseous necrosis is a specific form of coagulation necrosis typically caused by mycobacteria (e.g. tuberculosis).
- Fat necrosis results from the action of lipases on fatty tissues (e.g. acute pancreatitis, breast tissue necrosis).
- Fibrinoid necrosis is caused by immune-mediated vascular damage. It is marked by deposition of fibrin-like proteinaceous material in arterial walls, which appears smudgy and eosinophilic on light microscopy.
## Arachnogenic necrosis
Spider bites are cited as causing necrosis in some areas. These claims are widely disputed. In the US at least, only the bites of spiders in the genus Loxosceles or brown recluse have been proven to consistently cause necrosis. Many other spider species are claimed to cause necrosis but in most cases firm evidence is lacking, partially because the early bite is often painless and the spider species seldom identified and because a common reaction by doctors to a possible necrotic spider bite is to remove the flesh pre-emptively.
Several species of spiders possess toxins proven to cause necrosis:
- Loxosceles spiders, including the brown recluse in the midwestern United States and the Chilean recluse in South America
Spiders suspected of, but not shown to cause necrosis:
- White-tailed spiders in Australia and New Zealand
- Hobo spider in northwestern USA
- Sac spider in United States and Australia | Necrosis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Necrosis (in Greek Νεκρός = Dead) is the name given to accidental death of cells and living tissue.
Necrosis is less orderly than apoptosis, which is part of programmed cell death. In contrast apoptosis, cleanup of cell debris by phagocytes of the immune system is generally more difficult, as the disorderly death generally does not send cell signals which tell nearby phagocytes to engulf the dying cell. This lack of signalling makes it harder for the immune system to locate and recycle dead cells which have died through necrosis than if the cell had undergone apoptosis. The release of intracellular content after cellular membrane damage is the cause of inflammation in necrosis.
# Causes
There are many causes of necrosis including prolonged exposure to injury, infection, cancer, infarction, poisons, bites from some spiders such as brown recluses and inflammation. Severe damage to one essential system in the cell leads to secondary damage to other systems, a so-called "cascade of effects". Necrosis can arise from lack of proper care to a wound site. Necrosis is accompanied by the release of special enzymes, that are stored by lysosomes, which are capable of digesting cell components or the entire cell itself. The injuries received by the cell may compromise the lysosome membrane, or may initiate an unorganized chain reaction which causes the release in enzymes. Unlike apoptosis, cells that die by necrosis may release harmful chemicals that damage other cells. In biopsy, necrosis is halted by fixation or freezing.
# Morphologic patterns
There are seven distinctive morphologic patterns of necrosis:
- Coagulative necrosis is typically seen in hypoxic environments (e.g. myocardial infarction, infarct of the spleen). Cell outlines remain after cell death and can be observed by light microscopy.
- Liquefactive necrosis is usually associated with cellular destruction and pus formation (e.g. pneumonia). This is typical of bacterial or, sometimes, fungal infections because of their ability to stimulate an inflammatory reaction. Curiously, ischemia (restriction of blood supply) in the brain produces liquefactive rather than coagulative necrosis.
- Gummatous necrosis is restricted to necrosis involving spirochaetal infections (e.g. syphilis).
- Haemorrhagic necrosis is due to blockage of the venous drainage of an organ or tissue (e.g. in testicular torsion).
- Caseous necrosis is a specific form of coagulation necrosis typically caused by mycobacteria (e.g. tuberculosis).
- Fat necrosis results from the action of lipases on fatty tissues (e.g. acute pancreatitis, breast tissue necrosis).
- Fibrinoid necrosis is caused by immune-mediated vascular damage. It is marked by deposition of fibrin-like proteinaceous material in arterial walls, which appears smudgy and eosinophilic on light microscopy.
## Arachnogenic necrosis
Spider bites are cited as causing necrosis in some areas. These claims are widely disputed. In the US at least, only the bites of spiders in the genus Loxosceles or brown recluse have been proven to consistently cause necrosis.[1] Many other spider species are claimed to cause necrosis but in most cases firm evidence is lacking, partially because the early bite is often painless and the spider species seldom identified and because a common reaction by doctors to a possible necrotic spider bite is to remove the flesh pre-emptively.
Several species of spiders possess toxins proven to cause necrosis:
- Loxosceles spiders, including the brown recluse in the midwestern United States and the Chilean recluse in South America[2][3]
Spiders suspected of, but not shown to cause necrosis:
- White-tailed spiders in Australia and New Zealand [4]
- Hobo spider in northwestern USA[5]
- Sac spider in United States and Australia[6] | https://www.wikidoc.org/index.php/Coagulation_necrosis | |
a787e4499aea8d4257a28a68678b03b303e1f137 | wikidoc | Coal tar | Coal tar
# Overview
Coal tar is a brown or black liquid of high viscosity, which smells of naphthalene and aromatic hydrocarbons. Coal tar is among the by-products when coal is carbonized to make coke or gasified to make coal gas. Coal tars are complex and variable mixtures of phenols, polycyclic aromatic hydrocarbons (PAHs), and heterocyclic compounds.
# Applications
Being flammable, coal tar is sometimes used for heating or to fire boilers. Like most heavy oils, it must be heated before it will flow easily.
It can be used in medicated shampoo, soap and ointment, as a treatment for dandruff and psoriasis, as well as being used to kill and repel head lice. When used as a medication in the U.S., coal tar preparations are considered an OTC (over-the-counter drug) pharmaceutical and are subject to regulation by the United States Food and Drug Administration. Name brands include Balnetar, Psoriasin, and Tegrin.
# Safety
According to the International Agency for Research on Cancer, preparations that include more than 5 percent of crude coal tar are Group 1 carcinogen.
Despite this, the National Psoriasis Foundation claims coal tar is a valuable, safe and inexpensive treatment option for millions of people with psoriasis and other scalp conditions, the FDA agrees with this and states that coal tar concentrations between 0.5% and 5% are safe and effective for psoriasis and that no scientific evidence suggests that the coal tar in the concentrations seen in non-prescription treatments is carcinogenic. The NPF states that coal tar contains approximately 10,000 different chemicals, of which only about 50% have been identified , and the composition of coal tar varies with its origin and type of coal (eg: lignite, bituminous or anthracite) used to make it, so much further research remains to be done on coal tar and its derivatives. | Coal tar
# Overview
Coal tar is a brown or black liquid of high viscosity, which smells of naphthalene and aromatic hydrocarbons. Coal tar is among the by-products when coal is carbonized to make coke or gasified to make coal gas. Coal tars are complex and variable mixtures of phenols, polycyclic aromatic hydrocarbons (PAHs), and heterocyclic compounds. [1]
# Applications
Being flammable, coal tar is sometimes used for heating or to fire boilers. Like most heavy oils, it must be heated before it will flow easily.
It can be used in medicated shampoo, soap and ointment, as a treatment for dandruff and psoriasis, as well as being used to kill and repel head lice. When used as a medication in the U.S., coal tar preparations are considered an OTC (over-the-counter drug) pharmaceutical and are subject to regulation by the United States Food and Drug Administration. Name brands include Balnetar, Psoriasin, and Tegrin.
# Safety
According to the International Agency for Research on Cancer, preparations that include more than 5 percent of crude coal tar are Group 1 carcinogen.
Despite this, the National Psoriasis Foundation claims coal tar is a valuable, safe and inexpensive treatment option for millions of people with psoriasis and other scalp conditions, [2] the FDA agrees with this and states that coal tar concentrations between 0.5% and 5% are safe and effective for psoriasis and that no scientific evidence suggests that the coal tar in the concentrations seen in non-prescription treatments is carcinogenic. The NPF states that coal tar contains approximately 10,000 different chemicals, of which only about 50% have been identified [3], and the composition of coal tar varies with its origin and type of coal (eg: lignite, bituminous or anthracite) used to make it, so much further research remains to be done on coal tar and its derivatives. | https://www.wikidoc.org/index.php/Coal-tar | |
30c1cf144c7ed106f898b3fb9b22e91b0f291326 | wikidoc | Coca tea | Coca tea
Coca tea, also called mate de coca, is a tisane (herbal tea) made using the leaves of the coca plant. It is made either by submerging the coca leaf or dipping a tea bag in hot water. The tea originates from the Andes mountain range, particularly Peru.
The leaves of the coca plant contain several alkaloids including cocaine; in fact, they comprise the sources for cocaine's chemical production, though the amount of cocaine in the leaves is so small, around 0.2%, that in order to make a gram of cocaine, 500 grams of coca leaves would be needed.
Owing to the presence of the stimulant alkaloids, the coca tea provides a source of energy similar to coffee. The tea is often sold commercially in filtering bags, each of which usually contains approximately one gram of the leaf. As coffee can be decaffeinated, the coca tea can also be decocainized; however, after undergoing such a process it will still contain a minute quantity of the drug (about 4 milligrams per tea-bag). When the cocaine is removed, the amount of cocaine is small enough for the product to legally sell in the USA according to the Single Convention on Narcotic Drugs. In the 1980s the tea was used to wean cocaine addicts off of the drug.
The coca plant comprises four main species and varieties of Erythroxylum coca, often spelled koka in Quechua and Aymara, is a plant in the family Erythroxylaceae, native to northwestern South America.
Though also known as mate, the mate de coca is not drunk through a straw like with mate of yerba mate, but as a tea.
# Classification and Nomenclature
Coca tea comes from the coca plant, which has the biological name Erythroxylum coca and is from the family Erythroxylaceae. It is often called "la Hoja de Coca" (the leaf of coca) or Coca del Peru (coca of Peru).
# Characteristics
Coca Tea is a natural product. The tea preserves all of the physical-chemical properties of the coca leaf. The product fulfills the Technical Peruvian Standard and can be sold nationally, although such use is being discouraged in part by the Single Convention on Narcotic Drugs.
The tea is greenish yellow color, and has a lightly bitter flavor, somewhat similar to that of green tea but with a slightly more naturally sweet taste.
# In South American Culture
## Medicinal Use
Coca tea consumption is common in many South American countries. Many indigenous tribes of the Andes mountain range also use the tea for medicinal and religious purposes.
The consumption of Coca tea, as well as chewing the leaves, increases the absorption of oxygen in blood, which helps combat altitude sickness, and has a marked digestive and carminative action.
## Tourism
On the "Inca Trail" to Machu Picchu, guides usually serve coca tea with every meal because it is widely believed to alleviate the symptoms of altitude sickness.
Traditionally, official governmental persons traveling to La Paz in Bolivia, located at almost 4,000 meters above mean sea level, are greeted with a mate de coca. News reports noted that Princess Anne and the late Pope John Paul II were served the beverage during their visits to the country.
# See further
- Coca eradication
- Coca-Cola
- Huallaga Valley | Coca tea
Coca tea, also called mate de coca, is a tisane (herbal tea) made using the leaves of the coca plant. It is made either by submerging the coca leaf or dipping a tea bag in hot water. The tea originates from the Andes mountain range, particularly Peru.
The leaves of the coca plant contain several alkaloids including cocaine;[1] in fact, they comprise the sources for cocaine's chemical production, though the amount of cocaine in the leaves is so small, around 0.2%,[1] that in order to make a gram of cocaine, 500 grams of coca leaves would be needed.[2][3]
Owing to the presence of the stimulant alkaloids, the coca tea provides a source of energy similar to coffee. The tea is often sold commercially in filtering bags, each of which usually contains approximately one gram of the leaf. As coffee can be decaffeinated, the coca tea can also be decocainized; however, after undergoing such a process it will still contain a minute quantity of the drug (about 4 milligrams per tea-bag).[4] When the cocaine is removed, the amount of cocaine is small enough for the product to legally sell in the USA according to the Single Convention on Narcotic Drugs. In the 1980s the tea was used to wean cocaine addicts off of the drug.[4]
The coca plant comprises four main species and varieties of Erythroxylum coca, often spelled koka in Quechua and Aymara, is a plant in the family Erythroxylaceae, native to northwestern South America.
Though also known as mate, the mate de coca is not drunk through a straw like with mate of yerba mate, but as a tea.
# Classification and Nomenclature
Coca tea comes from the coca plant, which has the biological name Erythroxylum coca and is from the family Erythroxylaceae. It is often called "la Hoja de Coca" (the leaf of coca) or Coca del Peru (coca of Peru).
# Characteristics
Coca Tea is a natural product. The tea preserves all of the physical-chemical properties of the coca leaf. The product fulfills the Technical Peruvian Standard and can be sold nationally, although such use is being discouraged in part by the Single Convention on Narcotic Drugs.
The tea is greenish yellow color, and has a lightly bitter flavor, somewhat similar to that of green tea but with a slightly more naturally sweet taste.
# In South American Culture
## Medicinal Use
Coca tea consumption is common in many South American countries. Many indigenous tribes of the Andes mountain range also use the tea for medicinal and religious purposes.[5][2]
The consumption of Coca tea, as well as chewing the leaves, increases the absorption of oxygen in blood, which helps combat altitude sickness, and has a marked digestive and carminative action.[1]
## Tourism
On the "Inca Trail" to Machu Picchu, guides usually serve coca tea with every meal because it is widely believed to alleviate the symptoms of altitude sickness.[6][7][8]
Traditionally, official governmental persons traveling to La Paz in Bolivia, located at almost 4,000 meters above mean sea level, are greeted with a mate de coca. News reports noted that Princess Anne and the late Pope John Paul II were served the beverage during their visits to the country.[citation needed]
# See further
- Coca eradication
- Coca-Cola
- Huallaga Valley | https://www.wikidoc.org/index.php/Coca_tea | |
833e5fff108fba323a2019e3d99ef01f435a0c3b | wikidoc | Cocawine | Cocawine
Cocawine was an alcoholic beverage that combined wine and cocaine. The most popular brand was Vin Mariani developed in 1863 by Corsican entrepreneur Angelo Mariani. It was a popular drink at the time.
In Atlanta, John Pemberton, a pharmacist, developed his own cocktail based on Vin Mariani and called it Pemberton's French Wine Coca. It proved popular among American consumers. But in 1886, when Georgia introduced Prohibition, he had to replace the wine in his recipe with non-alcoholic syrup. The new recipe was the origin of Coca-Cola.
At the end of the 19th century, the fear of drug abuse made coca-based drinks less popular. This eventually led to the outlawing of cocaine in the United States, and the removal of cocaine from Coca-Cola.
# Notes
- ↑ Jump up to: 1.0 1.1 1.2 "Coca Wine". www.cocaine.org. Retrieved 2007-02-12..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} | Cocawine
Cocawine was an alcoholic beverage that combined wine and cocaine. The most popular brand was Vin Mariani developed in 1863 by Corsican entrepreneur Angelo Mariani. It was a popular drink at the time.[1]
In Atlanta, John Pemberton, a pharmacist, developed his own cocktail based on Vin Mariani and called it Pemberton's French Wine Coca. It proved popular among American consumers. But in 1886, when Georgia introduced Prohibition, he had to replace the wine in his recipe with non-alcoholic syrup. The new recipe was the origin of Coca-Cola.[1]
At the end of the 19th century, the fear of drug abuse made coca-based drinks less popular. This eventually led to the outlawing of cocaine in the United States, and the removal of cocaine from Coca-Cola.[1]
# Notes
- ↑ Jump up to: 1.0 1.1 1.2 "Coca Wine". www.cocaine.org. Retrieved 2007-02-12..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | https://www.wikidoc.org/index.php/Cocawine | |
bfa4ecdb0edfd70b22274a7ff3c2a37574d37074 | wikidoc | Coccidia | Coccidia
For patient information click here
# Overview
Coccidia are microscopic, spore-forming, single-celled parasites belonging to the apicomplexan class Conoidasida. Coccidian parasites infect the intestinal tracts of animals, and are the largest group of apicomplexan protozoa.
Coccidia are obligate, intracellular parasites, which means that they must live and reproduce within an animal cell.
# Coccidiosis
Coccidiosis is the disease caused by coccidian infection. Coccidiosis is a parasitic disease of the intestinal tract of animals, caused by coccidian protozoa. The disease spreads from one animal to another by contact with infected feces, or ingestion of infected tissue. Diarrhea, which may become bloody in severe cases, is the primary symptom. Most animals infected with coccidia are asymptomatic; however, young or immuno-compromised animals may suffer severe symptoms, including death.
While coccidian organisms can infect a wide variety of animals, including humans and livestock, they are usually species-specific. One well-known exception is toxoplasmosis, caused by Toxoplasma gondii.
## Coccidia in dogs
People often first encounter coccidia when they acquire a young puppy who is infected. The infectious organisms are canine-specific and are not contagious to humans (compare to zoonotic diseases).
# Genera and species that cause coccidiosis
- Genus Isospora is the most common cause of intestinal coccidiosis in dogs and cats and is usually what is meant by coccidiosis. Species of Isospora are species specific, meaning they only infects one type of species. Species that infect dogs include I. canis, I. ohioensis, I. burrowsi, and I. neorivolta. Species that infect cats include I. felis and I. rivolta. The most common symptom is diarrhea. Sulfonamides are the most common treatment.
- Genus Cryptosporidium contains two species known to cause cryptosporidiosis, C. parvum and C. muris. Cattle are most commonly affected by Cryptosporidium, and their feces are often assumed to be a source of infection for other mammals including humans. Recent genetic analyses of Cryptosporidium in humans have identified Cryptosporidium hominis as a new species specific for humans. Infection occurs most commonly in individuals that are immunocompromised, e.g. dogs with canine distemper, cats with feline leukemia virus infection, and humans with AIDS. Very young puppies and kittens can also become infected with Cryptosporidium, but the infection is usually eliminated without treatment.
- Genus Hammondia is transmitted by ingestion of cysts found in the tissue of grazing animals and rodents. Dogs and cats are the definitive hosts, with the species H. heydorni infecting dogs and the species H. hammondi and H. pardalis infecting cats. Hammondia usually does not cause disease.
- Genus Besnoitia infect cats that ingest cysts found in the tissue of rodents and opossum, but usually does not cause disease.
- Genus Sarcocystis infect carnivores that ingest cysts from various intermediate hosts. It is possible for Sarcocystis to cause disease in dogs and cats.
- Genus Toxoplasma has one important species, Toxoplasma gondii. Cats are the definitive host, but all mammals and some fish, reptiles, and amphibians can be intermediate hosts. Therefore, only cat feces will hold infective oocysts, but infection through ingestion of cysts can occur with the tissue of any intermediate host. Toxoplasmosis occurs in humans usually as low-grade fever or muscle pain for a few days. A normal immune system will suppress the infection but the tissue cysts will persist in that animal or human for years or the rest of its life. In immunocompromised individuals, those dormant cysts can be reactivated and cause many lesions in the brain, heart, lungs, eyes, etc. Without a competent immune system, the animal or human will most likely die from the infection. For pregnant women, the fetus is at risk if the pregnant woman becomes infected for the first time during pregnancy. If the woman had been infected during childhood or adolescence, she will have an immunity that will protect her developing fetus during pregnancy. The most important misconception about the transmission of toxoplasmosis comes from statements like 'ingestion of raw or undercooked meat, or cat feces.' Kitchen hygiene is much more important because people do tend to taste marinades or sauces before being cooked, or chop meat then vegetables without properly cleaning the knife and cutting board. Many physicians mistakenly put panic in their pregnant clients and advise them to get rid of their cat without really warning them of the likely sources of infection. Adult cats are very unlikely to shed infective oocysts. Symptoms in cats include fever, weight loss, diarrhea, vomiting, uveitis, and central nervous system signs. Disease in dogs includes a rapidly progressive form seen in dogs also infected with distemper, and a neurological form causing paralysis, tremors, and seizures. Dogs and cats are usually treated with clindamycin.
- Genus Neospora has one important species, Neospora caninum, that affects dogs in a manner similar to toxoplasmosis. Neosporosis is difficult to treat.
- Genus Hepatozoon contains one species that causes hepatozoonosis in dogs and cats, Hepatozoon canis. Animals become infected by ingesting an infected Rhipicephalus sanguineus, also known as the brown dog tick. Symptoms include fever, weight loss, and pain of the spine and limbs.
The most common medications used to treat coccidian infections are in the sulphonamide family. Although unusual, sulphonamides can damage the tear glands in some dogs, causing keratoconjunctivitis sicca, or "dry eye", which may have a life-long impact. Some veterinarians recommend measuring tear production prior to sulphonamide administration, and at various intervals after administration. Other veterinarians will simply avoid using sulphonamides, instead choosing another product effective against coccidia.
Left untreated, the infection may clear of its own accord, or in some cases may continue to ravage an animal and cause permanent damage or, occasionally, death. | Coccidia
For patient information click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Coccidia are microscopic, spore-forming, single-celled parasites belonging to the apicomplexan class Conoidasida.[1] Coccidian parasites infect the intestinal tracts of animals[2], and are the largest group of apicomplexan protozoa.
Coccidia are obligate, intracellular parasites, which means that they must live and reproduce within an animal cell.
# Coccidiosis
Coccidiosis is the disease caused by coccidian infection. Coccidiosis is a parasitic disease of the intestinal tract of animals, caused by coccidian protozoa. The disease spreads from one animal to another by contact with infected feces, or ingestion of infected tissue. Diarrhea, which may become bloody in severe cases, is the primary symptom. Most animals infected with coccidia are asymptomatic; however, young or immuno-compromised animals may suffer severe symptoms, including death.
While coccidian organisms can infect a wide variety of animals, including humans and livestock, they are usually species-specific. One well-known exception is toxoplasmosis, caused by Toxoplasma gondii.
## Coccidia in dogs
People often first encounter coccidia when they acquire a young puppy who is infected. The infectious organisms are canine-specific and are not contagious to humans (compare to zoonotic diseases).
# Genera and species that cause coccidiosis
- Genus Isospora is the most common cause of intestinal coccidiosis in dogs and cats and is usually what is meant by coccidiosis. Species of Isospora are species specific, meaning they only infects one type of species. Species that infect dogs include I. canis, I. ohioensis, I. burrowsi, and I. neorivolta. Species that infect cats include I. felis and I. rivolta. The most common symptom is diarrhea. Sulfonamides are the most common treatment. [3]
- Genus Cryptosporidium contains two species known to cause cryptosporidiosis, C. parvum and C. muris. Cattle are most commonly affected by Cryptosporidium, and their feces are often assumed to be a source of infection for other mammals including humans. Recent genetic analyses of Cryptosporidium in humans have identified Cryptosporidium hominis as a new species specific for humans. Infection occurs most commonly in individuals that are immunocompromised, e.g. dogs with canine distemper, cats with feline leukemia virus infection, and humans with AIDS. Very young puppies and kittens can also become infected with Cryptosporidium, but the infection is usually eliminated without treatment.[3]
- Genus Hammondia is transmitted by ingestion of cysts found in the tissue of grazing animals and rodents. Dogs and cats are the definitive hosts, with the species H. heydorni infecting dogs and the species H. hammondi and H. pardalis infecting cats. Hammondia usually does not cause disease.[3]
- Genus Besnoitia infect cats that ingest cysts found in the tissue of rodents and opossum, but usually does not cause disease.[3]
- Genus Sarcocystis infect carnivores that ingest cysts from various intermediate hosts. It is possible for Sarcocystis to cause disease in dogs and cats.[3]
- Genus Toxoplasma has one important species, Toxoplasma gondii. Cats are the definitive host, but all mammals and some fish, reptiles, and amphibians can be intermediate hosts. Therefore, only cat feces will hold infective oocysts, but infection through ingestion of cysts can occur with the tissue of any intermediate host. Toxoplasmosis occurs in humans usually as low-grade fever or muscle pain for a few days. A normal immune system will suppress the infection but the tissue cysts will persist in that animal or human for years or the rest of its life. In immunocompromised individuals, those dormant cysts can be reactivated and cause many lesions in the brain, heart, lungs, eyes, etc. Without a competent immune system, the animal or human will most likely die from the infection. For pregnant women, the fetus is at risk if the pregnant woman becomes infected for the first time during pregnancy. If the woman had been infected during childhood or adolescence, she will have an immunity that will protect her developing fetus during pregnancy. The most important misconception about the transmission of toxoplasmosis comes from statements like 'ingestion of raw or undercooked meat, or cat feces.' Kitchen hygiene is much more important because people do tend to taste marinades or sauces before being cooked, or chop meat then vegetables without properly cleaning the knife and cutting board. Many physicians mistakenly put panic in their pregnant clients and advise them to get rid of their cat without really warning them of the likely sources of infection. Adult cats are very unlikely to shed infective oocysts. Symptoms in cats include fever, weight loss, diarrhea, vomiting, uveitis, and central nervous system signs. Disease in dogs includes a rapidly progressive form seen in dogs also infected with distemper, and a neurological form causing paralysis, tremors, and seizures. Dogs and cats are usually treated with clindamycin.[3]
- Genus Neospora has one important species, Neospora caninum, that affects dogs in a manner similar to toxoplasmosis. Neosporosis is difficult to treat.[3]
- Genus Hepatozoon contains one species that causes hepatozoonosis in dogs and cats, Hepatozoon canis. Animals become infected by ingesting an infected Rhipicephalus sanguineus, also known as the brown dog tick. Symptoms include fever, weight loss, and pain of the spine and limbs.
The most common medications used to treat coccidian infections are in the sulphonamide family. Although unusual, sulphonamides can damage the tear glands in some dogs, causing keratoconjunctivitis sicca, or "dry eye", which may have a life-long impact. Some veterinarians recommend measuring tear production prior to sulphonamide administration, and at various intervals after administration. Other veterinarians will simply avoid using sulphonamides, instead choosing another product effective against coccidia.
Left untreated, the infection may clear of its own accord, or in some cases may continue to ravage an animal and cause permanent damage or, occasionally, death. | https://www.wikidoc.org/index.php/Coccidia | |
c61ebb7066604cfa531447e6c1f451a0a8fbdb43 | wikidoc | Genetics | Genetics
Genetics, a discipline of biology, is the science of heredity and variation in living organisms. Knowledge of the inheritance of characteristics has been implicitly used since prehistoric times for improving crop plants and animals through selective breeding. However, the modern science of genetics, which seeks to understand the mechanisms of inheritance, only began with the work of Gregor Mendel in the mid-nineteenth century. Although he did not know the physical basis for heredity, Mendel observed that inheritance is fundamentally a discrete process where specific traits are inherited in an independent manner—these basic units of inheritance are now called genes.
Genes correspond to regions within DNA, a molecule composed of a chain of four different types of nucleotides—the sequence of this nucleotides is the genetic information organisms inherit. DNA naturally occurs in a double stranded form, with nucleotides on each strand complementary to each other. Each strand can act as a template for synthesis of a new partner strand—this is the physical mechanism for the copying and inheritance of genetic information.
The sequence of nucleotides in DNA is used by cells to produce specific sequences of amino acids, creating proteins—a correspondence known as the genetic code. This sequence of amino acids in a protein determines how it folds into a three-dimensional structure, this structure is, in turn, responsible for the protein's function. Proteins carry out almost all the functions needed for cells to live and reproduce. A change to DNA sequence can change a protein's structure and behavior, and this can have dramatic consequences in the cell and on the organism as a whole.
Although genetics plays a large role in determining the appearance and behavior of organisms, it is the interaction of genetics with the environment an organism experiences that determines the ultimate outcome. For example, while genes play a role in determining a person's height, the nutrition and health that person experiences in childhood also have a large effect.
# History
Although the science of genetics has its origins in the work of Gregor Mendel in the mid-nineteenth century, various theories of inheritance preceded Mendel. These theories generally assumed that there existed an inheritance of acquired characteristics: the belief that individuals inherit traits that have been strengthened in their parents. Today, the theory is commonly associated with Jean-Baptiste Lamarck, who used this pattern of inheritance to explain the evolution of various traits within species (these changes are now understood to be the product of natural selection rather than a product of soft inheritance).
## Mendelian and classical genetics
The modern science of genetics traces its roots to the observations made by Gregor Johann Mendel, a German-Czech Augustinian monk and scientist who made detailed studies of the nature of inheritance in plants. In his paper "Versuche über Pflanzenhybriden" ("Experiments on Plant Hybridization"), presented in 1865 to the Brunn Natural History Society, Gregor Mendel traced the inheritance patterns of certain traits in pea plants and showed that they could be described mathematically. Although not all features show these patterns of Mendelian inheritance, his work suggested the utility of the application of statistics to the study of inheritance.
The significance of Mendel's observations was not understood until early in the twentieth century, after his death, when his research was re-discovered by other scientists working on similar problems. The word genetics itself was coined in 1905 by William Bateson, a significant proponent of Mendel's work, in a letter to Adam Sedgwick. (The adjective genetic, derived from the Greek word genno (γεννώ): to give birth, predates the noun and was first used in a biological sense in 1860.) Bateson publicly promoted and popularized usage of word genetics to describe the study of inheritance in his inaugural address to the Third International Conference on Plant Hybridization in London, England, in 1906.
In the decades following rediscovery and popularization of Mendel's work, numerous experiments sought to elucidate the molecular basis of DNA. In 1910 Thomas Hunt Morgan argued that genes reside on chromosomes, based on observations of a sex-linked white eye mutation in fruit flies. In 1913 his student Alfred Sturtevant used the phenomenon of genetic linkage and the associated recombination rates to demonstrate and map the linear arrangement of genes upon the chromosome.
## Molecular genetics
Although chromosomes were known to contain genes and composed of both protein and DNA, it was unknown which was critical for heredity or how the process occurred. In 1928, Frederick Griffith published his discovery of the phenomenon of transformation (see Griffith's experiment); sixteen years later, in 1944, Oswald Theodore Avery, Colin McLeod and Maclyn McCarty used this phenomenon to isolate and identify the molecule responsible for transformation as DNA. The Hershey-Chase experiment in 1952 identified DNA (rather than protein) as the genetic material of the viruses that infect bacteria, further evidence that DNA was the molecule responsible for inheritance.
James D. Watson and Francis Crick solved the structure of DNA in 1953, using the X-ray crystallography work of Rosalind Franklin that indicated the molecule had a helical structure. Their double-helix model paired a sequence of nucleotides with complementary nucleotides on the other strand. This structure not only provided a physical explanation for how information is contained within the order of the nucleotides, but also suggested a simple mechanism for duplication—through separation of strands and the reconstruction of partner strands based on the nucleotide sequences. Although the structure explained the process of inheritance, it was still unknown how DNA influenced the behavior of cells. In the following years scientists sought to understand how DNA controls the process of protein production within ribosomes, eventually discovering the transcription of DNA into messenger RNA and cracking the genetic code, which links the nucleotide sequence of messenger RNA to the amino acid sequence of protein.
With this molecular understanding of inheritance, an explosion of research that applied this new knowledge to biology became possible. One early development was chain-termination DNA sequencing in 1977, which enabled the determination of nucleotide sequences on DNA. In 1983 the polymerase chain reaction, developed by Kary Banks Mullis, provided a simple method for isolating and amplifying segments of DNA. These and other techniques, through the pooled efforts of the Human Genome Project and parallel private effort by Celera Genomics, culminated in the sequencing of the human genome in 2003.
# Features of inheritance
## Discrete inheritance and Mendel's laws
At its most fundamental level, inheritance in organisms occurs by means of discrete traits, called genes. This property was first observed by Gregor Mendel, who studied the segregation of heritable traits in pea plants. In his experiments studying the trait for flower color, Mendel observed that the flowers of each pea plant were either purple or white—and never an intermediate between the two colors. These different, discrete versions of the same gene are called alleles.
In the case of pea plants, each organism has two alleles of each gene, and the plants inherit one allele from each parent. Many organisms, including humans, have this pattern of inheritance. Organisms with two copies of the same allele are called homozygous, while organisms with two different alleles are heterozygous.
The set of alleles for a given organism is called its genotype, while the observable trait the organism has is called its phenotype. When organisms are heterozygous, often one allele is called dominant as its qualities dominate the phenotype of the organism, while the other allele is called recessive as its qualities recede and are not observed. Some alleles do not have complete dominance and instead have incomplete dominance by expressing an intermediate phenotype, or codominance by expressing both alleles at once.
When a pair of organisms reproduce sexually, their offspring randomly inherit one of the two alleles from each parent. These observations of discrete inheritance and the segregation of alleles are collectively known as Mendel's first law or the Law of Segregation.
## Notation and diagrams
Geneticists use diagrams and symbols to describe inheritance. A gene is represented by a letter (or letters)—the capitalized letter represents the dominant allele and the recessive is represented by lowercase. Often a "+" symbol is used to mark the usual, non-mutant allele for a gene.
In fertilization and breeding experiments (and especially when discussing Mendel's) the parents are referred to as the "P" generation and the offspring as the "F1" (first filial) generation. When the F1 offspring mate with each other, the offspring are called the "F2" (second filial) generation. One of the common diagrams used to predict the result of cross-breeding is the Punnett square.
When studying human genetic diseases, geneticists often use pedigree charts to represent the inheritance of traits. These charts map the inheritance of a trait in a family tree.
## Interactions of multiple genes
Organisms have thousands of genes, and in sexually reproducing organisms assortment of these genes are generally independent of each other. This means that the inheritance of an allele for yellow or green pea color is unrelated to the inheritance of alleles for white or purple flowers. This phenomenon, known as "Mendel's second law" or the "Law of independent assortment", means that the alleles of different genes get shuffled between parents to form offspring with many different combinations. (Some genes do not assort independently, demonstrating genetic linkage, a topic discussed later in this article.)
Often different genes can interact in a way that influences the same trait. In the blue-eyed Mary, for example, there exists a gene with alleles that determine the color of flowers: blue or magenta. Another gene, however, controls whether the flowers have color at all: color or white. When a plant has two copies of this white allele, its flowers are white—regardless of whether the first gene has blue or magenta alleles. This interaction between genes is called epistasis, with the second gene epistatic to the first.
Many traits are not discrete features (eg. purple or white flowers) but are instead continuous features (eg. human height and skin color). These complex traits are the product of interactions of many genes. The influence of these genes is mediated, to varying degrees, by the environment an organism has experienced. The degree to which an organism's genes contribute to a complex trait is called heritability. Measurement of the heritability of a trait is relative, although—in a more variable environment, the environment has a bigger influence on the total variation of the trait. For example, human height is a complex trait with a heritability of 89% in the United States. In Nigeria, however, where people experience a more variable access to good nutrition and health care, height has a heritability of only 62%.
# Molecular basis for inheritance
## DNA and chromosomes
The molecular basis for genes is deoxyribonucleic acid (DNA). DNA is composed of a chain of nucleotides, of which there are four types: adenine (A), cytosine (C), guanine (G), and thymine (T). Genetic information exists in the sequence of these nucleotides, and genes exist as stretches of sequence along the DNA chain. Viruses are the only exception to this rule—sometimes viruses use the very similar molecule RNA instead of DNA as their genetic material.
DNA normally exists as a double-stranded molecule, coiled into the shape of a double-helix. Each nucleotide in DNA preferentially pairs with its partner nucleotide on the opposite strand: A pairs with T, and C pairs with G. Thus, in its two-stranded form, each strand effectively contains all necessary information, redundant with its partner strand. This structure of DNA is the physical basis for inheritance: DNA replication duplicates the genetic information by splitting the strands and using each strand as a template for synthesis of a new partner strand.
Genes are arranged linearly along long chains of DNA sequence, called chromosomes. In bacteria, each cell has a single circular chromosome, while eukaryotic organisms (which includes plants and animals) have their DNA arranged in multiple linear chromosomes. These DNA strands are often extremely long; the largest human chromosome, for example, is about 247 million base pairs in length. The DNA of a chromosome is associated with structural proteins that organize, compact, and control access to the DNA, forming a material called chromatin; in eukaryotes chromatin is usually composed of nucleosomes, repeating units of DNA wound around a core of histone proteins. The full set of hereditary material in an organism (usually the combined DNA sequences of all chromosomes) is called the genome.
While haploid organisms have only one copy of each chromosome, most animals and many plants are diploid, containing two of each chromosome and thus two copies of every gene. The two alleles for a gene are located on identical loci of sister chromatids, each allele inherited from a different parent.
An exception exists in the sex chromosomes, specialized chromosomes many animals have evolved that play a role in determining the sex of an organism. In humans and other mammals the Y chromosome has very few genes and triggers the development of male sexual characteristics, while the X chromosome is similar to the other chromosomes and contains many genes unrelated to sex determination. Females have two copies of the X chromosome, but males have one Y and only one X chromosome—this difference in X chromosome copy numbers leads to the unusual inheritance patterns of sex linked disorders.
## Reproduction
When cells divide, their full genome is copied and each daughter cell inherits one copy. This is the simplest form of reproduction and is the basis for asexual reproduction. Asexual reproduction can also occur in multicellular organisms, producing offspring that inherit their genome from a single parent. Offspring that are genetically identical to their parents are called clones.
Eukaryotic organisms often use sexual reproduction to generate offspring that contain a mixture of genetic material inherited from two different parents. The process of sexual reproduction generally alternates between forms that contain single copies of the genome (haploid) and double copies (diploid). Haploid cells fuse and combine genetic material to create a diploid cell with paired chromosomes. Diploid organisms form haploids by dividing, without replicating their DNA, to create daughter cells that randomly inherit one of each pair of chromosomes. Most animals and many plants are diploid for most of their lifespan, with the haploid form reduced to single cell gametes.
Although they do not use the haploid/diploid method of sexual reproduction, bacteria have many methods of acquiring new genetic information. Some bacteria can undergo conjugation, transferring a small circular piece of DNA to another bacterium. Bacteria can also take up raw DNA fragments found in the environment and integrate them into their genome, a phenomenon known as transformation. This processes result in horizontal gene transfer, transmitting fragments of genetic information between organisms that would otherwise be unrelated.
## Recombination and linkage
The diploid nature of chromosomes allows for genes on different chromosomes to assort independently during sexual reproduction, recombining to form new combinations of genes. Genes on the same chromosome would theoretically never recombine, however, were it not for the process of chromosomal crossover. During crossover, chromosomes exchange stretches of DNA, effectively shuffling the gene alleles between the chromosomes. This process of chromosomal crossover generally occurs during meiosis, a series of cell divisions that creates haploid germ cells that later combine with other germ cells to form child organisms.
The probability of chromosomal crossover occurring between two given points on the chromosome is related to the distance between them. For an arbitrarily long distance, the probability of crossover is high enough that the inheritance of the genes is effectively uncorrelated. For genes that are closer together, however, the lower probability of crossover means that the genes demonstrate genetic linkage—alleles for the two genes tend to be inherited together. The amounts of linkage between a series of genes can be combined to form a linear linkage map that roughly describes the arrangement of the genes along the chromosome.
# Gene expression
## Genetic code
Genes generally express their functional effect through the production of proteins, which are complex molecules responsible for most functions in the cell. Proteins are chains of amino acids, and the DNA sequence of a gene (through an RNA intermediate) is used to produce a specific protein sequence. Each group of three nucleotides in the sequence, called a codon, corresponds to one of the twenty possible amino acids in protein—this correspondence is called the genetic code. The flow of information is unidirectional: information is transferred from nucleotide sequences into the amino acid sequence of proteins, but never from protein back into the sequence of DNA—a phenomenon Francis Crick called the central dogma of molecular biology.
The specific sequence of amino acids results in a unique three-dimensional structure for that protein, and the three-dimensional structures of protein are related to their function. Some are simple structural molecules, like the fibers formed by the protein collagen. Proteins can bind to other proteins and simple molecules, sometimes acting as enzymes by facilitating chemical reactions within the bound molecules (without changing the structure of the protein itself). Protein structure is dynamic; the protein hemoglobin bends into slightly different forms as it facilitates the capture, transport, and release of oxygen molecules within mammalian blood.
A single nucleotide difference within DNA can cause a single change in the amino acid sequence of a protein. Because protein structures are the result of their amino acid sequences, some changes can dramatically change the properties of a protein by destabilizing the structure or changing the surface of the protein in a way that changes its interaction with other proteins and molecules. For example, sickle-cell anemia is a human genetic disease that results from a single base difference within the coding region for the β-globin section of hemoglobin, causing a single amino acid change that changes hemoglobin's physical properties. Sickle-cell versions of hemoglobin stick to themselves, stacking to form fibers that distort the shape of red blood cells carrying the protein. These sickle-shaped cells no longer flow smoothly through blood vessels, having a tendency to clot or degrade, causing the medical problems associated with the disease.
## Nature vs. nurture
Although genes contain all the information an organism uses to function, the environment plays an important role in determining the ultimate phenotype—a dichotomy often referred to as "nature vs. nurture". The phenotype of an organism depends on the interaction of genetics with the environment. One example of this is the case of temperature-sensitive mutations. Often, a single amino acid change within the sequence of a protein does not change its behavior and interactions with other molecules, but it does destabilize the structure. In a high temperature environment, where molecules are moving more quickly and hitting each other, this results in the protein losing its structure and failing to function. In a low temperature environment, however, the protein's structure is stable and functions normally. This type of mutation is visible in the coat coloration of Siamese cats, where a mutation in an enzyme responsible for pigment production causes it to destabilize and lose function at high temperatures. The protein remains functional in areas of skin that are colder—legs, ears, tail, and face—and so the cat has dark fur at its extremities.
Environment also plays a dramatic role in effects of the human genetic disease phenylketonuria. The mutation that causes phenylketonuria disrupts the ability of the body to break down the amino acid phenylalanine, causing a toxic build-up of an intermediate molecule that, in turn, causes severe symptoms of progressive mental retardation and seizures. If someone with the phenylketonuria mutation is kept on a strict diet that avoids this amino acid, however, they remain normal and healthy.
## Gene regulation
The genome of a given organism contains thousands of genes, but not all these genes need to be active at any given moment. A gene is expressed when it is being transcribed into mRNA (and translated into protein), and there exist many cellular methods of controlling the expression of genes such that proteins are produced only when needed by the cell. Transcription factors are regulatory proteins that bind to the start of genes, either promoting or inhibiting the transcription of the gene. Within the genome of Escherichia coli bacteria, for example, there exists a series of genes necessary for the synthesis of the amino acid tryptophan. However, when tryptophan is already available to the cell, these genes for tryptophan synthesis are no longer needed. The presence of tryptophan directly affects the activity of the genes—tryptophan molecules bind to the tryptophan repressor (a transcription factor), changing the repressor's structure such that the repressor binds to the genes. The tryptophan repressor blocks the transcription and expression of the genes, thereby creating negative feedback regulation of the tryptophan synthesis process.
Differences in gene expression are especially clear within multicellular organisms, where cells all contain the same genome but have very different structures and behaviors due to the expression of different sets of genes. All the cells in a multicellular organism derive from a single cell, differentiating into different cell types in response to external and intercellular signals and gradually establishing different patterns of gene expression to create different behaviors. No single gene is responsible for the development of structures within multicellular organisms, these patterns arise from the complex interactions between many cells.
Within eukaryotes there exist structural features of chromatin that influence the transcription of genes, often in the form of modifications to DNA and chromatin that are stably inherited by daughter cells. These features are called "epigenetic" because they exist "on top" of the DNA sequence and retain inheritance from one cell generation to the next. Because of epigenetic features, different cell types grown within the same medium can retain very different properties. Although epigenetic features are generally dynamic over the course of development, some, like the phenomenon of paramutation, have multigenerational inheritance and exist as rare exceptions to the general rule of DNA as the basis for inheritance.
# Genetic change
## Mutations
During the process of DNA replication, errors occasionally occur in the polymerization of the second strand. These errors, called mutations, can have an impact on the phenotype of an organism, especially if they occur within the protein coding sequence of a gene. Error rates are usually very low—1 error in every 10–100 million bases—due to the "proofreading" ability of DNA polymerases. (Without proofreading error rates are a thousand-fold higher; because many viruses rely on DNA and RNA polymerases that lack proofreading ability they experience higher mutation rates.) Processes that increase the rate of changes in DNA are called mutagenic: mutagenic chemicals promote errors in DNA replication, often by interfering with the structure of base-pairing, while UV radiation induces mutations by causing damage to the DNA structure. Chemical damage to DNA occurs naturally as well, and cells use DNA repair mechanisms to repair mismatches and breaks in DNA—nevertheless, the repair sometimes fails to return the DNA to its original sequence.
In organisms that use chromosomal crossover to exchange DNA and recombine genes, errors in alignment during meiosis can also cause mutations. Errors in crossover are especially likely when similar sequences cause partner chromosomes to adopt a mistaken alignment; this makes some regions in genomes more prone to mutating in this way. These errors create large structural changes in DNA sequence—duplications, inversions or deletions of entire regions, or the accidental exchanging of whole parts between different chromosomes (called translocation).
## Natural selection and evolution
Mutations produce organisms with different genotypes, and those differences can result in different phenotypes. Many genetic mutations have a negligible effect on an organism's phenotype, health, and reproductive fitness. Mutations that do have an effect are often deleterious, but occasionally mutations arise that are beneficial in the current environmental context of the organism.
File:Eukaryote tree.svg
Population genetics research studies the distributions of these genetic differences within populations and how the distributions change over time. Changes in the frequency of an allele in a population can be influenced by natural selection, where a given allele's higher rate of survival and reproduction causes it to become more frequent in the population over time. Genetic drift can also occur, where chance events lead to random changes in allele frequency.
Over many generations, the genomes of organisms can change, resulting in the phenomenon of evolution. Mutations and the selection for beneficial mutations can cause a species to evolve into forms that better survive their environment, a process called adaptation. New species are formed through the process of speciation, a process often caused by geographical separations that allow different populations to genetically diverge.
As sequences diverge and change during the process of evolution, these differences between sequences can be used as a molecular clock to calculate the evolutionary distance between them. Genetic comparisons are generally considered the most accurate method of characterizing the relatedness between species, an improvement over the sometimes deceptive comparison of phenotypic characteristics. The evolutionary distances between species can be combined to form evolutionary trees—these trees represent the common descent and divergence of species over time, although they cannot represent the transfer of genetic material between unrelated species (known as horizontal gene transfer and most common in bacteria).
# Research and technology
## Model organisms and genetics
Although geneticists originally studied inheritance in a wide range of organisms, researchers began to specialize in studying the genetics of a particular subset of organisms. The fact that significant research already existed for a given organism would encourage new researchers to choose it for further study, and so eventually a few model organisms became the basis for most genetics research. Common research topics in model organism genetics include the study of gene regulation and the involvement of genes in development and cancer.
Organisms were chosen, in part, for convenience—short generation times and facile genetic manipulation made some organisms popular genetics research tools. Widely used model organisms include the gut bacterium Escherichia coli, the plant Arabidopsis thaliana, baker's yeast (Saccharomyces cerevisiae), the nematode Caenorhabditis elegans, the common fruit fly (Drosophila melanogaster), and the common house mouse (Mus musculus).
## Medical genetics research
Medical genetics seeks to understand how genetic variation relates to human health and disease. When searching for an unknown gene that may be involved in a disease, researchers commonly use genetic linkage and genetic pedigree charts to find the location on the genome associated with the disease. At the population level, researchers take advantage of Mendelian randomization to look for locations in the genome that are associated with diseases, a technique especially useful for multigenic traits not clearly defined by a single gene. Once a candidate gene is found, further research is often done on the same gene (called an orthologous gene) in model organisms. In addition to studying genetic diseases, the increased availability of genotyping techniques has led to the field of pharmacogenetics—studying how genotype can affect drug responses.
Although it is not an inherited disease, cancer is also considered a genetic disease. The process of cancer development in the body is a combination of events. Mutations occasionally occur within cells in the body as they divide—while these mutations will not be inherited by any offspring, they can affect the behavior of cells, sometimes causing them to grow and divide more frequently. There are biological mechanisms that attempt to stop this process—signals are given to inappropriately dividing cells that should trigger cell death, but sometimes additional mutations occur that cause cells to ignore these messages. An internal process of natural selection occurs within the body and eventually mutations accumulate within cells to promote their own growth, creating a cancerous tumor that grows and invades various tissues of the body.
In an effort to speed up the progress of medical research, ten individuals made their genetic information, medical histories, ethnic backgrounds, and other phenotypes publicly available on October 21, 2008. The ten individuals, all of whom have at least the equivalent of masters degree in genetics, are the first set of participants in the Harvard based Personal Genome Project]. Project leader George Church hopes to change the public perception that individuals should keep their genetic information private by exploring the consequences of making genetic and medical information publicly accessible. Officials from the project hope to eventually enroll up to 100,000 participants.
## Research techniques
DNA can be manipulated in the laboratory. Restriction enzymes are a commonly used enzyme that cuts DNA at specific sequences, producing predictable fragments of DNA. The use of ligation enzymes allows these fragments to be reconnected, and by ligating fragments of DNA together from different sources, researchers can create recombinant DNA. Often associated with genetically modified organisms, recombinant DNA is commonly used in the context of plasmids—short circular DNA fragments with a few genes on them. By inserting plasmids into bacteria and growing those bacteria on plates of agar (to isolate clones of bacteria cells), researchers can clonally amplify the inserted fragment of DNA (a process known as molecular cloning). (Cloning can also refer to the creation of clonal organisms, through various techniques.)
DNA can also be amplified using a procedure called the polymerase chain reaction (PCR). By using specific short sequences of DNA, PCR can isolate and exponentially amplify a targeted region of DNA. Because it can amplify from extremely small amounts of DNA, PCR is also often used to detect the presence of specific DNA sequences.
## DNA sequencing and genomics
One of the most fundamental technologies developed to study genetics, DNA sequencing allows researchers to determine the sequence of nucleotides in DNA fragments. Developed in 1977 by Frederick Sanger and coworkers, chain-termination sequencing is now routinely used to sequence DNA fragments. With this technology, researchers have been able to study the molecular sequences associated with many human diseases. As sequencing has become less expensive and with the aid of computational tools, researchers have sequenced the genomes of many organisms by stitching together the sequences of many different fragments (a process called genome assembly). These technologies were used to sequence the human genome, leading to the completion of the Human Genome Project in 2003.
The large amount of sequences available has created the field of genomics, research that uses computational tools to search for and analyze patterns in the full genomes of organisms. Genomics can also be considered a subfield of bioinformatics, which uses computational approaches to analyze large sets of biological data. | Genetics
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
Genetics, a discipline of biology, is the science of heredity and variation in living organisms.[1][2] Knowledge of the inheritance of characteristics has been implicitly used since prehistoric times for improving crop plants and animals through selective breeding. However, the modern science of genetics, which seeks to understand the mechanisms of inheritance, only began with the work of Gregor Mendel in the mid-nineteenth century.[3] Although he did not know the physical basis for heredity, Mendel observed that inheritance is fundamentally a discrete process where specific traits are inherited in an independent manner—these basic units of inheritance are now called genes.
Genes correspond to regions within DNA, a molecule composed of a chain of four different types of nucleotides—the sequence of this nucleotides is the genetic information organisms inherit. DNA naturally occurs in a double stranded form, with nucleotides on each strand complementary to each other. Each strand can act as a template for synthesis of a new partner strand—this is the physical mechanism for the copying and inheritance of genetic information.
The sequence of nucleotides in DNA is used by cells to produce specific sequences of amino acids, creating proteins—a correspondence known as the genetic code. This sequence of amino acids in a protein determines how it folds into a three-dimensional structure, this structure is, in turn, responsible for the protein's function. Proteins carry out almost all the functions needed for cells to live and reproduce. A change to DNA sequence can change a protein's structure and behavior, and this can have dramatic consequences in the cell and on the organism as a whole.
Although genetics plays a large role in determining the appearance and behavior of organisms, it is the interaction of genetics with the environment an organism experiences that determines the ultimate outcome. For example, while genes play a role in determining a person's height, the nutrition and health that person experiences in childhood also have a large effect.
# History
Although the science of genetics has its origins in the work of Gregor Mendel in the mid-nineteenth century, various theories of inheritance preceded Mendel. These theories generally assumed that there existed an inheritance of acquired characteristics: the belief that individuals inherit traits that have been strengthened in their parents. Today, the theory is commonly associated with Jean-Baptiste Lamarck, who used this pattern of inheritance to explain the evolution of various traits within species (these changes are now understood to be the product of natural selection rather than a product of soft inheritance).[4]
## Mendelian and classical genetics
The modern science of genetics traces its roots to the observations made by Gregor Johann Mendel, a German-Czech Augustinian monk and scientist who made detailed studies of the nature of inheritance in plants. In his paper "Versuche über Pflanzenhybriden" ("Experiments on Plant Hybridization"), presented in 1865 to the Brunn Natural History Society, Gregor Mendel traced the inheritance patterns of certain traits in pea plants and showed that they could be described mathematically.[5] Although not all features show these patterns of Mendelian inheritance, his work suggested the utility of the application of statistics to the study of inheritance.
The significance of Mendel's observations was not understood until early in the twentieth century, after his death, when his research was re-discovered by other scientists working on similar problems. The word genetics itself was coined in 1905 by William Bateson, a significant proponent of Mendel's work, in a letter to Adam Sedgwick.[6][7] (The adjective genetic, derived from the Greek word genno (γεννώ): to give birth, predates the noun and was first used in a biological sense in 1860.[8]) Bateson publicly promoted and popularized usage of word genetics to describe the study of inheritance in his inaugural address to the Third International Conference on Plant Hybridization in London, England, in 1906.[9]
In the decades following rediscovery and popularization of Mendel's work, numerous experiments sought to elucidate the molecular basis of DNA. In 1910 Thomas Hunt Morgan argued that genes reside on chromosomes, based on observations of a sex-linked white eye mutation in fruit flies.[10] In 1913 his student Alfred Sturtevant used the phenomenon of genetic linkage and the associated recombination rates to demonstrate and map the linear arrangement of genes upon the chromosome.[11]
## Molecular genetics
Although chromosomes were known to contain genes and composed of both protein and DNA, it was unknown which was critical for heredity or how the process occurred. In 1928, Frederick Griffith published his discovery of the phenomenon of transformation (see Griffith's experiment); sixteen years later, in 1944, Oswald Theodore Avery, Colin McLeod and Maclyn McCarty used this phenomenon to isolate and identify the molecule responsible for transformation as DNA.[12] The Hershey-Chase experiment in 1952 identified DNA (rather than protein) as the genetic material of the viruses that infect bacteria, further evidence that DNA was the molecule responsible for inheritance.[13]
James D. Watson and Francis Crick solved the structure of DNA in 1953, using the X-ray crystallography work of Rosalind Franklin that indicated the molecule had a helical structure.[14][15] Their double-helix model paired a sequence of nucleotides with complementary nucleotides on the other strand.[16] This structure not only provided a physical explanation for how information is contained within the order of the nucleotides, but also suggested a simple mechanism for duplication—through separation of strands and the reconstruction of partner strands based on the nucleotide sequences. Although the structure explained the process of inheritance, it was still unknown how DNA influenced the behavior of cells. In the following years scientists sought to understand how DNA controls the process of protein production within ribosomes, eventually discovering the transcription of DNA into messenger RNA and cracking the genetic code, which links the nucleotide sequence of messenger RNA to the amino acid sequence of protein.
With this molecular understanding of inheritance, an explosion of research that applied this new knowledge to biology became possible. One early development was chain-termination DNA sequencing in 1977, which enabled the determination of nucleotide sequences on DNA.[17] In 1983 the polymerase chain reaction, developed by Kary Banks Mullis, provided a simple method for isolating and amplifying segments of DNA.[18] These and other techniques, through the pooled efforts of the Human Genome Project and parallel private effort by Celera Genomics, culminated in the sequencing of the human genome in 2003.[19]
# Features of inheritance
## Discrete inheritance and Mendel's laws
At its most fundamental level, inheritance in organisms occurs by means of discrete traits, called genes.[20] This property was first observed by Gregor Mendel, who studied the segregation of heritable traits in pea plants.[5][21] In his experiments studying the trait for flower color, Mendel observed that the flowers of each pea plant were either purple or white—and never an intermediate between the two colors. These different, discrete versions of the same gene are called alleles.
In the case of pea plants, each organism has two alleles of each gene, and the plants inherit one allele from each parent.[22] Many organisms, including humans, have this pattern of inheritance. Organisms with two copies of the same allele are called homozygous, while organisms with two different alleles are heterozygous.
The set of alleles for a given organism is called its genotype, while the observable trait the organism has is called its phenotype. When organisms are heterozygous, often one allele is called dominant as its qualities dominate the phenotype of the organism, while the other allele is called recessive as its qualities recede and are not observed. Some alleles do not have complete dominance and instead have incomplete dominance by expressing an intermediate phenotype, or codominance by expressing both alleles at once.[23]
When a pair of organisms reproduce sexually, their offspring randomly inherit one of the two alleles from each parent. These observations of discrete inheritance and the segregation of alleles are collectively known as Mendel's first law or the Law of Segregation.
## Notation and diagrams
Geneticists use diagrams and symbols to describe inheritance. A gene is represented by a letter (or letters)—the capitalized letter represents the dominant allele and the recessive is represented by lowercase.[24] Often a "+" symbol is used to mark the usual, non-mutant allele for a gene.
In fertilization and breeding experiments (and especially when discussing Mendel's) the parents are referred to as the "P" generation and the offspring as the "F1" (first filial) generation. When the F1 offspring mate with each other, the offspring are called the "F2" (second filial) generation. One of the common diagrams used to predict the result of cross-breeding is the Punnett square.
When studying human genetic diseases, geneticists often use pedigree charts to represent the inheritance of traits.[25] These charts map the inheritance of a trait in a family tree.
## Interactions of multiple genes
Organisms have thousands of genes, and in sexually reproducing organisms assortment of these genes are generally independent of each other. This means that the inheritance of an allele for yellow or green pea color is unrelated to the inheritance of alleles for white or purple flowers. This phenomenon, known as "Mendel's second law" or the "Law of independent assortment", means that the alleles of different genes get shuffled between parents to form offspring with many different combinations. (Some genes do not assort independently, demonstrating genetic linkage, a topic discussed later in this article.)
Often different genes can interact in a way that influences the same trait. In the blue-eyed Mary, for example, there exists a gene with alleles that determine the color of flowers: blue or magenta. Another gene, however, controls whether the flowers have color at all: color or white. When a plant has two copies of this white allele, its flowers are white—regardless of whether the first gene has blue or magenta alleles. This interaction between genes is called epistasis, with the second gene epistatic to the first.[26]
Many traits are not discrete features (eg. purple or white flowers) but are instead continuous features (eg. human height and skin color). These complex traits are the product of interactions of many genes.[27] The influence of these genes is mediated, to varying degrees, by the environment an organism has experienced. The degree to which an organism's genes contribute to a complex trait is called heritability.[28] Measurement of the heritability of a trait is relative, although—in a more variable environment, the environment has a bigger influence on the total variation of the trait. For example, human height is a complex trait with a heritability of 89% in the United States. In Nigeria, however, where people experience a more variable access to good nutrition and health care, height has a heritability of only 62%.[29]
# Molecular basis for inheritance
## DNA and chromosomes
The molecular basis for genes is deoxyribonucleic acid (DNA). DNA is composed of a chain of nucleotides, of which there are four types: adenine (A), cytosine (C), guanine (G), and thymine (T). Genetic information exists in the sequence of these nucleotides, and genes exist as stretches of sequence along the DNA chain.[30] Viruses are the only exception to this rule—sometimes viruses use the very similar molecule RNA instead of DNA as their genetic material.[31]
DNA normally exists as a double-stranded molecule, coiled into the shape of a double-helix. Each nucleotide in DNA preferentially pairs with its partner nucleotide on the opposite strand: A pairs with T, and C pairs with G. Thus, in its two-stranded form, each strand effectively contains all necessary information, redundant with its partner strand. This structure of DNA is the physical basis for inheritance: DNA replication duplicates the genetic information by splitting the strands and using each strand as a template for synthesis of a new partner strand.[32]
Genes are arranged linearly along long chains of DNA sequence, called chromosomes. In bacteria, each cell has a single circular chromosome, while eukaryotic organisms (which includes plants and animals) have their DNA arranged in multiple linear chromosomes. These DNA strands are often extremely long; the largest human chromosome, for example, is about 247 million base pairs in length.[33] The DNA of a chromosome is associated with structural proteins that organize, compact, and control access to the DNA, forming a material called chromatin; in eukaryotes chromatin is usually composed of nucleosomes, repeating units of DNA wound around a core of histone proteins.[34] The full set of hereditary material in an organism (usually the combined DNA sequences of all chromosomes) is called the genome.
While haploid organisms have only one copy of each chromosome, most animals and many plants are diploid, containing two of each chromosome and thus two copies of every gene.[35] The two alleles for a gene are located on identical loci of sister chromatids, each allele inherited from a different parent.
An exception exists in the sex chromosomes, specialized chromosomes many animals have evolved that play a role in determining the sex of an organism.[36] In humans and other mammals the Y chromosome has very few genes and triggers the development of male sexual characteristics, while the X chromosome is similar to the other chromosomes and contains many genes unrelated to sex determination. Females have two copies of the X chromosome, but males have one Y and only one X chromosome—this difference in X chromosome copy numbers leads to the unusual inheritance patterns of sex linked disorders.
## Reproduction
When cells divide, their full genome is copied and each daughter cell inherits one copy. This is the simplest form of reproduction and is the basis for asexual reproduction. Asexual reproduction can also occur in multicellular organisms, producing offspring that inherit their genome from a single parent. Offspring that are genetically identical to their parents are called clones.
Eukaryotic organisms often use sexual reproduction to generate offspring that contain a mixture of genetic material inherited from two different parents. The process of sexual reproduction generally alternates between forms that contain single copies of the genome (haploid) and double copies (diploid).[35] Haploid cells fuse and combine genetic material to create a diploid cell with paired chromosomes. Diploid organisms form haploids by dividing, without replicating their DNA, to create daughter cells that randomly inherit one of each pair of chromosomes. Most animals and many plants are diploid for most of their lifespan, with the haploid form reduced to single cell gametes.
Although they do not use the haploid/diploid method of sexual reproduction, bacteria have many methods of acquiring new genetic information. Some bacteria can undergo conjugation, transferring a small circular piece of DNA to another bacterium.[37] Bacteria can also take up raw DNA fragments found in the environment and integrate them into their genome, a phenomenon known as transformation.[38] This processes result in horizontal gene transfer, transmitting fragments of genetic information between organisms that would otherwise be unrelated.
## Recombination and linkage
The diploid nature of chromosomes allows for genes on different chromosomes to assort independently during sexual reproduction, recombining to form new combinations of genes. Genes on the same chromosome would theoretically never recombine, however, were it not for the process of chromosomal crossover. During crossover, chromosomes exchange stretches of DNA, effectively shuffling the gene alleles between the chromosomes.[39] This process of chromosomal crossover generally occurs during meiosis, a series of cell divisions that creates haploid germ cells that later combine with other germ cells to form child organisms.
The probability of chromosomal crossover occurring between two given points on the chromosome is related to the distance between them. For an arbitrarily long distance, the probability of crossover is high enough that the inheritance of the genes is effectively uncorrelated. For genes that are closer together, however, the lower probability of crossover means that the genes demonstrate genetic linkage—alleles for the two genes tend to be inherited together. The amounts of linkage between a series of genes can be combined to form a linear linkage map that roughly describes the arrangement of the genes along the chromosome.[40]
# Gene expression
## Genetic code
Genes generally express their functional effect through the production of proteins, which are complex molecules responsible for most functions in the cell.[41] Proteins are chains of amino acids, and the DNA sequence of a gene (through an RNA intermediate) is used to produce a specific protein sequence. Each group of three nucleotides in the sequence, called a codon, corresponds to one of the twenty possible amino acids in protein—this correspondence is called the genetic code.[42] The flow of information is unidirectional: information is transferred from nucleotide sequences into the amino acid sequence of proteins, but never from protein back into the sequence of DNA—a phenomenon Francis Crick called the central dogma of molecular biology.[43]
The specific sequence of amino acids results in a unique three-dimensional structure for that protein, and the three-dimensional structures of protein are related to their function.[44][45] Some are simple structural molecules, like the fibers formed by the protein collagen. Proteins can bind to other proteins and simple molecules, sometimes acting as enzymes by facilitating chemical reactions within the bound molecules (without changing the structure of the protein itself). Protein structure is dynamic; the protein hemoglobin bends into slightly different forms as it facilitates the capture, transport, and release of oxygen molecules within mammalian blood.
A single nucleotide difference within DNA can cause a single change in the amino acid sequence of a protein. Because protein structures are the result of their amino acid sequences, some changes can dramatically change the properties of a protein by destabilizing the structure or changing the surface of the protein in a way that changes its interaction with other proteins and molecules. For example, sickle-cell anemia is a human genetic disease that results from a single base difference within the coding region for the β-globin section of hemoglobin, causing a single amino acid change that changes hemoglobin's physical properties.[46] Sickle-cell versions of hemoglobin stick to themselves, stacking to form fibers that distort the shape of red blood cells carrying the protein. These sickle-shaped cells no longer flow smoothly through blood vessels, having a tendency to clot or degrade, causing the medical problems associated with the disease.
## Nature vs. nurture
Although genes contain all the information an organism uses to function, the environment plays an important role in determining the ultimate phenotype—a dichotomy often referred to as "nature vs. nurture". The phenotype of an organism depends on the interaction of genetics with the environment. One example of this is the case of temperature-sensitive mutations. Often, a single amino acid change within the sequence of a protein does not change its behavior and interactions with other molecules, but it does destabilize the structure. In a high temperature environment, where molecules are moving more quickly and hitting each other, this results in the protein losing its structure and failing to function. In a low temperature environment, however, the protein's structure is stable and functions normally. This type of mutation is visible in the coat coloration of Siamese cats, where a mutation in an enzyme responsible for pigment production causes it to destabilize and lose function at high temperatures.[47] The protein remains functional in areas of skin that are colder—legs, ears, tail, and face—and so the cat has dark fur at its extremities.
Environment also plays a dramatic role in effects of the human genetic disease phenylketonuria.[48] The mutation that causes phenylketonuria disrupts the ability of the body to break down the amino acid phenylalanine, causing a toxic build-up of an intermediate molecule that, in turn, causes severe symptoms of progressive mental retardation and seizures. If someone with the phenylketonuria mutation is kept on a strict diet that avoids this amino acid, however, they remain normal and healthy.
## Gene regulation
The genome of a given organism contains thousands of genes, but not all these genes need to be active at any given moment. A gene is expressed when it is being transcribed into mRNA (and translated into protein), and there exist many cellular methods of controlling the expression of genes such that proteins are produced only when needed by the cell. Transcription factors are regulatory proteins that bind to the start of genes, either promoting or inhibiting the transcription of the gene.[49] Within the genome of Escherichia coli bacteria, for example, there exists a series of genes necessary for the synthesis of the amino acid tryptophan. However, when tryptophan is already available to the cell, these genes for tryptophan synthesis are no longer needed. The presence of tryptophan directly affects the activity of the genes—tryptophan molecules bind to the tryptophan repressor (a transcription factor), changing the repressor's structure such that the repressor binds to the genes. The tryptophan repressor blocks the transcription and expression of the genes, thereby creating negative feedback regulation of the tryptophan synthesis process.[50]
Differences in gene expression are especially clear within multicellular organisms, where cells all contain the same genome but have very different structures and behaviors due to the expression of different sets of genes. All the cells in a multicellular organism derive from a single cell, differentiating into different cell types in response to external and intercellular signals and gradually establishing different patterns of gene expression to create different behaviors. No single gene is responsible for the development of structures within multicellular organisms, these patterns arise from the complex interactions between many cells.
Within eukaryotes there exist structural features of chromatin that influence the transcription of genes, often in the form of modifications to DNA and chromatin that are stably inherited by daughter cells.[51] These features are called "epigenetic" because they exist "on top" of the DNA sequence and retain inheritance from one cell generation to the next. Because of epigenetic features, different cell types grown within the same medium can retain very different properties. Although epigenetic features are generally dynamic over the course of development, some, like the phenomenon of paramutation, have multigenerational inheritance and exist as rare exceptions to the general rule of DNA as the basis for inheritance.[52]
# Genetic change
## Mutations
During the process of DNA replication, errors occasionally occur in the polymerization of the second strand. These errors, called mutations, can have an impact on the phenotype of an organism, especially if they occur within the protein coding sequence of a gene. Error rates are usually very low—1 error in every 10–100 million bases—due to the "proofreading" ability of DNA polymerases.[53][54] (Without proofreading error rates are a thousand-fold higher; because many viruses rely on DNA and RNA polymerases that lack proofreading ability they experience higher mutation rates.) Processes that increase the rate of changes in DNA are called mutagenic: mutagenic chemicals promote errors in DNA replication, often by interfering with the structure of base-pairing, while UV radiation induces mutations by causing damage to the DNA structure.[55] Chemical damage to DNA occurs naturally as well, and cells use DNA repair mechanisms to repair mismatches and breaks in DNA—nevertheless, the repair sometimes fails to return the DNA to its original sequence.
In organisms that use chromosomal crossover to exchange DNA and recombine genes, errors in alignment during meiosis can also cause mutations.[56] Errors in crossover are especially likely when similar sequences cause partner chromosomes to adopt a mistaken alignment; this makes some regions in genomes more prone to mutating in this way. These errors create large structural changes in DNA sequence—duplications, inversions or deletions of entire regions, or the accidental exchanging of whole parts between different chromosomes (called translocation).
## Natural selection and evolution
Mutations produce organisms with different genotypes, and those differences can result in different phenotypes. Many genetic mutations have a negligible effect on an organism's phenotype, health, and reproductive fitness. Mutations that do have an effect are often deleterious, but occasionally mutations arise that are beneficial in the current environmental context of the organism.
File:Eukaryote tree.svg
Population genetics research studies the distributions of these genetic differences within populations and how the distributions change over time.[57] Changes in the frequency of an allele in a population can be influenced by natural selection, where a given allele's higher rate of survival and reproduction causes it to become more frequent in the population over time.[58] Genetic drift can also occur, where chance events lead to random changes in allele frequency.[59]
Over many generations, the genomes of organisms can change, resulting in the phenomenon of evolution. Mutations and the selection for beneficial mutations can cause a species to evolve into forms that better survive their environment, a process called adaptation.[60] New species are formed through the process of speciation, a process often caused by geographical separations that allow different populations to genetically diverge.[61]
As sequences diverge and change during the process of evolution, these differences between sequences can be used as a molecular clock to calculate the evolutionary distance between them.[62] Genetic comparisons are generally considered the most accurate method of characterizing the relatedness between species, an improvement over the sometimes deceptive comparison of phenotypic characteristics. The evolutionary distances between species can be combined to form evolutionary trees—these trees represent the common descent and divergence of species over time, although they cannot represent the transfer of genetic material between unrelated species (known as horizontal gene transfer and most common in bacteria).
# Research and technology
## Model organisms and genetics
Although geneticists originally studied inheritance in a wide range of organisms, researchers began to specialize in studying the genetics of a particular subset of organisms. The fact that significant research already existed for a given organism would encourage new researchers to choose it for further study, and so eventually a few model organisms became the basis for most genetics research.[63] Common research topics in model organism genetics include the study of gene regulation and the involvement of genes in development and cancer.
Organisms were chosen, in part, for convenience—short generation times and facile genetic manipulation made some organisms popular genetics research tools. Widely used model organisms include the gut bacterium Escherichia coli, the plant Arabidopsis thaliana, baker's yeast (Saccharomyces cerevisiae), the nematode Caenorhabditis elegans, the common fruit fly (Drosophila melanogaster), and the common house mouse (Mus musculus).
## Medical genetics research
Medical genetics seeks to understand how genetic variation relates to human health and disease.[64] When searching for an unknown gene that may be involved in a disease, researchers commonly use genetic linkage and genetic pedigree charts to find the location on the genome associated with the disease. At the population level, researchers take advantage of Mendelian randomization to look for locations in the genome that are associated with diseases, a technique especially useful for multigenic traits not clearly defined by a single gene.[65] Once a candidate gene is found, further research is often done on the same gene (called an orthologous gene) in model organisms. In addition to studying genetic diseases, the increased availability of genotyping techniques has led to the field of pharmacogenetics—studying how genotype can affect drug responses.[66]
Although it is not an inherited disease, cancer is also considered a genetic disease.[67] The process of cancer development in the body is a combination of events. Mutations occasionally occur within cells in the body as they divide—while these mutations will not be inherited by any offspring, they can affect the behavior of cells, sometimes causing them to grow and divide more frequently. There are biological mechanisms that attempt to stop this process—signals are given to inappropriately dividing cells that should trigger cell death, but sometimes additional mutations occur that cause cells to ignore these messages. An internal process of natural selection occurs within the body and eventually mutations accumulate within cells to promote their own growth, creating a cancerous tumor that grows and invades various tissues of the body.
In an effort to speed up the progress of medical research, ten individuals made their genetic information, medical histories, ethnic backgrounds, and other phenotypes publicly available on October 21, 2008. The ten individuals, all of whom have at least the equivalent of masters degree in genetics, are the first set of participants in the Harvard based Personal Genome Project]. Project leader George Church hopes to change the public perception that individuals should keep their genetic information private by exploring the consequences of making genetic and medical information publicly accessible. Officials from the project hope to eventually enroll up to 100,000 participants.[68]
## Research techniques
DNA can be manipulated in the laboratory. Restriction enzymes are a commonly used enzyme that cuts DNA at specific sequences, producing predictable fragments of DNA.[69] The use of ligation enzymes allows these fragments to be reconnected, and by ligating fragments of DNA together from different sources, researchers can create recombinant DNA. Often associated with genetically modified organisms, recombinant DNA is commonly used in the context of plasmids—short circular DNA fragments with a few genes on them. By inserting plasmids into bacteria and growing those bacteria on plates of agar (to isolate clones of bacteria cells), researchers can clonally amplify the inserted fragment of DNA (a process known as molecular cloning). (Cloning can also refer to the creation of clonal organisms, through various techniques.)
DNA can also be amplified using a procedure called the polymerase chain reaction (PCR).[70] By using specific short sequences of DNA, PCR can isolate and exponentially amplify a targeted region of DNA. Because it can amplify from extremely small amounts of DNA, PCR is also often used to detect the presence of specific DNA sequences.
## DNA sequencing and genomics
One of the most fundamental technologies developed to study genetics, DNA sequencing allows researchers to determine the sequence of nucleotides in DNA fragments. Developed in 1977 by Frederick Sanger and coworkers, chain-termination sequencing is now routinely used to sequence DNA fragments.[71] With this technology, researchers have been able to study the molecular sequences associated with many human diseases. As sequencing has become less expensive and with the aid of computational tools, researchers have sequenced the genomes of many organisms by stitching together the sequences of many different fragments (a process called genome assembly).[72] These technologies were used to sequence the human genome, leading to the completion of the Human Genome Project in 2003.[19]
The large amount of sequences available has created the field of genomics, research that uses computational tools to search for and analyze patterns in the full genomes of organisms. Genomics can also be considered a subfield of bioinformatics, which uses computational approaches to analyze large sets of biological data. | https://www.wikidoc.org/index.php/Code_for | |
345f01022dbece7b0dcb98b814415137d908a1a1 | wikidoc | Glycerol | Glycerol
# Overview
Glycerol is a chemical compound also commonly called glycerin or glycerine. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol is a sugar alcohol, and is sweet-tasting and of low toxicity. Glycerol has three hydrophilic alcoholic hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. Its surface tension is 64.00 mN/m at 20 °C , and it has a temperature coefficient of -0.0598 mN/(m K). The glycerol substructure is a central component of many lipids.
# Synthesis and production
Until recently, synthetic glycerol was mainly manufactured at an industrial scale from epichlorohydrin. Since glycerol forms the backbone of triglycerides, it is produced on saponification or transesterification. Soap-making and biodiesel production are respective examples.
Glycerol is a 10% by-product of biodiesel production (via the transesterification of vegetable oils). This has led to a glut of crude glycerol in the market, making the epichlorohydrin process no longer economical.
Current levels of glycerol production are running at about 350,000 tons per annum in the USA, and 600,000 tpa in Europe. This will increase as it implements EU directive 2003/30/EC which requires replacement of 5.75% of petroleum fuels with biofuel, across all Member States by 2010.
# Applications
In foods and beverages, glycerol serves as humectant, solvent and sweetener, and may help preserve foods. It is also used as filler in commercially prepared low-fat foods (e.g., cookies), and as a thickening agent in liqueurs. Glycerol also serves as a way, along with water, to preserve certain types of leaves. Glycerol is also used as a sugar substitute. In this regard, it has approximately 27 calories per teaspoon and is 60% as sweet as sucrose. Although it has about the same food energy as table sugar, it does not raise blood sugar levels, nor does it feed the bacteria that form plaques and cause dental cavities. As a food additive, glycerol is also known as E number E422.
In organic synthesis, glycerol is used as a readily available prochiral building block.
## Feedstock
It is one of the major raw materials for the manufacture of polyols for flexible foams, and to a lesser extent rigid polyurethane foams.
Glycerol is used to produce nitroglycerin, which is an essential ingredient of smokeless gunpowder and various munitions. Reliance on soap-making to supply co-product glycerine made it difficult to increase production to meet wartime demand. Hence, synthetic glycerin processes were national defense priorities in the days leading up to World War II.
Glycerol is also used to manufacture mono- and di-glycerides for use as emulsifiers, as well as polyglycerol esters going into shortenings and margarine.
## Research laboratory usage
Glycerol is a common component of solvents for enzymatic reagents stored at temperatures below zero degrees Celsius due to the depression of the freezing temperature of solutions with high concentrations of glycerol. It is also dissolved in water to reduce damage by ice crystals to laboratory organisms that are stored in frozen solutions, such as bacteria, nematodes, and fruit flies. Samples are loaded into agarose gel electrophoresis mixed in loading buffers that mainly consist of glycerol; when the sample is injected into wells, the glycerol causes the solution to sink through the running buffer to the bottom of the well.
## Pharmaceutical and personal care applications
Glycerol is used in medical and pharmaceutical and personal care preparations, mainly as a means of improving smoothness, providing lubrication and as a humectant. It is found in cough syrups, elixirs and expectorants, toothpaste, mouthwashes, skin care products, shaving cream, hair care products, and soaps.
As a 10% solution, glycerol prevents tannins from precipitating in ethanol extracts of plants (tinctures). It is also used as a substitute for ethanol as a solvent in preparing herbal extractions. It is less extractive and is approximately 30% less able to be absorbed by the body. Fluid extract manufacturers often extract herbs in hot water before adding glycerin to make glycerites.
Used as a laxative when introduced into the rectum in suppository or liquid (enema) form; irritates the bowel and induces a hyperosmotic effect.
Glycerol is a component of glycerol soap, which is made from denatured alcohol, glycerol, sodium castorate (from castor]]), sodium cocoate, sodium tallowate, sucrose, water, and parfum (fragrance). Sometimes one adds sodium laureth sulfate. This kind of soap is used by people with sensitive, easily-irritated skin because it prevents skin dryness with its moisturizing properties. It is possible to make glycerol soap at home.
It is also used in de-/anti-icing fluids, as in vitrification of blood cells for storage in liquid nitrogen
## Potential uses
A great deal of research is being conducted to try to make value-added molecules from crude glycerol (typically containing 20 % water and residual esterification catalyst) obtained from biodiesel production, as an alternative to disposal by incineration. One such program to add value to this glut of glycerol is the UK-based initiative The Glycerol Challenge. Some potential uses for glycerol include the following:
- Hydrogen gas production unit
- Glycerine acetate (as a potential fuel additive)
- Compost additive
- Citric acid production
- Cosmetic bonding agent for makeup, including: eye shadow, lipstick, lipgloss, and lotions and also including eyedrops as well
- Conversion to propylene glycol.
- Conversion to acrolein
- Conversion to ethanol
- Conversion to epichlorhydrin, a raw material for epoxy resins.
# Metabolism
Glycerol is a precursor for synthesis of triacylglycerols and of phospholipids in the liver and adipose tissue. When the body uses stored fat as a source of energy, glycerol and fatty acids are released into the bloodstream. The glycerol component can be converted to glucose by the liver and provides energy for cellular metabolism.
Before glycerol can enter the pathway of glycolysis or gluconeogenesis (depending on physiological conditions), it must be converted to their intermediate glyceraldehyde 3-phosphate in the following steps:
The enzyme glycerol kinase is present only in the liver. In adipose tissue, glycerol 3-phosphate is obtained from dihydroxyacetone phosphate (DHAP) with the enzyme glycerol-3-phosphate dehydrogenase.
# Danger of contamination with diethylene glycol
On May 4, 2007, the US Food and Drug Administration advised all US makers of medicines to test all batches of glycerine for the toxic diethylene glycol. This follows an occurrence of 100 fatal poisonings in Panama resulting from a Chinese factory deliberately falsifying records in order to export the cheaper diethylene glycol as the more expensive glycerol. Glycerine and diethylene glycol are similar in appearance, smell, and taste. The US Federal Food, Drug, and Cosmetic Act was passed following the 1937 "Elixir Sulfanilamide" incident of poisoning caused by diethylene glycol contamination of medicine. | Glycerol
Template:Chembox new
# Overview
Glycerol is a chemical compound also commonly called glycerin or glycerine. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol is a sugar alcohol, and is sweet-tasting and of low toxicity. Glycerol has three hydrophilic alcoholic hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. Its surface tension is 64.00 mN/m at 20 °C , and it has a temperature coefficient of -0.0598 mN/(m K). The glycerol substructure is a central component of many lipids.
# Synthesis and production
Until recently, synthetic glycerol was mainly manufactured at an industrial scale from epichlorohydrin. Since glycerol forms the backbone of triglycerides, it is produced on saponification or transesterification. Soap-making and biodiesel production are respective examples.
Glycerol is a 10% by-product of biodiesel production (via the transesterification of vegetable oils). This has led to a glut of crude glycerol in the market, making the epichlorohydrin process no longer economical.
Current levels of glycerol production are running at about 350,000 tons per annum in the USA, and 600,000 tpa in Europe. This will increase as it implements EU directive 2003/30/EC which requires replacement of 5.75% of petroleum fuels with biofuel, across all Member States by 2010[1].
# Applications
In foods and beverages, glycerol serves as humectant, solvent and sweetener, and may help preserve foods. It is also used as filler in commercially prepared low-fat foods (e.g., cookies), and as a thickening agent in liqueurs. Glycerol also serves as a way, along with water, to preserve certain types of leaves. Glycerol is also used as a sugar substitute. In this regard, it has approximately 27 calories per teaspoon and is 60% as sweet as sucrose. Although it has about the same food energy as table sugar, it does not raise blood sugar levels, nor does it feed the bacteria that form plaques and cause dental cavities. As a food additive, glycerol is also known as E number E422.
In organic synthesis, glycerol is used as a readily available prochiral building block.
## Feedstock
It is one of the major raw materials for the manufacture of polyols for flexible foams, and to a lesser extent rigid polyurethane foams.
Glycerol is used to produce nitroglycerin, which is an essential ingredient of smokeless gunpowder and various munitions. Reliance on soap-making to supply co-product glycerine made it difficult to increase production to meet wartime demand. Hence, synthetic glycerin processes were national defense priorities in the days leading up to World War II.
Glycerol is also used to manufacture mono- and di-glycerides for use as emulsifiers, as well as polyglycerol esters going into shortenings and margarine.
## Research laboratory usage
Glycerol is a common component of solvents for enzymatic reagents stored at temperatures below zero degrees Celsius due to the depression of the freezing temperature of solutions with high concentrations of glycerol. It is also dissolved in water to reduce damage by ice crystals to laboratory organisms that are stored in frozen solutions, such as bacteria, nematodes, and fruit flies. Samples are loaded into agarose gel electrophoresis mixed in loading buffers that mainly consist of glycerol; when the sample is injected into wells, the glycerol causes the solution to sink through the running buffer to the bottom of the well.
## Pharmaceutical and personal care applications
Glycerol is used in medical and pharmaceutical and personal care preparations, mainly as a means of improving smoothness, providing lubrication and as a humectant. It is found in cough syrups, elixirs and expectorants, toothpaste, mouthwashes, skin care products, shaving cream, hair care products, and soaps.
As a 10% solution, glycerol prevents tannins from precipitating in ethanol extracts of plants (tinctures). It is also used as a substitute for ethanol as a solvent in preparing herbal extractions. It is less extractive and is approximately 30% less able to be absorbed by the body. Fluid extract manufacturers often extract herbs in hot water before adding glycerin to make glycerites.[2][3][4]
Used as a laxative when introduced into the rectum in suppository or liquid (enema) form; irritates the bowel and induces a hyperosmotic effect.
Glycerol is a component of glycerol soap, which is made from denatured alcohol, glycerol, sodium castorate (from castor]]), sodium cocoate, sodium tallowate, sucrose, water, and parfum (fragrance). Sometimes one adds sodium laureth sulfate. This kind of soap is used by people with sensitive, easily-irritated skin because it prevents skin dryness with its moisturizing properties. It is possible to make glycerol soap at home.
It is also used in de-/anti-icing fluids, as in vitrification of blood cells for storage in liquid nitrogen
## Potential uses
A great deal of research is being conducted to try to make value-added molecules from crude glycerol (typically containing 20 % water and residual esterification catalyst) obtained from biodiesel production, as an alternative to disposal by incineration. One such program to add value to this glut of glycerol is the UK-based initiative The Glycerol Challenge. Some potential uses for glycerol include the following:
- Hydrogen gas production unit
- Glycerine acetate (as a potential fuel additive)[5]
- Compost additive
- Citric acid production
- Cosmetic bonding agent for makeup, including: eye shadow, lipstick, lipgloss, and lotions and also including eyedrops as well
- Conversion to propylene glycol[6].
- Conversion to acrolein[7][8]
- Conversion to ethanol[9]
- Conversion to epichlorhydrin[10], a raw material for epoxy resins.
# Metabolism
Glycerol is a precursor for synthesis of triacylglycerols and of phospholipids in the liver and adipose tissue. When the body uses stored fat as a source of energy, glycerol and fatty acids are released into the bloodstream. The glycerol component can be converted to glucose by the liver and provides energy for cellular metabolism.
Before glycerol can enter the pathway of glycolysis or gluconeogenesis (depending on physiological conditions), it must be converted to their intermediate glyceraldehyde 3-phosphate in the following steps:
The enzyme glycerol kinase is present only in the liver. In adipose tissue, glycerol 3-phosphate is obtained from dihydroxyacetone phosphate (DHAP) with the enzyme glycerol-3-phosphate dehydrogenase.
# Danger of contamination with diethylene glycol
On May 4, 2007, the US Food and Drug Administration advised all US makers of medicines to test all batches of glycerine for the toxic diethylene glycol.[11] This follows an occurrence of 100 fatal poisonings in Panama resulting from a Chinese factory deliberately falsifying records in order to export the cheaper diethylene glycol as the more expensive glycerol.[12] Glycerine and diethylene glycol are similar in appearance, smell, and taste. The US Federal Food, Drug, and Cosmetic Act was passed following the 1937 "Elixir Sulfanilamide" incident of poisoning caused by diethylene glycol contamination of medicine. | https://www.wikidoc.org/index.php/Colace_Glycerin_Suppositories | |
56ff4485e313390b3386c83f466822e99d7edb6a | wikidoc | Colipase | Colipase
Colipase is a protein co-enzyme required for optimal enzyme activity of pancreatic lipase. It is secreted by the pancreas in an inactive form, procolipase, which is activated in the intestinal lumen by trypsin. Its function is to prevent the inhibitory effect of bile salts on the lipase-catalyzed intraduodenal hydrolysis of dietary long-chain triglycerides.
In humans, the colipase protein is encoded by the CLPS gene.
# Protein domain
Colipase is also a family of evolutionarily related proteins.
Colipase is a small protein cofactor needed by pancreatic lipase for efficient dietary lipid hydrolysis. Efficient absorption of dietary fats is dependent on the action of pancreatic triglyceride lipase. Colipase binds to the C-terminal, non-catalytic domain of lipase, thereby stabilising an active conformation and considerably increasing the hydrophobicity of its binding site. Structural studies of the complex and of colipase alone have revealed the functionality of its architecture.
Colipase is a small protein (12K) with five conserved disulphide bonds. Structural analogies have been recognised between a developmental protein (Dickkopf), the pancreatic lipase C-terminal domain, the N-terminal domains of lipoxygenases and the C-terminal domain of alpha-toxin. These non-catalytic domains in the latter enzymes are important for interaction with membrane. It has not been established if these domains are also involved in eventual protein cofactor binding as is the case for pancreatic lipase. | Colipase
Colipase is a protein co-enzyme required for optimal enzyme activity of pancreatic lipase. It is secreted by the pancreas in an inactive form, procolipase, which is activated in the intestinal lumen by trypsin. Its function is to prevent the inhibitory effect of bile salts on the lipase-catalyzed intraduodenal hydrolysis of dietary long-chain triglycerides.
In humans, the colipase protein is encoded by the CLPS gene.[1]
# Protein domain
Colipase is also a family of evolutionarily related proteins.
Colipase is a small protein cofactor needed by pancreatic lipase for efficient dietary lipid hydrolysis. Efficient absorption of dietary fats is dependent on the action of pancreatic triglyceride lipase. Colipase binds to the C-terminal, non-catalytic domain of lipase, thereby stabilising an active conformation and considerably increasing the hydrophobicity of its binding site. Structural studies of the complex and of colipase alone have revealed the functionality of its architecture.[2][3]
Colipase is a small protein (12K) with five conserved disulphide bonds. Structural analogies have been recognised between a developmental protein (Dickkopf), the pancreatic lipase C-terminal domain, the N-terminal domains of lipoxygenases and the C-terminal domain of alpha-toxin. These non-catalytic domains in the latter enzymes are important for interaction with membrane. It has not been established if these domains are also involved in eventual protein cofactor binding as is the case for pancreatic lipase.[3] | https://www.wikidoc.org/index.php/Colipase | |
b2f70c0e0b141290ba4fbcaebe6cc954a73f3dc8 | wikidoc | Colistin | Colistin
# Overview
Colistin (polymyxin E) is a polymyxin antibiotic produced by certain strains of Bacillus polymyxa var. colistinus. Colistin is a mixture of cyclic polypeptides colistin A and B. Colistin is effective against Gram-negative bacilli, except Proteus and Burkholderia cepacia.
# Administration and posology
## Forms
There are two forms of colistin (also known as 'the nuke bomb' of antibiotics) available commercially: colistin sulfate and colistimethate sodium (colistin methanesulphonate sodium, colistin sulfomethate sodium). Colistin sulfate is cationic, colistimethate sodium is anionic; colistin sulphate is stable, but colistimethate sodium is readily hydrolysed to a variety of methanesulfonated derivatives. Colistin sulfate and colistimethate sodium are eliminated from the body by different routes. With respect to Pseudomonas aeruginosa, colistimethate is the inactive prodrug of colistin. The two drugs are not interchangeable.
- Colistimethate sodium may be used to treat Pseudomonas aeruginosa infections in cystic fibrosis patients and it has come into recent use for treating multidrug-resistant Acinetobacter infection, although resistant forms have been reported. Colistimethate sodium has also been given intrathecally and intraventricularly in Acinetobacter baumanii and Pseudomonas aeruginosa meningitis/ventriculitis Some studies have indicated that colistin may be useful for treating infections caused by carbapenem-resistant isolates of Acinetobacter baumannii.
- Colistin sulfate may be used to treat intestinal infections, or to suppress colonic flora. Colistin sulfate is also used as topical creams, powders, and otic solutions.
## Dosage
Colistin sulfate and colistimethate sodium may both be given intravenously, but the dosing is complicated. Colistimethate sodium manufactured by Dumex-Alpharma(Colomycin injection®) is prescribed in international units, but colistimethate sodium manufactured by Parkdale Pharmaceuticals (Coly-Mycin M Parenteral®) is prescribed in milligrams of colistin base:
- Colomycin 1,000,000 units is 80mg colistimethate;
- Coly-mycin M 150mg "colistin base" is 360mg colistimethate or 4,500,000 units.
Because colistin was introduced into clinical practice over 50 years ago, it was never subject to the regulations that modern drugs are subject to, and therefore there is no standardised dosing of colistin and no detailed trials on pharmacology or pharmacokinetics: the optimal dosing of colistin for most infections is therefore unknown. Colomycin has a recommended intravenous dose of 1 to 2 million units thrice daily for patients weighing 60kg or more with normal renal function, Coly-Mycin has a recommended dose of 2.5 to 5mg/kg colistin base a day, which is equivalent to 6 to 12 mg/kg colistimethate sodium per day. For a 60kg man, therefore, the recommended dose for Colomycin is 240 to 480mg of colistimethate sodium, yet the recommended dose for Coly-Mycin is 360 to 720mg of colistimethate sodium. Likewise, the recommended "maximum" dose for each preparation is different (480mg for Colomycin and 720mg for Coly-Mycin). Each country has different generic preparations of colistin and the recommended dose will depend on the manufacturer. This complete absence of any regulation or standardisation of dose makes intravenous colistin dosing a nightmare for any physician.
Colistin has been used in combination with rifampicin, and there is in-vitro evidence of synergy, and the combination has been used successfully in patients. There is also in-vitro evidence of synergy for colistimethate sodium used in combination with other antipseudomonal antibiotics .
Colistimethate sodium aerosol (Promixin®; Colomycin Injection®) is used to treat pulmonary infections, especially in cystic fibrosis. In the UK, the recommended adult dose is 1 - 2 million units (80 - 160mg) nebulised colistimethate twice daily.
# Mode of action
Colistin is polycationic and has both hydrophilic and lipophilic moieties. These interact with the bacterial cytoplasmic membrane, changing its permeability. This effect is bactericidal.
# Resistance
Resistance to colistin is currently rare, but is described. At present there is no agreement about how to look for colistin resistance. The Société Française de Microbiologie uses a cut off of 2mg/l, whereas the British Society for Antimicrobial Chemotherapy sets a cutoff of 4mg/l or less as sensitive, and 8mg/ml or more as resistant. There are not currently any US standards for measuring colistin sensitivity.
# Pharmacokinetics
There is no clinically useful absorption of colistin from the gastrointestinal tract. For systemic infection, colistin must therefore be given by injection.
Colistimethate is eliminated by the kidneys, but colistin is supposed to be eliminated by non-renal mechanism(s) that are as yet not characterised.
# Adverse reactions
The main toxicities described with intravenous treatment are nephrotoxicity (damage to the kidneys) and neurotoxicity (damage to the nerves), but this may reflect the very high doses given, which are much higher than the doses currently recommended by any manufacturer and for which no adjustment was made for renal disease. Neuro- and nephrotoxic effects appear to be transient and subside on discontinuation of therapy or reduction in dose .
At a dose of 160mg colistimethate IV every eight hours, very little nephrotoxicity is seen. Indeed, colistin appears to have less toxicity than the aminoglycosides that subsequently replaced it, and colistin has been used for extended periods of up to six months with no ill effects.
The main toxicity described with aerosolised treatment is bronchospasm which can be treated or prevented with the use of beta2-agonists such as salbutamol or following a desensitisation protocol.
# Further reading
- Li J, Nation RL, Tunridge JD; et al. (2006). "Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections". Lancet Infect Dis. 6 (8): 589&ndash, 601.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Li J , Nation RL, Milne RW; et al. (2005). "Evaluation of colistin as an agent against multi-resistant Gram-negative bacteria". Int J Antimicrob Agents. 25: 11&ndash, 25.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) | Colistin
# Overview
Colistin (polymyxin E) is a polymyxin antibiotic produced by certain strains of Bacillus polymyxa var. colistinus. Colistin is a mixture of cyclic polypeptides colistin A and B. Colistin is effective against Gram-negative bacilli, except Proteus and Burkholderia cepacia.
# Administration and posology
## Forms
There are two forms of colistin (also known as 'the nuke bomb' of antibiotics) available commercially: colistin sulfate and colistimethate sodium (colistin methanesulphonate sodium, colistin sulfomethate sodium). Colistin sulfate is cationic, colistimethate sodium is anionic; colistin sulphate is stable, but colistimethate sodium is readily hydrolysed to a variety of methanesulfonated derivatives. Colistin sulfate and colistimethate sodium are eliminated from the body by different routes. With respect to Pseudomonas aeruginosa, colistimethate is the inactive prodrug of colistin. The two drugs are not interchangeable.
- Colistimethate sodium may be used to treat Pseudomonas aeruginosa infections in cystic fibrosis patients and it has come into recent use for treating multidrug-resistant Acinetobacter infection, although resistant forms have been reported.[1][2] Colistimethate sodium has also been given intrathecally and intraventricularly in Acinetobacter baumanii and Pseudomonas aeruginosa meningitis/ventriculitis [3][4][5][6] Some studies have indicated that colistin may be useful for treating infections caused by carbapenem-resistant isolates of Acinetobacter baumannii.[2]
- Colistin sulfate may be used to treat intestinal infections, or to suppress colonic flora. Colistin sulfate is also used as topical creams, powders, and otic solutions.
## Dosage
Colistin sulfate and colistimethate sodium may both be given intravenously, but the dosing is complicated. Colistimethate sodium manufactured by Dumex-Alpharma(Colomycin injection®) is prescribed in international units, but colistimethate sodium manufactured by Parkdale Pharmaceuticals (Coly-Mycin M Parenteral®) is prescribed in milligrams of colistin base:
- Colomycin 1,000,000 units is 80mg colistimethate;[7]
- Coly-mycin M 150mg "colistin base" is 360mg colistimethate or 4,500,000 units.[8]
Because colistin was introduced into clinical practice over 50 years ago, it was never subject to the regulations that modern drugs are subject to, and therefore there is no standardised dosing of colistin and no detailed trials on pharmacology or pharmacokinetics: the optimal dosing of colistin for most infections is therefore unknown. Colomycin has a recommended intravenous dose of 1 to 2 million units thrice daily for patients weighing 60kg or more with normal renal function, Coly-Mycin has a recommended dose of 2.5 to 5mg/kg colistin base a day, which is equivalent to 6 to 12 mg/kg colistimethate sodium per day. For a 60kg man, therefore, the recommended dose for Colomycin is 240 to 480mg of colistimethate sodium, yet the recommended dose for Coly-Mycin is 360 to 720mg of colistimethate sodium. Likewise, the recommended "maximum" dose for each preparation is different (480mg for Colomycin and 720mg for Coly-Mycin). Each country has different generic preparations of colistin and the recommended dose will depend on the manufacturer. This complete absence of any regulation or standardisation of dose makes intravenous colistin dosing a nightmare for any physician.
Colistin has been used in combination with rifampicin, and there is in-vitro evidence of synergy,[9][10] and the combination has been used successfully in patients.[11] There is also in-vitro evidence of synergy for colistimethate sodium used in combination with other antipseudomonal antibiotics [12].
Colistimethate sodium aerosol (Promixin®; Colomycin Injection®) is used to treat pulmonary infections, especially in cystic fibrosis. In the UK, the recommended adult dose is 1 - 2 million units (80 - 160mg) nebulised colistimethate twice daily.[13][14]
# Mode of action
Colistin is polycationic and has both hydrophilic and lipophilic moieties. These interact with the bacterial cytoplasmic membrane, changing its permeability. This effect is bactericidal.
# Resistance
Resistance to colistin is currently rare, but is described. At present there is no agreement about how to look for colistin resistance. The Société Française de Microbiologie uses a cut off of 2mg/l, whereas the British Society for Antimicrobial Chemotherapy sets a cutoff of 4mg/l or less as sensitive, and 8mg/ml or more as resistant. There are not currently any US standards for measuring colistin sensitivity.
# Pharmacokinetics
There is no clinically useful absorption of colistin from the gastrointestinal tract. For systemic infection, colistin must therefore be given by injection.
Colistimethate is eliminated by the kidneys, but colistin is supposed to be eliminated by non-renal mechanism(s) that are as yet not characterised.[15][16]
# Adverse reactions
The main toxicities described with intravenous treatment are nephrotoxicity (damage to the kidneys) and neurotoxicity (damage to the nerves),[17][18][19][20] but this may reflect the very high doses given, which are much higher than the doses currently recommended by any manufacturer and for which no adjustment was made for renal disease. Neuro- and nephrotoxic effects appear to be transient and subside on discontinuation of therapy or reduction in dose [21].
At a dose of 160mg colistimethate IV every eight hours, very little nephrotoxicity is seen.[22][23] Indeed, colistin appears to have less toxicity than the aminoglycosides that subsequently replaced it, and colistin has been used for extended periods of up to six months with no ill effects.[24]
The main toxicity described with aerosolised treatment is bronchospasm [25] which can be treated or prevented with the use of beta2-agonists such as salbutamol [26] or following a desensitisation protocol[27].
# Further reading
- Li J, Nation RL, Tunridge JD; et al. (2006). "Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections". Lancet Infect Dis. 6 (8): 589&ndash, 601.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Li J , Nation RL, Milne RW; et al. (2005). "Evaluation of colistin as an agent against multi-resistant Gram-negative bacteria". Int J Antimicrob Agents. 25: 11&ndash, 25.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) | https://www.wikidoc.org/index.php/Colistin | |
a1d26c01b0f4fcf847c874e99032c8f0aab901a9 | wikidoc | Colitose | Colitose
Colitose is a 3,6-dideoxysugar that has been isolated from the O-antigen of certain Gram-negative bacteria such as Escherichia coli, Yersinia pseudotuberculosis, Salmonella enterica, Vibrio cholerae, and in marine bacteria such as Pseudoalteromonas sp. This sugar has not been isolated from eukaryotes. First isolated in 1958, it was assumed to be an obscure and relatively unimportant monosaccharide. However, recent work with glycosyltransferases suggest that obscure sugars such as colitose can be incorporated into existing natural product scaffolds, thereby constructing novel and potentially therapeutic compounds.
# Biosynthesis
The biosynthesis of colitose involves a set of four enzymes: mannose-1-phosphate guanylyltransferase (ColE), GDP-mannose 4,6-dehydratase (ColB), GDP-4-keto-6-deoxymannose-3-dehydratase (ColD), and GDP-L-colitose synthase (ColC)1. These enzymes and intermediates are shown in the image below. For clarity, groups modified by the previous enzymatic step are highlighted in yellow.
File:Pathway1.jpg
The biosynthesis of colitose begins by “tagging” mannose-1-phosphate with a GMP moiety, yielding GDP-mannose. This reaction is carried out by ColE. In the next step, ColB, a short-chain dehydrogenase-reductase enzyme, uses a tightly-bound NADP to first oxidize C-4 and then remove the hydroxyl at C-6. The resulting product, GDP-4-keto-6-deoxymannose, then reacts with ColD, a pyridoxal-5’-phosphate-dependent enzyme, which removes the hydroxyl at C-3. In the final step, the product of ColD, GDP-4-keto-3,6-dideoxymannose, reacts with ColC, which reduces the ketone functionality at C-4 back to an alcohol and inverts the configuration about C-5.
The resulting product, GDP-L-colitose, is then incorporated into the O-antigen by glycosyltransferases and O-antigen processing proteins. Further reactions join the O-antigen to the core polysaccharide to form the full lipopolysaccharide. | Colitose
Template:Chembox new
Colitose is a 3,6-dideoxysugar that has been isolated from the O-antigen of certain Gram-negative bacteria such as Escherichia coli, Yersinia pseudotuberculosis, Salmonella enterica, Vibrio cholerae, and in marine bacteria such as Pseudoalteromonas sp.[1] This sugar has not been isolated from eukaryotes. First isolated in 1958,[2] it was assumed to be an obscure and relatively unimportant monosaccharide. However, recent work with glycosyltransferases suggest that obscure sugars such as colitose can be incorporated into existing natural product scaffolds, thereby constructing novel and potentially therapeutic compounds.[3]
# Biosynthesis
The biosynthesis of colitose involves a set of four enzymes: mannose-1-phosphate guanylyltransferase (ColE), GDP-mannose 4,6-dehydratase (ColB), GDP-4-keto-6-deoxymannose-3-dehydratase (ColD), and GDP-L-colitose synthase (ColC)1. These enzymes and intermediates are shown in the image below. For clarity, groups modified by the previous enzymatic step are highlighted in yellow.
File:Pathway1.jpg
The biosynthesis of colitose begins by “tagging” mannose-1-phosphate with a GMP moiety, yielding GDP-mannose. This reaction is carried out by ColE. In the next step, ColB, a short-chain dehydrogenase-reductase enzyme, uses a tightly-bound NADP to first oxidize C-4 and then remove the hydroxyl at C-6. The resulting product, GDP-4-keto-6-deoxymannose, then reacts with ColD, a pyridoxal-5’-phosphate-dependent enzyme, which removes the hydroxyl at C-3. In the final step, the product of ColD, GDP-4-keto-3,6-dideoxymannose, reacts with ColC, which reduces the ketone functionality at C-4 back to an alcohol and inverts the configuration about C-5.[1]
The resulting product, GDP-L-colitose, is then incorporated into the O-antigen by glycosyltransferases and O-antigen processing proteins. Further reactions join the O-antigen to the core polysaccharide to form the full lipopolysaccharide. | https://www.wikidoc.org/index.php/Colitose | |
6cd90687424d7bbe12217fb06dbacfdc9ac67524 | wikidoc | Collagen | Collagen
Collagen is the main protein of connective tissue in animals and the most abundant protein in mammals, making up about 25% of the total protein content.
# Uses
Collagen is one of the long, fibrous structural proteins whose functions are quite different from those of globular proteins such as enzymes; tough bundles of collagen called collagen fibers are a major component of the extracellular matrix that supports most tissues and gives cells structure from the outside, but collagen is also found inside certain cells. Collagen has great tensile strength, and is the main component of fascia, cartilage, ligaments, tendons, bone and teeth. Along with soft keratin, it is responsible for skin strength and elasticity, and its degradation leads to wrinkles that accompany aging. It strengthens blood vessels and plays a role in tissue development. It is present in the cornea and lens of the eye in crystalline form. It is also used in cosmetic surgery and burns surgery.
## Industrial uses
If collagen is partially hydrolyzed, the three tropocollagen strands separate into globular, random coils, producing gelatin, which is used in many foods, including flavored gelatin desserts. Besides food, gelatin has been used in pharmaceutical, cosmetic, and photography industries.
Nutritionally, collagen and gelatin are poor quality protein since they do not contain all the essential amino acids that the human body requires - they are not complete proteins. Manufacturers of collagen-based dietary supplements claim that their products can improve skin and fingernail quality as well as joint health. However, mainstream scientific research has not shown any evidence to support these claims. Individuals with problems in these areas are more likely to be suffering from some other underlying condition rather than protein deficiency.
From the Greek for glue, kolla, the word collagen means "glue producer" and refers to the early process of boiling the skin and sinews of horses and other animals to obtain glue. Collagen adhesive was used by Egyptians about 4,000 years ago, and Native Americans used it in bows about 1,500 years ago. The oldest glue in the world, carbon dated as more than 8,000 years old, was found to be collagen — used as a protective lining on rope baskets and embroidered fabrics, and to hold utensils together; also in crisscross decorations on human skulls. Collagen normally converts to gelatin, but survived due to the dry conditions. Animal glues are thermoplastic, softening again upon reheating, and so they are still used in making musical instruments such as fine violins and guitars, which may have to be reopened for repairs — an application incompatible with tough, synthetic plastic adhesives, which are permanent. Animal sinews and skins, including leather, have been used to make useful articles for millennia.
Gelatin-resorcinol-formaldehyde glue (and with formaldehyde replaced by less-toxic pentanedial and ethanedial) has been used to repair experimental incisions in rabbit lungs.
## Medical uses
Collagen has been widely used in cosmetic surgery, as a healing aid for burn patients for reconstruction of bone and a wide variety of dental, orthopedic and surgical purposes. Some points of interest are:
- when used cosmetically, there is a chance of allergic reactions causing prolonged redness; however, this can be virtually eliminated by simple and inconspicuous patch testing prior to cosmetic use, and
- most medical collagen is derived from young beef cattle (bovine) from certified BSE (Bovine spongiform encephalopathy) free animals. Most manufacturers use donor animals from either "closed herds", or from countries which have never had a reported case of BSE such as Australia and New Zealand.
- porcine (pig) tissue is also widely used for producing collagen sheet for a variety of surgical purposes.
- due to the care in donor animal breeding and selection, as well as the technology used in the preparation of collagen from animal sources, the chance of immune reactions or disease transmission has been virtually eliminated.
- alternatives using the patient's own fat, hyaluronic acid or polyacrylamide gel are readily available.
Collagens are widely employed in the construction of artificial skin substitutes used in the management of severe burns, as well as for a wide range of dental, orthopedic, and surgical purposes. These collagens may be derived from bovine, equine or porcine, and even human, sources and are sometimes used in combination with silicones, glycosaminoglycans, fibroblasts, growth factors and other substances.
Collagen is also sold commercially as a joint mobility supplement. This lacks supportive research as the proteins would just be broken down into its base amino acids during digestion, and could go to a variety of places besides the joints depending upon need and DNA orders.
Recently an alternative to animal-derived collagen has become available. Although expensive, this human collagen, derived from donor cadavers, placentas and aborted fetuses, may minimize the possibility of immune reactions.
# Composition and structure
The tropocollagen or "collagen molecule" subunit is a rod about 300 nm long and 1.5 nm in diameter, made up of three polypeptide strands, each of which is a left-handed helix, not to be confused with the commonly occurring alpha helix, which is right-handed. These three left-handed helices are twisted together into a right-handed coiled coil, a triple helix, a cooperative quaternary structure stabilized by numerous hydrogen bonds. Tropocollagen subunits spontaneously self-assemble, with regularly staggered ends, into even larger arrays in the extracellular spaces of tissues. There is some covalent crosslinking within the triple helices, and a variable amount of covalent crosslinking between tropocollagen helices, to form the different types of collagen found in different mature tissues — similar to the situation found with the α-keratins in hair. Collagen's insolubility was a barrier to study until it was found that tropocollagen from young animals can be extracted because it is not yet fully crosslinked.
Collagen fibrils are collagen molecules packed into an organized overlapping bundle. Collagen fibers are bundles of fibrils.
A distinctive feature of collagen is the regular arrangement of amino acids in each of the three chains of these collagen subunits. The sequence often follows the pattern Gly-X-Pro or Gly-X-Hyp, where X may be any of various other amino acid residues. Gly-Pro-Hyp occurs frequently. This kind of regular repetition and high glycine content is found in only a few other fibrous proteins, such as silk fibroin. 75-80% of silk is (approximately) -Gly-Ala-Gly-Ala- with 10% serine — and elastin is rich in glycine, proline, and alanine (Ala), whose side group is a small, inert methyl. Such high glycine and regular repetitions are never found in globular proteins. Chemically-reactive side groups are not needed in structural proteins as they are in enzymes and transport proteins. The high content of Proline and Hydroxyproline rings, with their geometrically constrained carboxyl and (secondary) amino groups, accounts for the tendency of the individual polypeptide strands to form left-handed helices spontaneously, without any intrachain hydrogen bonding.
Because glycine is the smallest amino acid, it plays a unique role in fibrous structural proteins. In collagen, Gly is required at every third position because the assembly of the triple helix puts this residue at the interior (axis) of the helix, where there is no space for a larger side group than glycine’s single hydrogen atom. For the same reason, the rings of the Pro and Hyp must point outward. These two amino acids thermally stabilize the triple helix — Hyp even more so than Pro — and less of them is required in animals such as fish, whose body temperatures are low.
In bone, entire collagen triple helices lie in a parallel, staggered array. 40 nm gaps between the ends of the tropocollagen subunits probably serve as nucleation sites for the deposition of long, hard, fine crystals of the mineral component, which is (approximately) hydroxyapatite, Ca5(PO4)3(OH), with some phosphate. It is in this way that certain kinds of cartilage turn into bone. Collagen gives bone its elasticity and contributes to fracture resistance.
# Types of collagen and associated disorders
Collagen occurs in many places throughout the body. There are 28 types of collagen described in literature.
Collagen diseases commonly arise from genetic defects that affect the biosynthesis, assembly, postranslational modification, secretion, or other processes in the normal production of collagen.
# Staining
In histology, collagen is brightly eosinophilic (pink) in standard H&E slides. The dye methyl violet may be used to stain the collagen in tissue samples.
The dye methyl blue can also be used to stain collagen and immunohistochemical stains are available if required.
The best stain for use in differentiating collagen from other fibers is Masson's trichrome stain.
Collagen is birefringent when stained with Sirius red F3B (C.I. 35782).
# Synthesis
## Amino acids
Collagen has an unusual amino acid composition and sequence:
- Glycine (Gly) is found at almost every third residue
- Proline (Pro) makes up about 9% of collagen
- Collagen contains two uncommon derivative amino acids not directly inserted during translation. These amino acids are found at specific locations relative to glycine and are modified post-translationally by different enzymes, both of which require vitamin C as a cofactor.
Hydroxyproline (Hyp), derived from proline.
Hydroxylysine, derived from lysine. Depending on the type of collagen, varying numbers of hydroxylysines have disaccharides attached to them.
- Hydroxyproline (Hyp), derived from proline.
- Hydroxylysine, derived from lysine. Depending on the type of collagen, varying numbers of hydroxylysines have disaccharides attached to them.
## Collagen I formation
Most collagen forms in a similar manner, but the following process is typical for type I:
- Inside the cell
Three peptide chains are formed (2 alpha-1 and 1 alpha-2 chain) in ribosomes along the Rough Endoplasmic Reticulum (RER). These peptide chains (known as preprocollagen) have registration peptides on each end; and a signal peptide is also attached to each
Peptide chains are sent into the lumen of the RER
Signal Peptides are cleaved inside the RER and the chains are now known as procollagen
Hydroxylation of lysine and proline amino acids occurs inside the lumen. This process is dependent on Ascorbic Acid (Vitamin C) as a cofactor
Glycosylation of specific hydroxylated amino acid occurs
Triple helical structure is formed inside the RER
Procollagen is shipped to the golgi apparatus, where it is packaged and secreted by exocytosis
- Three peptide chains are formed (2 alpha-1 and 1 alpha-2 chain) in ribosomes along the Rough Endoplasmic Reticulum (RER). These peptide chains (known as preprocollagen) have registration peptides on each end; and a signal peptide is also attached to each
- Peptide chains are sent into the lumen of the RER
- Signal Peptides are cleaved inside the RER and the chains are now known as procollagen
- Hydroxylation of lysine and proline amino acids occurs inside the lumen. This process is dependent on Ascorbic Acid (Vitamin C) as a cofactor
- Glycosylation of specific hydroxylated amino acid occurs
- Triple helical structure is formed inside the RER
- Procollagen is shipped to the golgi apparatus, where it is packaged and secreted by exocytosis
- Outside the cell
Registration peptides are cleaved and tropocollagen is formed by procollagen peptidase.
Multiple tropocollagen molecules form collagen fibrils, and multiple collagen fibrils form into collagen fibers
Collagen is attached to cell membranes via several types of protein, including fibronectin and integrin.
- Registration peptides are cleaved and tropocollagen is formed by procollagen peptidase.
- Multiple tropocollagen molecules form collagen fibrils, and multiple collagen fibrils form into collagen fibers
- Collagen is attached to cell membranes via several types of protein, including fibronectin and integrin.
## Synthetic pathogenesis
Vitamin C deficiency causes scurvy, a serious and painful disease in which defective collagen prevents the formation of strong connective tissue. Gums deteriorate and bleed, with loss of teeth; skin discolors, and wounds do not heal. Prior to the eighteenth century, this condition was notorious among long duration military, particularly naval, expeditions during which participants were deprived of foods containing Vitamin C. In the human body, a malfunction of the immune system, called an autoimmune disease, results in an immune response in which healthy collagen fibers are systematically destroyed with inflammation of surrounding tissues. The resulting disease processes are called Lupus erythematosus, and rheumatoid arthritis, or collagen tissue disorders.
Many bacteria and viruses have virulence factors which destroy collagen or interfere with its production. | Collagen
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Collagen is the main protein of connective tissue in animals and the most abundant protein in mammals, [1] making up about 25% of the total protein content.
# Uses
Collagen is one of the long, fibrous structural proteins whose functions are quite different from those of globular proteins such as enzymes; tough bundles of collagen called collagen fibers are a major component of the extracellular matrix that supports most tissues and gives cells structure from the outside, but collagen is also found inside certain cells. Collagen has great tensile strength, and is the main component of fascia, cartilage, ligaments, tendons, bone and teeth. Along with soft keratin, it is responsible for skin strength and elasticity, and its degradation leads to wrinkles that accompany aging. It strengthens blood vessels and plays a role in tissue development. It is present in the cornea and lens of the eye in crystalline form. It is also used in cosmetic surgery and burns surgery.
## Industrial uses
If collagen is partially hydrolyzed, the three tropocollagen strands separate into globular, random coils, producing gelatin, which is used in many foods, including flavored gelatin desserts. Besides food, gelatin has been used in pharmaceutical, cosmetic, and photography industries.[2]
Nutritionally, collagen and gelatin are poor quality protein since they do not contain all the essential amino acids that the human body requires - they are not complete proteins. Manufacturers of collagen-based dietary supplements claim that their products can improve skin and fingernail quality as well as joint health. However, mainstream scientific research has not shown any evidence to support these claims. Individuals with problems in these areas are more likely to be suffering from some other underlying condition rather than protein deficiency.
From the Greek for glue, kolla, the word collagen means "glue producer" and refers to the early process of boiling the skin and sinews of horses and other animals to obtain glue. Collagen adhesive was used by Egyptians about 4,000 years ago, and Native Americans used it in bows about 1,500 years ago. The oldest glue in the world, carbon dated as more than 8,000 years old, was found to be collagen — used as a protective lining on rope baskets and embroidered fabrics, and to hold utensils together; also in crisscross decorations on human skulls.[3] Collagen normally converts to gelatin, but survived due to the dry conditions. Animal glues are thermoplastic, softening again upon reheating, and so they are still used in making musical instruments such as fine violins and guitars, which may have to be reopened for repairs — an application incompatible with tough, synthetic plastic adhesives, which are permanent. Animal sinews and skins, including leather, have been used to make useful articles for millennia.
Gelatin-resorcinol-formaldehyde glue (and with formaldehyde replaced by less-toxic pentanedial and ethanedial) has been used to repair experimental incisions in rabbit lungs.[4]
## Medical uses
Collagen has been widely used in cosmetic surgery, as a healing aid for burn patients for reconstruction of bone and a wide variety of dental, orthopedic and surgical purposes. Some points of interest are:
- when used cosmetically, there is a chance of allergic reactions causing prolonged redness; however, this can be virtually eliminated by simple and inconspicuous patch testing prior to cosmetic use, and
- most medical collagen is derived from young beef cattle (bovine) from certified BSE (Bovine spongiform encephalopathy) free animals. Most manufacturers use donor animals from either "closed herds", or from countries which have never had a reported case of BSE such as Australia and New Zealand.
- porcine (pig) tissue is also widely used for producing collagen sheet for a variety of surgical purposes.
- due to the care in donor animal breeding and selection, as well as the technology used in the preparation of collagen from animal sources, the chance of immune reactions or disease transmission has been virtually eliminated.
- alternatives using the patient's own fat, hyaluronic acid or polyacrylamide gel are readily available.
Collagens are widely employed in the construction of artificial skin substitutes used in the management of severe burns, as well as for a wide range of dental, orthopedic, and surgical purposes. These collagens may be derived from bovine, equine or porcine, and even human, sources and are sometimes used in combination with silicones, glycosaminoglycans, fibroblasts, growth factors and other substances.
Collagen is also sold commercially as a joint mobility supplement. This lacks supportive research as the proteins would just be broken down into its base amino acids during digestion, and could go to a variety of places besides the joints depending upon need and DNA orders.
Recently an alternative to animal-derived collagen has become available. Although expensive, this human collagen, derived from donor cadavers, placentas and aborted fetuses,[5] may minimize the possibility of immune reactions.
# Composition and structure
The tropocollagen or "collagen molecule" subunit is a rod about 300 nm long and 1.5 nm in diameter, made up of three polypeptide strands, each of which is a left-handed helix, not to be confused with the commonly occurring alpha helix, which is right-handed. These three left-handed helices are twisted together into a right-handed coiled coil, a triple helix, a cooperative quaternary structure stabilized by numerous hydrogen bonds. Tropocollagen subunits spontaneously self-assemble, with regularly staggered ends, into even larger arrays in the extracellular spaces of tissues. There is some covalent crosslinking within the triple helices, and a variable amount of covalent crosslinking between tropocollagen helices, to form the different types of collagen found in different mature tissues — similar to the situation found with the α-keratins in hair. Collagen's insolubility was a barrier to study until it was found that tropocollagen from young animals can be extracted because it is not yet fully crosslinked.
Collagen fibrils are collagen molecules packed into an organized overlapping bundle. Collagen fibers are bundles of fibrils.
A distinctive feature of collagen is the regular arrangement of amino acids in each of the three chains of these collagen subunits. The sequence often follows the pattern Gly-X-Pro or Gly-X-Hyp, where X may be any of various other amino acid residues. Gly-Pro-Hyp occurs frequently. This kind of regular repetition and high glycine content is found in only a few other fibrous proteins, such as silk fibroin. 75-80% of silk is (approximately) -Gly-Ala-Gly-Ala- with 10% serine — and elastin is rich in glycine, proline, and alanine (Ala), whose side group is a small, inert methyl. Such high glycine and regular repetitions are never found in globular proteins. Chemically-reactive side groups are not needed in structural proteins as they are in enzymes and transport proteins. The high content of Proline and Hydroxyproline rings, with their geometrically constrained carboxyl and (secondary) amino groups, accounts for the tendency of the individual polypeptide strands to form left-handed helices spontaneously, without any intrachain hydrogen bonding.
Because glycine is the smallest amino acid, it plays a unique role in fibrous structural proteins. In collagen, Gly is required at every third position because the assembly of the triple helix puts this residue at the interior (axis) of the helix, where there is no space for a larger side group than glycine’s single hydrogen atom. For the same reason, the rings of the Pro and Hyp must point outward. These two amino acids thermally stabilize the triple helix — Hyp even more so than Pro — and less of them is required in animals such as fish, whose body temperatures are low.
In bone, entire collagen triple helices lie in a parallel, staggered array. 40 nm gaps between the ends of the tropocollagen subunits probably serve as nucleation sites for the deposition of long, hard, fine crystals of the mineral component, which is (approximately) hydroxyapatite, Ca5(PO4)3(OH), with some phosphate. It is in this way that certain kinds of cartilage turn into bone. Collagen gives bone its elasticity and contributes to fracture resistance.
# Types of collagen and associated disorders
Collagen occurs in many places throughout the body. There are 28 types of collagen described in literature.
Collagen diseases commonly arise from genetic defects that affect the biosynthesis, assembly, postranslational modification, secretion, or other processes in the normal production of collagen.
# Staining
In histology, collagen is brightly eosinophilic (pink) in standard H&E slides. The dye methyl violet may be used to stain the collagen in tissue samples.
The dye methyl blue can also be used to stain collagen and immunohistochemical stains are available if required.
The best stain for use in differentiating collagen from other fibers is Masson's trichrome stain.
Collagen is birefringent when stained with Sirius red F3B (C.I. 35782). [6]
# Synthesis
## Amino acids
Collagen has an unusual amino acid composition and sequence:
- Glycine (Gly) is found at almost every third residue
- Proline (Pro) makes up about 9% of collagen
- Collagen contains two uncommon derivative amino acids not directly inserted during translation. These amino acids are found at specific locations relative to glycine and are modified post-translationally by different enzymes, both of which require vitamin C as a cofactor.
Hydroxyproline (Hyp), derived from proline.
Hydroxylysine, derived from lysine. Depending on the type of collagen, varying numbers of hydroxylysines have disaccharides attached to them.
- Hydroxyproline (Hyp), derived from proline.
- Hydroxylysine, derived from lysine. Depending on the type of collagen, varying numbers of hydroxylysines have disaccharides attached to them.
## Collagen I formation
Most collagen forms in a similar manner, but the following process is typical for type I:
- Inside the cell
Three peptide chains are formed (2 alpha-1 and 1 alpha-2 chain) in ribosomes along the Rough Endoplasmic Reticulum (RER). These peptide chains (known as preprocollagen) have registration peptides on each end; and a signal peptide is also attached to each
Peptide chains are sent into the lumen of the RER
Signal Peptides are cleaved inside the RER and the chains are now known as procollagen
Hydroxylation of lysine and proline amino acids occurs inside the lumen. This process is dependent on Ascorbic Acid (Vitamin C) as a cofactor
Glycosylation of specific hydroxylated amino acid occurs
Triple helical structure is formed inside the RER
Procollagen is shipped to the golgi apparatus, where it is packaged and secreted by exocytosis
- Three peptide chains are formed (2 alpha-1 and 1 alpha-2 chain) in ribosomes along the Rough Endoplasmic Reticulum (RER). These peptide chains (known as preprocollagen) have registration peptides on each end; and a signal peptide is also attached to each
- Peptide chains are sent into the lumen of the RER
- Signal Peptides are cleaved inside the RER and the chains are now known as procollagen
- Hydroxylation of lysine and proline amino acids occurs inside the lumen. This process is dependent on Ascorbic Acid (Vitamin C) as a cofactor
- Glycosylation of specific hydroxylated amino acid occurs
- Triple helical structure is formed inside the RER
- Procollagen is shipped to the golgi apparatus, where it is packaged and secreted by exocytosis
- Outside the cell
Registration peptides are cleaved and tropocollagen is formed by procollagen peptidase.
Multiple tropocollagen molecules form collagen fibrils, and multiple collagen fibrils form into collagen fibers
Collagen is attached to cell membranes via several types of protein, including fibronectin and integrin.
- Registration peptides are cleaved and tropocollagen is formed by procollagen peptidase.
- Multiple tropocollagen molecules form collagen fibrils, and multiple collagen fibrils form into collagen fibers
- Collagen is attached to cell membranes via several types of protein, including fibronectin and integrin.
## Synthetic pathogenesis
Vitamin C deficiency causes scurvy, a serious and painful disease in which defective collagen prevents the formation of strong connective tissue. Gums deteriorate and bleed, with loss of teeth; skin discolors, and wounds do not heal. Prior to the eighteenth century, this condition was notorious among long duration military, particularly naval, expeditions during which participants were deprived of foods containing Vitamin C. In the human body, a malfunction of the immune system, called an autoimmune disease, results in an immune response in which healthy collagen fibers are systematically destroyed with inflammation of surrounding tissues. The resulting disease processes are called Lupus erythematosus, and rheumatoid arthritis, or collagen tissue disorders.[7]
Many bacteria and viruses have virulence factors which destroy collagen or interfere with its production. | https://www.wikidoc.org/index.php/Collagen | |
d47520d600e07f7089a0f6c622d0dd5f4d596ae2 | wikidoc | Coloboma | Coloboma
A coloboma (also part of the rare Cat Eye syndrome) is a hole in one of the structures of the eye, such as the lens, eyelid, iris, retina, choroid or optic disc. The hole is present from birth and can be caused when a gap between two structures in the eye, which is present early in development in the uterus, fails to close up completely before a child is born. A coloboma can occur in one or both eyes.
The effects a coloboma has on the vision can be mild or more severe depending on the size and location of the gap. If, for example, only a small part of the iris is missing, vision may be normal, whereas if a large part of the retina or optic nerve is missing, vision may be poor and a large part of the visual field may be missing. This is more likely to cause problems with mobility if the lower visual field is absent. Other conditions can be associated with a coloboma. Sometimes the eye may be reduced in size, a condition called microphthalmia, or there may be glaucoma, nystagmus or strabismus (squint).
Some children with coloboma of the eye also have malformations in other parts of the body. There is a rare condition called CHARGE syndrome, in which coloboma is associated with cleft lip and/or palate, ear abnormalities and hearing impairment, choanal atresia, delays in growth and development, central nervous system anomalies and congenital heart defects.
The incidence of coloboma is estimated at around 0.5 to 0.7 per 10,000 births, making it a relatively rare condition.
# Differentiating coloboma from Other Diseases
Coloboma must be differentiated from retinoblastoma, Norrie disease, and Retinopathy of prematurity (ROP).
For more information on differential diagnosis of coloboma please click here
# Notes
- ↑ Hornby SJ, Adolph S, Gilbert CE, Dandona L, Foster A (March 2000). "Visual acuity in children with coloboma: clinical features and a new phenotypic classification system". Ophthalmology. 107 (3): 511–20. PMID 10711890..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}
- ↑ Butros LJ, Abramson DH, Dunkel IJ (March 2002). "Delayed diagnosis of retinoblastoma: analysis of degree, cause, and potential consequences". Pediatrics. 109 (3): E45. PMID 11875173.
- ↑ Sachdeva R, Schoenfield L, Marcotty A, Singh AD (June 2011). "Retinoblastoma with autoinfarction presenting as orbital cellulitis". J AAPOS. 15 (3): 302–4. doi:10.1016/j.jaapos.2011.02.013. PMID 21680213.
- ↑ Singh, Arun (2015). Clinical ophthalmic oncology : retinoblastoma. Heidelberg: Springer. ISBN 978-3-662-43451-2.
- ↑ Howard GM, Ellsworth RM (October 1965). "Differential diagnosis of retinoblastoma. A statistical survey of 500 children. I. Relative frequency of the lesions which simulate retinoblastoma". Am. J. Ophthalmol. 60 (4): 610–8. PMID 5897773. | Coloboma
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A coloboma (also part of the rare Cat Eye syndrome) is a hole in one of the structures of the eye, such as the lens, eyelid, iris, retina, choroid or optic disc. The hole is present from birth and can be caused when a gap between two structures in the eye, which is present early in development in the uterus, fails to close up completely before a child is born. A coloboma can occur in one or both eyes.
The effects a coloboma has on the vision can be mild or more severe depending on the size and location of the gap. If, for example, only a small part of the iris is missing, vision may be normal, whereas if a large part of the retina or optic nerve is missing, vision may be poor and a large part of the visual field may be missing. This is more likely to cause problems with mobility if the lower visual field is absent. Other conditions can be associated with a coloboma. Sometimes the eye may be reduced in size, a condition called microphthalmia, or there may be glaucoma, nystagmus or strabismus (squint).
Some children with coloboma of the eye also have malformations in other parts of the body. There is a rare condition called CHARGE syndrome, in which coloboma is associated with cleft lip and/or palate, ear abnormalities and hearing impairment, choanal atresia, delays in growth and development, central nervous system anomalies and congenital heart defects.
The incidence of coloboma is estimated at around 0.5 to 0.7 per 10,000 births, making it a relatively rare condition. [1]
# Differentiating coloboma from Other Diseases
Coloboma must be differentiated from retinoblastoma, Norrie disease, and Retinopathy of prematurity (ROP).[2][3][4][5]
For more information on differential diagnosis of coloboma please click here
# Notes
- ↑ Hornby SJ, Adolph S, Gilbert CE, Dandona L, Foster A (March 2000). "Visual acuity in children with coloboma: clinical features and a new phenotypic classification system". Ophthalmology. 107 (3): 511–20. PMID 10711890..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}
- ↑ Butros LJ, Abramson DH, Dunkel IJ (March 2002). "Delayed diagnosis of retinoblastoma: analysis of degree, cause, and potential consequences". Pediatrics. 109 (3): E45. PMID 11875173.
- ↑ Sachdeva R, Schoenfield L, Marcotty A, Singh AD (June 2011). "Retinoblastoma with autoinfarction presenting as orbital cellulitis". J AAPOS. 15 (3): 302–4. doi:10.1016/j.jaapos.2011.02.013. PMID 21680213.
- ↑ Singh, Arun (2015). Clinical ophthalmic oncology : retinoblastoma. Heidelberg: Springer. ISBN 978-3-662-43451-2.
- ↑ Howard GM, Ellsworth RM (October 1965). "Differential diagnosis of retinoblastoma. A statistical survey of 500 children. I. Relative frequency of the lesions which simulate retinoblastoma". Am. J. Ophthalmol. 60 (4): 610–8. PMID 5897773.
# External links
- Micro & Anophthalmic Children's Society
- The CHARGE Family Support Group
Template:Congenital malformations and deformations of eye, ear, face and neck
de:Kolobom
id:Koloboma
it:Coloboma
fi:Kolobooma
Template:WS | https://www.wikidoc.org/index.php/Coloboma | |
2012a1a511e02dcefeac3ce658e9c94e8644504d | wikidoc | ComPsych | ComPsych
Founded in 1984, ComPsych is the world’s largest provider of employee assistance programs (EAPs) and the leading provider of fully integrated EAP, behavioral health, work-life, wellness and HR and FMLA administration services under the GuidanceResources® brand. ComPsych provides services to more than 13,000 organizations and 33 million individuals in the U.S. and over 100 countries worldwide. Clients range from the Fortune 500 to smaller public and private concerns as well as government entities and Taft-Hartley groups. ComPsych creates “Build-to-Suit” programs which help employers attract and retain employees as well as improve employee productivity and performance. For more information, visit www.compsych.com.
# About ComPsych
ComPsych’s passion to over-deliver on expectations, continual commitment to quality, ingenuity, unparalleled service and partnership allow us to custom-design products that fit our customers’ needs. Just as the business environment is constantly changing, so are our services – staying a step ahead of organizational challenges, adapting to business needs and always responding to the unique issues of employees.
It is this dedication to aligning programs with business needs that helps our customers stay ahead – ComPsych provides employees with the right help at the right time, allowing them to be focused and performing on the job. And that allows organizations to improve productivity and efficiency, reduce costs and increase profitability.
ComPsych was founded in 1984 by Chairman and CEO Dr. Richard A. Chaifetz. Our relentless focus on our core competencies and commitment to providing the highest quality services has fueled year-over-year growth in our company, resulting in unmatched financial stability and long-standing customer partnerships. Organizations that choose GuidanceResources are the companies that stay ahead of their business challenges.
# ComPsych Products and Services
ComPsych GuidanceResources® is a fully integrated continuum of employee assistance, work-life, behavioral health and wellness services which help individuals improve their behavioral and physical health and address personal, family and life issues. GuidanceResources fuels high performance cultures, enabling organizations to attract and retain the best and the brightest, resulting in superior productivity, performance and profitability.
No matter what issue or personal concern an individual is facing - from emotional problems, relationship and family issues to legal, financial or wellness concerns - ComPsych GuidanceResources provides a team of professionals ready to help. Our consultative staff of behavioral specialists, work-life professionals, attorneys, financial experts, wellness professionals and concierges can be reached by phone, on the Web or in person - however desired.
Our integrated, "Build-to-Suit" programs meet the needs of each organization. We customize each program solution, offering the ultimate flexibility for your organization.
ComPsych distinguishes our GuidanceResources through a company-wide passion and dedication to over-deliver on client expectations. We call this "The ComPsych Experience."
## Employee Assistance Programs
### U.S.
Compassionate, responsive, professional. These words describe the unique way ComPsych delivers employee assistance programs (EAP). We provide personalized guidance services from behavioral experts 24 hours a day, seven days a week. Wherever employees and their families live, work or travel, our staff professionals are available to provide immediate help, with services throughout the U.S. and 92 countries. Our programs offer:
- Worldwide access 24 hours a day
- Program and session models designed specifically for your organization
- Substance-abuse and DOT assessment, training and intervention
- Critical incident consultation and intervention anywhere in the world
- Specialty provider networks
- Proactive account management
- Cutting-edge program communications
Our EAP is "Build-to-Suit" to meet the unique culture and philosophy of your organization.
### Worldwide
ComPsych is the world's largest provider of EAP services, using our trademark GuidanceResources brands. We provide the full array of EAP, work-life and critical incident support services for expatriates and host country nationals.
Management Offices
- Tokyo, Japan
- London, UK
- Madrid, Spain
- Hong Kong, China
- Beijing, China
- Shanghai, China
- São Paulo, Brazil
Regional Call Centers
- Tokyo, Japan
- London, UK
- New Delhi, India
- Shanghai, China
- Mexico City, Mexico
- Sao Paulo, Brazil
- Hato Rey, Puerto Rico
## Behavioral Health Programs
### Managed Behavioral Health
Controlling costs without sacrificing quality of care continues to be a paramount issue for organizations today. ComPsych's behavioral health programs deliver substantial cost savings while improving clinical outcomes and client satisfaction. We are passionate about balancing quality of care, effective access and streamlined administration with savings to the bottom line. Our programs offer:
- Program models on an administrative services (ASO) or risk basis
- Full integration with EAP and other ComPsych services
- 24 hour pre-certification
- Industry-leading claims administration
- Worldwide network for easy access
- Utilization management at all levels of care
- Comprehensive reporting of program outcomes
ComPsych managed care works - individuals receive the care they need, organizations receive the dollar cost savings.
### DisabilityAssistSM
Many disability claims include mental health and work-life issues as a result of the claimant's impairment - this can include depression, family and relationship issues or merely adjusting to a reduced quality of living. ComPsych's DisabilityAssist is a suite of services that addresses all dimensions of an employee's medical and mental health condition and directly complements an employer′s disability program. There are two program models: DisabilityAssist-Outreach and DisabilityAssist-Management.
DisabilityAssist-Outreach provides:
- Proactive outreach call from a master's level clinician
- Tailored response to individual needs
- Interactive communications to encourage program use
- Referrals to complementary resources
DisabilityAssist-Management provides:
- Case management of behavioral health-related claims
- Goal-focused treatment plans provided by ComPsych disability case managers
- Coordinated outreach with the provider and employee to reduce length of stay
- HR and manager education on mental health issues
- Comprehensive reporting on costs saved
DisabilityAssist helps organizations manage employee issues for a faster return to work and reduced disability claims costs.
## Work-Life Services
### FamilySource®
As life becomes increasingly busy and complex, wide-ranging personal issues create distractions that can affect workplace productivity. ComPsych's FamilySource work-life and personal convenience programs offer a consultative team of experts who provide information and referrals in areas such as child care, adoption, elder care, education, pet care and concierge services. Each client receives personalized attention and consultation on all aspects of their work-life needs. Our program provides:
- Unlimited interactive, telephonic and online expert guidance and resource search
- Prescreened referrals for child and elder care services
- Personalized information, referrals and recommendation packages
- Extensive, in-depth online content including video, audio, articles and recommended books
ComPsych creates the appropriate blend of specialists, resources, technology, information and materials to develop a "Build-to-Suit" comprehensive program supporting your work-life initiatives.
### LegalConnect®
Many individuals report legal issues significant enough to cause them to miss work. Divorce, estate planning, lawsuits, bankruptcy, adoptions and personal injury all present time-consuming concerns that take away from productivity in the workplace. ComPsych's LegalConnect provides immediate, confidential access to staff attorneys who are dedicated to providing practical and understandable information and assistance. Our program offers:
- Unlimited telephonic and online access to legal information by licensed attorneys
- Access to our credentialed nationwide network of lawyers for in-person consultation
- Referral to lawyers in the community at discounted fees
- Comprehensive resource database including self-help guides, low cost legal clinics and legal aid organizations
- A wide variety of no-cost legal options
LegalConnect removes the distractions that legal issues may cause, helping employees stay productive in the workplace.
### FinancialConnect®
Financial issues touch the life of every individual. Without the appropriate information or knowledge, these issues can become time-consuming and stressful, affecting job productivity. ComPsych's FinancialConnect service provides access to financial experts in areas such as family budgeting, credit problems, tax questions, estate planning, investment options, insurance, money management and retirement planning. Our program provides:
- Unlimited telephonic and online access
- On-staff CPAs and other financial experts
- Network of certified financial planners
- User-friendly online financial-planning tools
- Online video presentations by experts
- Recommended books and articles
With FinancialConnect, individuals receive tailored information and resources to take the right steps and address their financial concerns.
### ElderOutreach®
Research shows that elder-care issues affect one out of every four individuals. Adult care, unexpected illness, financial and legal planning as well as living arrangements require both time and expertise that most caregivers do not have. ComPsych's ElderOutreach provides a holistic approach to remove the distractions of elder-care issues, resulting in improved workplace productivity. Our program provides:
- Unlimited telephone and online access
- Pre-screened nationwide specialty network of elder-care licensed clinicians
- Personalized information, referral and recommendation packages
- In-home assessment and recommendation conducted by a licensed clinician
- Legal and financial expertise on elder-care issues
- Online videos, educational materials and recommended books and articles
Distance or lack of time can make giving care to elders a major source of stress in any individual's life. ElderOutreach professionals offer solutions through expert, compassionate and reliable support.
## Health and Wellness Programs
### HealthyGuidance®
HealthyGuidance is a holistic wellness program that targets behavior and lifestyles issues before they become significant illnesses. A natural extension of the EAP or behavioral health services, HealthyGuidance empowers employees to make healthy lifestyle changes.
HealthyGuidance provides guidance, encouragement and knowledge to the employee through a battery of health tests, literature, comprehensive online health information including personal health management tools and ongoing coaching. The offering complements an employer's health plan through front-end resolution of health risks, identifying lifestyle and behavioral issues early that, if not addressed, could exacerbate or lead to diseased states. The program includes:
- Comprehensive health risk assessments
- Extensive health content
- Interactive electronic communications
- Wellness coaching with behavioral, health and nutritional experts
- Action-oriented wellness seminars
- Employer support through supervisor training
## Online Services
### GuidanceResources® Online
GuidanceResources Online is ComPsych's comprehensive interactive service that provides individuals with instant guidance, information and helpful tools to address life issues, concerns and needs. GuidanceResources Online seamlessly integrates with ComPsych's off-line services to create a custom-tailored solution that offers:
- Thousands of expert-reviewed articles, news and videos
- Tools, surveys and self-assessment questionnaires
- Easy navigation and search by topic, life event and keyword
- Confidential, one-on-one expert assistance and feedback
- Personalized, scenario-based content recommendations
- Interactive chats and message boards
- Directories of child-care, elder-care, legal and financial professionals
- Integration with intranet and HR portals
Expert content, personalization and security create a one-of-a-kind user experience. By consistently focusing on individual's needs, GuidanceResources Online is a trusted resource that individuals can rely on for every aspect of their lives.
## HR Services
### FMLASource®
Heightened awareness of the Family and Medical Leave Act (FMLA) has increased costs and compliance risks for employers. ComPsych's FMLASource provides expert administration and consultation on all aspects of FMLA compliance. Employees receive a single source for timely information to help them understand how FMLA applies to their situation. Our program provides:
- Completely outsourced administration for FMLA compliance
- Expert consultation regarding the application of FMLA
- Training for managers on their responsibilities
- Online tracking of all FMLA requests and eligibility to ensure compliance
- Ongoing management reports to identify trends
FMLASource provides organizations with comprehensive FMLA administration, resulting in reduced staff expenses and litigation risks. Our FMLA experts eliminate the administrative burdens, ensuring your program is effectively managed.
### HRConsultSM
More than ever before, employers are faced with a widening range of organizational issues. ComPsych's HRConsult provides one-stop industry expertise to HR leaders with information, resources and perspective on issues they are facing. HRConsult provides consultation on issues such as:
- Employee attraction, retention and performance issues
- Substance abuse and DOT
- ADA and other government regulatory compliance
- Workplace violence, crisis intervention and employee security
- Hundreds of topics covered through training, seminars and developmental workshops
HRConsult provides a trusted resource to help organizations of all sizes effectively manage tough issues and improve performance.
## Critical Incident Services
### Crisis Intervention WorldwideSM
With increased threat and incidents of traumatic events, it is critical that organizations develop a plan for crisis intervention and support. ComPsych's Crisis Intervention Worldwide, with over 15 years of experience, is the world's largest crisis-management service. Our crisis experts advise and debrief on critical incidents, including violence, fatalities, robberies, natural disasters, kidnappings and terrorist attacks. Our service provides:
- Global access - 24 hours a day, seven days a week - to telephonic, online and on-site services
- ComPsych critical incident specialists located worldwide
- Immediate response time when necessary
- Preventive consultation and planning
- Post-event management reporting and recommendations
Crisis Intervention Worldwide offers the industry's most comprehensive support to help individuals and organizations move effectively through crisis situations. We provide a cost-effective insurance policy to protect against the unexpected. | ComPsych
Template:Infobox Company
Founded in 1984, ComPsych is the world’s largest provider of employee assistance programs (EAPs) and the leading provider of fully integrated EAP, behavioral health, work-life, wellness and HR and FMLA administration services under the GuidanceResources® brand. ComPsych provides services to more than 13,000 organizations and 33 million individuals in the U.S. and over 100 countries worldwide. Clients range from the Fortune 500 to smaller public and private concerns as well as government entities and Taft-Hartley groups. ComPsych creates “Build-to-Suit” programs which help employers attract and retain employees as well as improve employee productivity and performance. For more information, visit www.compsych.com.
# About ComPsych
ComPsych’s passion to over-deliver on expectations, continual commitment to quality, ingenuity, unparalleled service and partnership allow us to custom-design products that fit our customers’ needs. Just as the business environment is constantly changing, so are our services – staying a step ahead of organizational challenges, adapting to business needs and always responding to the unique issues of employees.
It is this dedication to aligning programs with business needs that helps our customers stay ahead – ComPsych provides employees with the right help at the right time, allowing them to be focused and performing on the job. And that allows organizations to improve productivity and efficiency, reduce costs and increase profitability.
ComPsych was founded in 1984 by Chairman and CEO Dr. Richard A. Chaifetz. Our relentless focus on our core competencies and commitment to providing the highest quality services has fueled year-over-year growth in our company, resulting in unmatched financial stability and long-standing customer partnerships. Organizations that choose GuidanceResources are the companies that stay ahead of their business challenges.
# ComPsych Products and Services
ComPsych GuidanceResources® is a fully integrated continuum of employee assistance, work-life, behavioral health and wellness services which help individuals improve their behavioral and physical health and address personal, family and life issues. GuidanceResources fuels high performance cultures, enabling organizations to attract and retain the best and the brightest, resulting in superior productivity, performance and profitability.
No matter what issue or personal concern an individual is facing - from emotional problems, relationship and family issues to legal, financial or wellness concerns - ComPsych GuidanceResources provides a team of professionals ready to help. Our consultative staff of behavioral specialists, work-life professionals, attorneys, financial experts, wellness professionals and concierges can be reached by phone, on the Web or in person - however desired.
Our integrated, "Build-to-Suit" programs meet the needs of each organization. We customize each program solution, offering the ultimate flexibility for your organization.
ComPsych distinguishes our GuidanceResources through a company-wide passion and dedication to over-deliver on client expectations. We call this "The ComPsych Experience."
## Employee Assistance Programs
### U.S.
Compassionate, responsive, professional. These words describe the unique way ComPsych delivers employee assistance programs (EAP). We provide personalized guidance services from behavioral experts 24 hours a day, seven days a week. Wherever employees and their families live, work or travel, our staff professionals are available to provide immediate help, with services throughout the U.S. and 92 countries. Our programs offer:
- Worldwide access 24 hours a day
- Program and session models designed specifically for your organization
- Substance-abuse and DOT assessment, training and intervention
- Critical incident consultation and intervention anywhere in the world
- Specialty provider networks
- Proactive account management
- Cutting-edge program communications
Our EAP is "Build-to-Suit" to meet the unique culture and philosophy of your organization.
### Worldwide
ComPsych is the world's largest provider of EAP services, using our trademark GuidanceResources brands. We provide the full array of EAP, work-life and critical incident support services for expatriates and host country nationals.
Management Offices
- Tokyo, Japan
- London, UK
- Madrid, Spain
- Hong Kong, China
- Beijing, China
- Shanghai, China
- São Paulo, Brazil
Regional Call Centers
- Tokyo, Japan
- London, UK
- New Delhi, India
- Shanghai, China
- Mexico City, Mexico
- Sao Paulo, Brazil
- Hato Rey, Puerto Rico
## Behavioral Health Programs
### Managed Behavioral Health
Controlling costs without sacrificing quality of care continues to be a paramount issue for organizations today. ComPsych's behavioral health programs deliver substantial cost savings while improving clinical outcomes and client satisfaction. We are passionate about balancing quality of care, effective access and streamlined administration with savings to the bottom line. Our programs offer:
- Program models on an administrative services (ASO) or risk basis
- Full integration with EAP and other ComPsych services
- 24 hour pre-certification
- Industry-leading claims administration
- Worldwide network for easy access
- Utilization management at all levels of care
- Comprehensive reporting of program outcomes
ComPsych managed care works - individuals receive the care they need, organizations receive the dollar cost savings.
### DisabilityAssistSM
Many disability claims include mental health and work-life issues as a result of the claimant's impairment - this can include depression, family and relationship issues or merely adjusting to a reduced quality of living. ComPsych's DisabilityAssist is a suite of services that addresses all dimensions of an employee's medical and mental health condition and directly complements an employer′s disability program. There are two program models: DisabilityAssist-Outreach and DisabilityAssist-Management.
DisabilityAssist-Outreach provides:
- Proactive outreach call from a master's level clinician
- Tailored response to individual needs
- Interactive communications to encourage program use
- Referrals to complementary resources
DisabilityAssist-Management provides:
- Case management of behavioral health-related claims
- Goal-focused treatment plans provided by ComPsych disability case managers
- Coordinated outreach with the provider and employee to reduce length of stay
- HR and manager education on mental health issues
- Comprehensive reporting on costs saved
DisabilityAssist helps organizations manage employee issues for a faster return to work and reduced disability claims costs.
## Work-Life Services
### FamilySource®
As life becomes increasingly busy and complex, wide-ranging personal issues create distractions that can affect workplace productivity. ComPsych's FamilySource work-life and personal convenience programs offer a consultative team of experts who provide information and referrals in areas such as child care, adoption, elder care, education, pet care and concierge services. Each client receives personalized attention and consultation on all aspects of their work-life needs. Our program provides:
- Unlimited interactive, telephonic and online expert guidance and resource search
- Prescreened referrals for child and elder care services
- Personalized information, referrals and recommendation packages
- Extensive, in-depth online content including video, audio, articles and recommended books
ComPsych creates the appropriate blend of specialists, resources, technology, information and materials to develop a "Build-to-Suit" comprehensive program supporting your work-life initiatives.
### LegalConnect®
Many individuals report legal issues significant enough to cause them to miss work. Divorce, estate planning, lawsuits, bankruptcy, adoptions and personal injury all present time-consuming concerns that take away from productivity in the workplace. ComPsych's LegalConnect provides immediate, confidential access to staff attorneys who are dedicated to providing practical and understandable information and assistance. Our program offers:
- Unlimited telephonic and online access to legal information by licensed attorneys
- Access to our credentialed nationwide network of lawyers for in-person consultation
- Referral to lawyers in the community at discounted fees
- Comprehensive resource database including self-help guides, low cost legal clinics and legal aid organizations
- A wide variety of no-cost legal options
LegalConnect removes the distractions that legal issues may cause, helping employees stay productive in the workplace.
### FinancialConnect®
Financial issues touch the life of every individual. Without the appropriate information or knowledge, these issues can become time-consuming and stressful, affecting job productivity. ComPsych's FinancialConnect service provides access to financial experts in areas such as family budgeting, credit problems, tax questions, estate planning, investment options, insurance, money management and retirement planning. Our program provides:
- Unlimited telephonic and online access
- On-staff CPAs and other financial experts
- Network of certified financial planners
- User-friendly online financial-planning tools
- Online video presentations by experts
- Recommended books and articles
With FinancialConnect, individuals receive tailored information and resources to take the right steps and address their financial concerns.
### ElderOutreach®
Research shows that elder-care issues affect one out of every four individuals. Adult care, unexpected illness, financial and legal planning as well as living arrangements require both time and expertise that most caregivers do not have. ComPsych's ElderOutreach provides a holistic approach to remove the distractions of elder-care issues, resulting in improved workplace productivity. Our program provides:
- Unlimited telephone and online access
- Pre-screened nationwide specialty network of elder-care licensed clinicians
- Personalized information, referral and recommendation packages
- In-home assessment and recommendation conducted by a licensed clinician
- Legal and financial expertise on elder-care issues
- Online videos, educational materials and recommended books and articles
Distance or lack of time can make giving care to elders a major source of stress in any individual's life. ElderOutreach professionals offer solutions through expert, compassionate and reliable support.
## Health and Wellness Programs
### HealthyGuidance®
HealthyGuidance is a holistic wellness program that targets behavior and lifestyles issues before they become significant illnesses. A natural extension of the EAP or behavioral health services, HealthyGuidance empowers employees to make healthy lifestyle changes.
HealthyGuidance provides guidance, encouragement and knowledge to the employee through a battery of health tests, literature, comprehensive online health information including personal health management tools and ongoing coaching. The offering complements an employer's health plan through front-end resolution of health risks, identifying lifestyle and behavioral issues early that, if not addressed, could exacerbate or lead to diseased states. The program includes:
- Comprehensive health risk assessments
- Extensive health content
- Interactive electronic communications
- Wellness coaching with behavioral, health and nutritional experts
- Action-oriented wellness seminars
- Employer support through supervisor training
## Online Services
### GuidanceResources® Online
GuidanceResources Online is ComPsych's comprehensive interactive service that provides individuals with instant guidance, information and helpful tools to address life issues, concerns and needs. GuidanceResources Online seamlessly integrates with ComPsych's off-line services to create a custom-tailored solution that offers:
- Thousands of expert-reviewed articles, news and videos
- Tools, surveys and self-assessment questionnaires
- Easy navigation and search by topic, life event and keyword
- Confidential, one-on-one expert assistance and feedback
- Personalized, scenario-based content recommendations
- Interactive chats and message boards
- Directories of child-care, elder-care, legal and financial professionals
- Integration with intranet and HR portals
Expert content, personalization and security create a one-of-a-kind user experience. By consistently focusing on individual's needs, GuidanceResources Online is a trusted resource that individuals can rely on for every aspect of their lives.
## HR Services
### FMLASource®
Heightened awareness of the Family and Medical Leave Act (FMLA) has increased costs and compliance risks for employers. ComPsych's FMLASource provides expert administration and consultation on all aspects of FMLA compliance. Employees receive a single source for timely information to help them understand how FMLA applies to their situation. Our program provides:
- Completely outsourced administration for FMLA compliance
- Expert consultation regarding the application of FMLA
- Training for managers on their responsibilities
- Online tracking of all FMLA requests and eligibility to ensure compliance
- Ongoing management reports to identify trends
FMLASource provides organizations with comprehensive FMLA administration, resulting in reduced staff expenses and litigation risks. Our FMLA experts eliminate the administrative burdens, ensuring your program is effectively managed.
### HRConsultSM
More than ever before, employers are faced with a widening range of organizational issues. ComPsych's HRConsult provides one-stop industry expertise to HR leaders with information, resources and perspective on issues they are facing. HRConsult provides consultation on issues such as:
- Employee attraction, retention and performance issues
- Substance abuse and DOT
- ADA and other government regulatory compliance
- Workplace violence, crisis intervention and employee security
- Hundreds of topics covered through training, seminars and developmental workshops
HRConsult provides a trusted resource to help organizations of all sizes effectively manage tough issues and improve performance.
## Critical Incident Services
### Crisis Intervention WorldwideSM
With increased threat and incidents of traumatic events, it is critical that organizations develop a plan for crisis intervention and support. ComPsych's Crisis Intervention Worldwide, with over 15 years of experience, is the world's largest crisis-management service. Our crisis experts advise and debrief on critical incidents, including violence, fatalities, robberies, natural disasters, kidnappings and terrorist attacks. Our service provides:
- Global access - 24 hours a day, seven days a week - to telephonic, online and on-site services
- ComPsych critical incident specialists located worldwide
- Immediate response time when necessary
- Preventive consultation and planning
- Post-event management reporting and recommendations
Crisis Intervention Worldwide offers the industry's most comprehensive support to help individuals and organizations move effectively through crisis situations. We provide a cost-effective insurance policy to protect against the unexpected. | https://www.wikidoc.org/index.php/ComPsych | |
450dddc56b4d4d211d9df780d348b7e6b24c7b9e | wikidoc | Combivir | Combivir
Combivir is the brand name for a pharmaceutical treatment for HIV infection. It is a fixed dose combination of two antiretroviral drugs, lamivudine (also called 3TC, with the brand name Epivir) and zidovudine (also called AZT, with the brand name Retrovir ). The combination of the two drugs has a stronger effect than either drug alone.
Both lamivudine and zidovudine are reverse transcriptase inhibitors, which block the action of an enzyme, reverse transcriptase, that the virus requires for reproduction. It reduces the viral load in the body and raises CD4 cell count.
It was approved by the FDA on September 26, 1997, making it the thirteenth approved antiretroviral. It is marketed by GlaxoSmithKline. | Combivir
Combivir is the brand name for a pharmaceutical treatment for HIV infection. It is a fixed dose combination of two antiretroviral drugs, lamivudine (also called 3TC, with the brand name Epivir) and zidovudine (also called AZT, with the brand name Retrovir ). The combination of the two drugs has a stronger effect than either drug alone.
Both lamivudine and zidovudine are reverse transcriptase inhibitors, which block the action of an enzyme, reverse transcriptase, that the virus requires for reproduction. It reduces the viral load in the body and raises CD4 cell count.
It was approved by the FDA on September 26, 1997, making it the thirteenth approved antiretroviral. It is marketed by GlaxoSmithKline.
Template:Treatment-stub | https://www.wikidoc.org/index.php/Combivir | |
0f935299a4bbf2c25dbb78b3d2d637e7ca612844 | wikidoc | Condylox | Condylox
# Overview
Condylox is a topical gel used on the skin to treat external genital warts, caused by one form of the Human Papillomavirus (HPV).
# Application
The gel is applied to warts as pointed out by a doctor. It is applied once in the morning and once in the evening for 3 days, followed by a 4 day rest period.
# Side Effects
Application can be immediately followed by burning or itching. Small sores, itching and peeling skin can also follow. Most people using the gel do not report these side effects. | Condylox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Condylox is a topical gel used on the skin to treat external genital warts, caused by one form of the Human Papillomavirus (HPV).
# Application
The gel is applied to warts as pointed out by a doctor. It is applied once in the morning and once in the evening for 3 days, followed by a 4 day rest period.
# Side Effects
Application can be immediately followed by burning or itching. Small sores, itching and peeling skin can also follow. Most people using the gel do not report these side effects.
Template:Drug-stub | https://www.wikidoc.org/index.php/Condylox |
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