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8de3abe74df4a6747f6755093affb6ed3343e631 | wikidoc | MELD Score | MELD Score
# Overview
The Model for End-Stage Liver Disease (MELD) is a reliable measure of mortality risk in patients with end-stage liver disease. It is used as a disease severity index to help prioritize allocation of organs for transplant. The new system, known as the Model for End-Stage Liver Disease (MELD) score, leaves no room for subjective criteria favoritism or hospital-shopping, as it is based on a mathematical equation. The equation seeks to calculate a patient’s likelihood of dying within three months from their liver disease. In other words under the MELD scoring system - the sickest patient gets the liver transplant. It is more recent than the Child-Pugh score.
# Historical Perspective
This model was derived from a heterogeneous group of patients at 4 medical centers in the United States and validated in an independent data set from the Netherlands.
The original version of the MELD scale as developed by investigators at Mayo Clinic. It was initially described by Kamath et al in 2001 and modified by Wiesner et al, also in 2001. A number of modification have been made by UNOS (United Network for Organ Sharing) to the model for its implementation in organ allocation for liver transplantation. The Model for End-Stage Liver Disease (MELD) score has been used by the Organ Procurement and Transplantation Network (OPTN) since February 2002 as the basis for allocation of deceased donor livers for transplantation among adults in the United States.
# Calculation of MELD Score
The MELD Calculator is a utility that allows you to enter hypothetical or actual parameters and calculate a MELD score for an individual patient. The MELD/PELD Calculator uses the specific formulas approved by the OPTN/UNOS Board of Directors and used for the allocation of livers by the OPTN match system. The MELD score calculation uses-
- Serum creatinine (mg/dl) *
- Bilirubin (mg/dl)
- INR
For candidates on dialysis, defined as having 2 or more dialysis treatments within the prior week; or candidates who have received 24 hours of CVVHD (Continuous Veno-venous Hemodialysis) within the prior week, will have their serum creatinine level automatically set to 4.0 mg/dl. The MELD Calculator is used for candidates who are 12 years and older.
# MELD Formula
The MELD (Model for End Stage Liver Disease) is a more objective prognostic score, requiring however a calculation software. The MELD score is calculated using the following formula
- MELD Score = 0.957 x Loge(creatinine mg/dL) + 0.378 x Loge(bilirubin mg/dL) + 1.120 x Loge(INR)+ 0.6431
Multiply the score by 10 and round to the nearest whole number. Laboratory values less than 1.0 are set to 1.0 for the purposes of the MELD score calculation.
-r MELD score= 3.8 + 11.2 + 9.6 + 6.4
Caveats with the score include:
- The maximum score given for MELD is 40. All values higher than 40 are given a score of 40
- If the patient has been dialyzed twice within the last 7 days, then the value for serum creatinine used should be 4.0
- Any value less than one is given a value of 1 (i.e. if bilirubin is 0.8, a value of 1.0 is used).
## Mortality Outcome
In interpreting the MELD Score in hospitalized patients, the 3 month mortality is:
- 40 or more — 71.3% mortality
- 30–39 — 52.6% mortality
- 20–29 — 19.6% mortality
- 10–19 — 6.0% mortality
- <9 — 1.9% mortality
# The MELD caclulators
A variety of calculators which are specific to a particular clinical scenerio are as follows --
- The above mentioned UNOS MELD score has laboratory values of INR, total bilirubin and serum creatinine that are <1.0 are set to 1.0. It is used while setting priority for allocating deceased donor organs for liver transplantation.
- The first MELD score does not use upper or lower limits for laboratory values. Hence, they could have negative values to positive infinity. These are not used for allocation purposes while considering liver transplantation.
- A MELD score calculator to predict 90-day mortality in patients with alcoholic hepatitis
- A MELD score calculator for predicting postoperative mortality risk in patients with cirrhosis. This calculator is based upon the first published MELD score, thus the etiology of liver disease is required for the calculation
- A MELD-Na calculator, which incorporates serum sodium into the model
# Comparing Child-Pugh and MELD score
The limitations of Child-Pugh score are as follows-
- Its based on subjective parameters like ascites and encephalopathy. Not only do these criterias vary with observers but also they may be affected by interventions like diuretics etc.
- It has a "ceiling and floor" effect. Example- a serum albumin value of 2.8 versus 1.5 will be highly varied clinically but it is rewarded the same point on Child-Pugh.
- Laboratory to laboratory variations in albumin and prothrombin values.
The points where MELD definitely edges over Child-Pugh score are-
- It relies on few, readily available, objective variables.
- Applicable to diverse set of patients with liver disease.
- Identifies and distinguishes the various points of severity along the disease spectrum.
The points where MELD lags behind are -
- Like Child-Pugh score, it is not immune to laboratory variations in INR and creatinine values.
Studies have compared the accuracy of MELD versus the Child-Pugh score for predicting the survival of patients on liver transplant waiting list have shown an equivalence but not superiority. The objective criteria used in the MELD score have led to widespread adoption of MELD as an accurate mortality predictor in patients awaiting liver transplantation.
# Improving MELD score
The proposed modifications that are on way for MELD score are as follows--
- MELDNa — Serum sodium levels decrease in cirrhotic patients. One school of thought suggests that in the setting of hyponatremia, it would be advisable to include serum sodium levels in the MELD model. Improvement in accuracy of the MELD score has been noted in studies.
- Reweighting of MELD components — MELD formula is getting updated in its weightage being given to coefficients. The updated formula gives lower weightage to serum creatinine and INR and higher to bilirubin. | MELD Score
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Suvekchha Devkota ; Shankar Kumar, M.B.B.S. [2]]
# Overview
The Model for End-Stage Liver Disease (MELD) is a reliable measure of mortality risk in patients with end-stage liver disease. It is used as a disease severity index to help prioritize allocation of organs for transplant. The new system, known as the Model for End-Stage Liver Disease (MELD) score, leaves no room for subjective criteria favoritism or hospital-shopping, as it is based on a mathematical equation. The equation seeks to calculate a patient’s likelihood of dying within three months from their liver disease. In other words under the MELD scoring system - the sickest patient gets the liver transplant. It is more recent than the Child-Pugh score.
# Historical Perspective
This model was derived from a heterogeneous group of patients at 4 medical centers in the United States and validated in an independent data set from the Netherlands.[1]
The original version of the MELD scale as developed by investigators at Mayo Clinic. It was initially described by Kamath et al in 2001 and modified by Wiesner et al, also in 2001. A number of modification have been made by UNOS (United Network for Organ Sharing) to the model for its implementation in organ allocation for liver transplantation. The Model for End-Stage Liver Disease (MELD) score has been used by the Organ Procurement and Transplantation Network (OPTN) since February 2002 as the basis for allocation of deceased donor livers for transplantation among adults in the United States.[2]
# Calculation of MELD Score
The MELD Calculator is a utility that allows you to enter hypothetical or actual parameters and calculate a MELD score for an individual patient. The MELD/PELD Calculator uses the specific formulas approved by the OPTN/UNOS Board of Directors and used for the allocation of livers by the OPTN match system. The MELD score calculation uses-
- Serum creatinine (mg/dl) *
- Bilirubin (mg/dl)
- INR
For candidates on dialysis, defined as having 2 or more dialysis treatments within the prior week; or candidates who have received 24 hours of CVVHD (Continuous Veno-venous Hemodialysis) within the prior week, will have their serum creatinine level automatically set to 4.0 mg/dl. The MELD Calculator is used for candidates who are 12 years and older.
# MELD Formula
The MELD (Model for End Stage Liver Disease) is a more objective prognostic score, requiring however a calculation software. [3] The MELD score is calculated using the following formula
- MELD Score = 0.957 x Loge(creatinine mg/dL) + 0.378 x Loge(bilirubin mg/dL) + 1.120 x Loge(INR)+ 0.6431
Multiply the score by 10 and round to the nearest whole number. Laboratory values less than 1.0 are set to 1.0 for the purposes of the MELD score calculation.
or MELD score= 3.8[Ln serum bilirubin (mg/dL)] + 11.2[Ln INR] + 9.6[Ln serum creatinine (mg/dL)] + 6.4
Caveats with the score include:
- The maximum score given for MELD is 40. All values higher than 40 are given a score of 40
- If the patient has been dialyzed twice within the last 7 days, then the value for serum creatinine used should be 4.0
- Any value less than one is given a value of 1 (i.e. if bilirubin is 0.8, a value of 1.0 is used).
## Mortality Outcome
In interpreting the MELD Score in hospitalized patients, the 3 month mortality is: [4]
- 40 or more — 71.3% mortality
- 30–39 — 52.6% mortality
- 20–29 — 19.6% mortality
- 10–19 — 6.0% mortality
- <9 — 1.9% mortality
# The MELD caclulators
A variety of calculators which are specific to a particular clinical scenerio are as follows --
- The above mentioned UNOS MELD score has laboratory values of INR, total bilirubin and serum creatinine that are <1.0 are set to 1.0. It is used while setting priority for allocating deceased donor organs for liver transplantation.[3]
- The first MELD score does not use upper or lower limits for laboratory values. Hence, they could have negative values to positive infinity. These are not used for allocation purposes while considering liver transplantation.[4]
- A MELD score calculator to predict 90-day mortality in patients with alcoholic hepatitis [5]
- A MELD score calculator for predicting postoperative mortality risk in patients with cirrhosis. This calculator is based upon the first published MELD score, thus the etiology of liver disease is required for the calculation [6]
- A MELD-Na calculator, which incorporates serum sodium into the model [7]
# Comparing Child-Pugh and MELD score
The limitations of Child-Pugh score are as follows-
- Its based on subjective parameters like ascites and encephalopathy. Not only do these criterias vary with observers but also they may be affected by interventions like diuretics etc.
- It has a "ceiling and floor" effect. Example- a serum albumin value of 2.8 versus 1.5 will be highly varied clinically but it is rewarded the same point on Child-Pugh.
- Laboratory to laboratory variations in albumin and prothrombin values.[1]
The points where MELD definitely edges over Child-Pugh score are-
- It relies on few, readily available, objective variables.
- Applicable to diverse set of patients with liver disease.
- Identifies and distinguishes the various points of severity along the disease spectrum.
The points where MELD lags behind are -
- Like Child-Pugh score, it is not immune to laboratory variations in INR and creatinine values.[5][6][7][8][9]
Studies have compared the accuracy of MELD versus the Child-Pugh score for predicting the survival of patients on liver transplant waiting list have shown an equivalence but not superiority. [10]The objective criteria used in the MELD score have led to widespread adoption of MELD as an accurate mortality predictor in patients awaiting liver transplantation.
# Improving MELD score
The proposed modifications that are on way for MELD score are as follows--
- MELDNa — Serum sodium levels decrease in cirrhotic patients. One school of thought suggests that in the setting of hyponatremia, it would be advisable to include serum sodium levels in the MELD model. Improvement in accuracy of the MELD score has been noted in studies.[11][12][13][14][15][16]
- Reweighting of MELD components — MELD formula is getting updated in its weightage being given to coefficients. The updated formula gives lower weightage to serum creatinine and INR and higher to bilirubin.[17] | https://www.wikidoc.org/index.php/MELD | |
0cc15788a16c0abf8d7e0ecab8e277af80930de8 | wikidoc | MLX (gene) | MLX (gene)
Max-like protein X is a protein that in humans is encoded by the MLX gene.
# Function
The product of this gene belongs to the family of basic helix-loop-helix leucine zipper (bHLH-Zip) transcription factors. These factors form heterodimers with Mad proteins and play a role in proliferation, determination and differentiation. This gene product may act to diversify Mad family function by its restricted association with a subset of the Mad family of transcriptional repressors, namely Mad1 and Mad4. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene.
# Interactions
MLX (gene) has been shown to interact with MNT, MXD1 and MLXIPL. | MLX (gene)
Max-like protein X is a protein that in humans is encoded by the MLX gene.[1][2]
# Function
The product of this gene belongs to the family of basic helix-loop-helix leucine zipper (bHLH-Zip) transcription factors. These factors form heterodimers with Mad proteins and play a role in proliferation, determination and differentiation. This gene product may act to diversify Mad family function by its restricted association with a subset of the Mad family of transcriptional repressors, namely Mad1 and Mad4. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene.[2]
# Interactions
MLX (gene) has been shown to interact with MNT,[3][4] MXD1[3][4] and MLXIPL.[3] | https://www.wikidoc.org/index.php/MLX_(gene) | |
0a25d76142f236399da8890c4c44ec74e1a1024f | wikidoc | MN1 (gene) | MN1 (gene)
MN1 is a gene found on human chromosome 22, with gene map locus 22q12.3-qter. Its official full name is meningioma (disrupted in balanced translocation) 1 because it is disrupted by a balanced translocation (4;22) in a meningioma.
# Function
MN1 is a transcription coregulator that enhances or represses RAR/RXR-mediated gene transcription through interaction with RAC3 and p300. MN1 also acts as a coactivator of the vitamin D receptor.
# Clinical significance
Its inactivation may be part of the cause of certain meningiomas. A potential link to leukemia including acute myeloid leukemia has also been described. | MN1 (gene)
MN1 is a gene found on human chromosome 22, with gene map locus 22q12.3-qter.[1] Its official full name is meningioma (disrupted in balanced translocation) 1 because it is disrupted by a balanced translocation (4;22) in a meningioma.
# Function
MN1 is a transcription coregulator that enhances or represses RAR/RXR-mediated gene transcription through interaction with RAC3 and p300.[2] MN1 also acts as a coactivator of the vitamin D receptor.[3]
# Clinical significance
Its inactivation may be part of the cause of certain meningiomas.[1] A potential link to leukemia[4] including acute myeloid leukemia[5] has also been described. | https://www.wikidoc.org/index.php/MN1_(gene) | |
bbc2fbe6276bfd367eb4d63819642fa8d9bad7d0 | wikidoc | MNT (gene) | MNT (gene)
MNT (Max's Next Tango) is a Max-binding protein that is encoded by the MNT gene
# Function
The Myc/Max/Mad network comprises a group of transcription factors that co-interact to regulate gene-specific transcriptional activation or repression. This gene encodes a protein member of the Myc/Max/Mad network. This protein has a basic-Helix-Loop-Helix-zipper domain (bHLHzip) with which it binds the canonical DNA sequence CANNTG, known as the E box, following heterodimerization with Max proteins. This protein is a transcriptional repressor and an antagonist of Myc-dependent transcriptional activation and cell growth. This protein represses transcription by binding to DNA and recruiting Sin3 corepressor proteins through its N-terminal Sin3-interaction domain
# Interactions
MNT (gene) has been shown to interact with MLX, SIN3A and MAX. | MNT (gene)
MNT (Max's Next Tango) is a Max-binding protein that is encoded by the MNT gene [1][2][3]
# Function
The Myc/Max/Mad network comprises a group of transcription factors that co-interact to regulate gene-specific transcriptional activation or repression. This gene encodes a protein member of the Myc/Max/Mad network. This protein has a basic-Helix-Loop-Helix-zipper domain (bHLHzip) with which it binds the canonical DNA sequence CANNTG, known as the E box, following heterodimerization with Max proteins. This protein is a transcriptional repressor and an antagonist of Myc-dependent transcriptional activation and cell growth. This protein represses transcription by binding to DNA and recruiting Sin3 corepressor proteins through its N-terminal Sin3-interaction domain [1][4]
# Interactions
MNT (gene) has been shown to interact with MLX,[5][6] SIN3A[7] and MAX.[7] | https://www.wikidoc.org/index.php/MNT_(gene) | |
e670e9fb3c94e1b623886f266ec7f44b57cde111 | wikidoc | MYB (gene) | MYB (gene)
Myb genes are part of a large gene family of transcription factors found in animals and plants. In humans, it includes Myb-related protein B and Myb proto-oncogene like 1.
# Function
## Animals
Myb proto-oncogene protein is a member of the MYB (myeloblastosis) family of transcription factors. The protein contains three domains, an N-terminal DNA-binding domain, a central transcriptional activation domain and a C-terminal domain involved in transcriptional repression.
## Plants
MYB factors represent a family of proteins that include the conserved MYB DNA-binding domain. Plants contain a MYB-protein subfamily that is characterised by the R2R3-type MYB domain.
In maize, phlobaphenes are synthesized in the flavonoids synthetic pathway from polymerisation of flavan-4-ols which encodes an R2R3 myb-like transcriptional activator of the A1 gene encoding for the dihydroflavonol 4-reductase (reducing dihydroflavonols into flavan-4-ols) while another gene (Suppressor of Pericarp Pigmentation 1 or SPP1) acts as a suppressor. The maize P gene encodes a Myb homolog that recognizes the sequence CCT/AACC, in sharp contrast with the C/TAACGG bound by vertebrate Myb proteins.
In sorghum, the corresponding yellow seed 1 gene (y1) also encodes a R2R3 type of Myb domain protein that regulates the expression of chalcone synthase, chalcone isomerase and dihydroflavonol reductase genes required for the biosynthesis of 3-deoxyflavonoids.
Ruby is a MYB transcriptional activator of genes that produce anthocyanin in citrus fruits. In most citrus varieties Ruby is non-functional, but in blood oranges it upregulates anthocyanin production to produce the characteristic red color of the fruit. | MYB (gene)
Myb genes are part of a large gene family of transcription factors found in animals and plants. In humans, it includes Myb-related protein B and Myb proto-oncogene like 1.[1][2]
# Function
## Animals
Myb proto-oncogene protein is a member of the MYB (myeloblastosis) family of transcription factors. The protein contains three domains, an N-terminal DNA-binding domain, a central transcriptional activation domain and a C-terminal domain involved in transcriptional repression.
## Plants
MYB factors represent a family of proteins that include the conserved MYB DNA-binding domain. Plants contain a MYB-protein subfamily that is characterised by the R2R3-type MYB domain.[3]
In maize, phlobaphenes are synthesized in the flavonoids synthetic pathway[4] from polymerisation of flavan-4-ols[5][6] which encodes an R2R3 myb-like transcriptional activator[7] of the A1 gene encoding for the dihydroflavonol 4-reductase (reducing dihydroflavonols into flavan-4-ols)[8] while another gene (Suppressor of Pericarp Pigmentation 1 or SPP1) acts as a suppressor.[9] The maize P gene encodes a Myb homolog that recognizes the sequence CCT/AACC, in sharp contrast with the C/TAACGG bound by vertebrate Myb proteins.[10]
In sorghum, the corresponding yellow seed 1 gene (y1)[11] also encodes a R2R3 type of Myb domain protein that regulates the expression of chalcone synthase, chalcone isomerase and dihydroflavonol reductase genes required for the biosynthesis of 3-deoxyflavonoids.[12]
Ruby is a MYB transcriptional activator of genes that produce anthocyanin in citrus fruits. In most citrus varieties Ruby is non-functional, but in blood oranges it upregulates anthocyanin production to produce the characteristic red color of the fruit.[13] | https://www.wikidoc.org/index.php/MYB_(gene) | |
054c37f65c159efab400e2f164db06e4754cd773 | wikidoc | Stamulumab | Stamulumab
Stamulumab (MYO-029) is an experimental myostatin inhibiting drug developed by Wyeth Pharmaceuticals for the treatment of muscular dystrophy. MYO-029 was formulated and tested by Wyeth in Collegeville, PA. Myostatin is a protein that inhibits the growth of muscle tissue, MYO-029 is a recombinant human antibody designed to bind to and inhibit the activity of myostatin.
Stamulumab is a G1 immunoglobulin antibody which binds to myostatin and prevents it from binding to its target site, thus inhibiting the growth-limiting action of myostatin on muscle tissue. Research completed in 2002 found that Stamulumab might one day prove to be an effective treatment for Duchenne muscular dystrophy
# Phase 1 and 2 Trials
- Wyeth undertook a Phase 1 and 2 clinical trial in 2005 and 2006 of MY0-029. The multiple ascending does trial (36 patients per cohort) contained some measures of efficacy. The trial's participants included people afflicted with Facioscapulohumeral muscular dystrophy, Becker's muscular dystrophy, and Limb-girdle muscular dystrophy. Through 2007 Wyeth has been analyzing the results and there is hope for news and/or a publication by the fourth quarter of 2007.
# Related
- ACVR2B is similar to Stamulumab but is not an antibody; rather, it provides a portion of the molecule to which myostatin would normally bind thus preventing the myostatin from binding with the actual molecule. | Stamulumab
Template:Drugbox-mab
Stamulumab (MYO-029[1]) is an experimental myostatin inhibiting drug developed by Wyeth Pharmaceuticals for the treatment of muscular dystrophy. MYO-029 was formulated and tested by Wyeth in Collegeville, PA.[2] Myostatin is a protein that inhibits the growth of muscle tissue, MYO-029 is a recombinant human antibody designed to bind to and inhibit the activity of myostatin.[3]
Stamulumab is a G1 immunoglobulin antibody which binds to myostatin and prevents it from binding to its target site, thus inhibiting the growth-limiting action of myostatin on muscle tissue. Research completed in 2002 found that Stamulumab might one day prove to be an effective treatment for Duchenne muscular dystrophy[4]
# Phase 1 and 2 Trials
- Wyeth undertook a Phase 1 and 2 clinical trial in 2005 and 2006 of MY0-029. The multiple ascending does trial (36 patients per cohort) contained some measures of efficacy. The trial's participants included people afflicted with Facioscapulohumeral muscular dystrophy, Becker's muscular dystrophy, and Limb-girdle muscular dystrophy. Through 2007 Wyeth has been analyzing the results and there is hope for news and/or a publication by the fourth quarter of 2007. [2][5][6]
# Related
- ACVR2B is similar to Stamulumab but is not an antibody; rather, it provides a portion of the molecule to which myostatin would normally bind thus preventing the myostatin from binding with the actual molecule[7]. | https://www.wikidoc.org/index.php/MYO-029 | |
2c81d99cbe0d4d62dfbbe628395a009d026b1b20 | wikidoc | Maceration | Maceration
Maceration is a word that derives from the Latin maceratus ("to soften"; past participle of macerare). It may refer to:
- Maceration, in chemistry and herbalism, the preparation of an extract by soaking material (such as animal skins or parts of fibrous plants) in water, vegetable oil or some organic solvent. The word may also refer to the same process when used to produce perfume stock.
- Maceration (wine), in viticulture, the steeping of grape skins and solids in must, where alcohol later acts as a solvent to extract colour, tannin and aroma from the skins during the wine fermentation process.
- A macerator, in sewage treatment, a machine that reduces solids to small pieces in order to deal with rags and other solid waste.
- Maceration (bone), a method of separating of bone from soft body tissue by controlled putrefaction.
- A macerator, in chicken farming, a high-speed grinder used to slaughter unwanted male chicks in large numbers.
- Maceration, in biology, is the mechanical grinding or kneading of semi-solid food in the stomach into chyme.
- Maceration, in dermatology, is the softening and whitening of skin kept constantly wet, leaving it more vulnerable to infection or damage by tearing. | Maceration
Maceration is a word that derives from the Latin maceratus ("to soften"; past participle of macerare). It may refer to:
- Maceration, in chemistry and herbalism, the preparation of an extract by soaking material (such as animal skins or parts of fibrous plants) in water, vegetable oil or some organic solvent. The word may also refer to the same process when used to produce perfume stock.
- Maceration (wine), in viticulture, the steeping of grape skins and solids in must, where alcohol later acts as a solvent to extract colour, tannin and aroma from the skins during the wine fermentation process.
- A macerator, in sewage treatment, a machine that reduces solids to small pieces in order to deal with rags and other solid waste.
- Maceration (bone), a method of separating of bone from soft body tissue by controlled putrefaction.
- A macerator, in chicken farming, a high-speed grinder used to slaughter unwanted male chicks in large numbers.
- Maceration, in biology, is the mechanical grinding or kneading of semi-solid food in the stomach into chyme.
- Maceration, in dermatology, is the softening and whitening of skin kept constantly wet, leaving it more vulnerable to infection or damage by tearing. | https://www.wikidoc.org/index.php/Macerate | |
7ae547220410dff27f8182a7c4373039a3791876 | wikidoc | Macitentan | Macitentan
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Macitentan is an endothelin receptor antagonist and antihypertensive that is FDA approved for the {{{indicationType}}} of pulmonary artery hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include anemia, influenza, headache, urinary tract infections, bronchitis, nasopharyngitis, and pharyngitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Opsumit® is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression. Disease progression included: death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment). Opsumit also reduced hospitalization for PAH.
- Effectiveness was established in a long-term study in PAH patients with predominantly WHO Functional Class II-III symptoms treated for an average of 2 years. Patients were treated with Opsumit monotherapy or in combination with phosphodiesterase-5 inhibitors or inhaled prostanoids. Patients had idiopathic and heritable PAH (57%), PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%).
- Dosing Information
- The recommended dosage of Opsumit is 10 mg once daily for oral administration. Doses higher than 10 mg once daily have not been studied in patients with PAH and are not recommended.
- Initiate treatment with Opsumit in females of reproductive potential only after a negative pregnancy test. Obtain monthly pregnancy test during treatment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Macitentan in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Macitentan in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Macitentan in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- The safety and efficacy of Opsumit in children have not been established.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Macitentan in pediatric patients.
# Contraindications
- Pregnancy
- Opsumit may cause fetal harm when administered to a pregnant woman. Opsumit is contraindicated in females who are pregnant. Opsumit was consistently shown to have teratogenic effects when administered to animals. If Opsumit is used during pregnancy, apprise the patient of the potential hazard to a fetus.
# Warnings
- Embryo-fetal Toxicity
- Opsumit may cause fetal harm when administered during pregnancy and is contraindicated for use in females who are pregnant. In females of reproductive potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable contraceptive methods and obtain monthly pregnancy tests.
- Opsumit is available for females through the Opsumit REMS Program, a restricted distribution program.
- Opsumit REMS Program
- For all females, Opsumit is available only through a restricted program called the Opsumit REMS Program, because of the risk of embryo-fetal toxicity.
- Notable requirements of the Opsumit REMS Program include the following:
- Prescribers must be certified with the program by enrolling and completing training.
- All females, regardless of reproductive potential, must enroll in the Opsumit REMS Program prior to initiating Opsumit. Male patients are not enrolled in the REMS.
- Females of reproductive potential must comply with the pregnancy testing and contraception requirements.
- Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive Opsumit.
- Further information is available at www.OpsumitREMS.com or 1-866-228-3546. Information on Opsumit certified pharmacies or wholesale distributors is available through Actelion Pathways at 1-866-228-3546.
- Hepatotoxicity
- Other ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure. The incidence of elevated aminotransferases in the study of Opsumit in PAH is shown in Table 1.
- In the placebo-controlled study of Opsumit, discontinuations for hepatic adverse events were 3.3% in the Opsumit 10 mg group vs. 1.6% for placebo. Obtain liver enzyme tests prior to initiation of Opsumit and repeat during treatment as clinically indicated.
- Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching). If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 × ULN, or by clinical symptoms of hepatotoxicity, discontinue Opsumit. Consider re-initiation of Opsumit when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity.
- Hemoglobin Decrease
- Decreases in hemoglobin concentration and hematocrit have occurred following administration of other ERAs and were observed in clinical studies with Opsumit. These decreases occurred early and stabilized thereafter. In the placebo-controlled study of Opsumit in PAH, Opsumit 10 mg caused a mean decrease in hemoglobin from baseline to up to 18 months of about 1.0 g/dL compared to no change in the placebo group. A decrease in hemoglobin to below 10.0 g/dL was reported in 8.7% of the Opsumit 10 mg group and in 3.4% of the placebo group. Decreases in hemoglobin seldom require transfusion. Initiation of Opsumit is not recommended in patients with severe anemia. Measure hemoglobin prior to initiation of treatment and repeat during treatment as clinically indicated.
- Pulmonary Edema with Pulmonary Veno-occlusive Disease (PVOD)
- Should signs of pulmonary edema occur, consider the possibility of associated PVOD. If confirmed, discontinue Opsumit.
- Decreased Sperm Counts
- Other ERAs have caused adverse effects on spermatogenesis. Counsel men about potential effects on fertility.
# 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 clinical practice.
- Safety data for Opsumit were obtained primarily from one placebo-controlled clinical study in 742 patients with PAH (SERAPHIN study). The exposure to Opsumit in this trial was up to 3.6 years with a median exposure of about 2 years (N=542 for 1 year; N=429 for 2 years; and N=98 for more than 3 years). The overall incidence of treatment discontinuations because of adverse events was similar across Opsumit 10 mg and placebo treatment groups (approximately 11%).
- Table 2 presents adverse reactions more frequent on Opsumit than on placebo by ≥3%.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Macitentan in the drug label.
# Drug Interactions
- Strong CYP3A4 Inducers
- Strong inducers of CYP3A4 such as rifampin significantly reduce macitentan exposure. Concomitant use of Opsumit with strong CYP3A4 inducers should be avoided.
- Strong CYP3A4 Inhibitors
- Concomitant use of strong CYP3A4 inhibitors like ketoconazole approximately double macitentan exposure. Many HIV drugs like ritonavir are strong inhibitors of CYP3A4. Avoid concomitant use of Opsumit with strong CYP3A4 inhibitors. Use other PAH treatment options when strong CYP3A4 inhibitors are needed as part of HIV treatment.
- At plasma levels obtained with dosing at 10 mg once daily, macitentan has no relevant inhibitory or inducing effects on CYP enzymes, and is neither a substrate nor an inhibitor of the multi-drug resistance protein (P-gp, MDR-1). Macitentan and its active metabolite are neither substrates nor inhibitors of the organic anion transporting polypeptides (OATP1B1 and OATP1B3) and do not significantly interact with proteins involved in hepatic bile salt transport, i.e., the bile salt export pump (BSEP) and the sodium-dependent taurocholate co-transporting polypeptide (NTCP).
- Effect of other drugs on macitentan: The effect of other drugs on macitentan and its active metabolite are studied in healthy subjects and are shown in Figure 1 below.
- Effects of other strong CYP3A4 inhibitors such as ritonavir on macitentan were not studied, but are likely to result in an increase in macitentan exposure at steady state similar to that seen with ketoconazole .
- Warfarin: Macitentan once daily dosing did not alter the exposure to R- and S-warfarin or their effect on international normalized ratio (INR).
- Sildenafil: At steady-state, the exposure to sildenafil 20 mg t.i.d. increased by 15% during concomitant administration of macitentan 10 mg once daily. This change is not considered clinically relevant.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category X
- Risk Summary
- Opsumit may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy. Macitentan was teratogenic in rabbits and rats at all doses tested. A no-effect dose was not established in either species. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential hazard to a fetus.
- Animal Data
- In both rabbits and rats, there were cardiovascular and mandibular arch fusion abnormalities. Administration of macitentan to female rats from late pregnancy through lactation caused reduced pup survival and impairment of the male fertility of the offspring at all dose levels tested.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Macitentan in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Macitentan during labor and delivery.
### Nursing Mothers
- It is not known whether Opsumit is present in human milk. Macitentan and its metabolites were present in the milk of lactating rats. Because many drugs are present in human milk and because of the potential for serious adverse reactions from macitentan in nursing infants, nursing mothers should discontinue nursing or discontinue Opsumit.
### Pediatric Use
- The safety and efficacy of Opsumit in children have not been established.
### Geriatic Use
- Of the total number of subjects in the clinical study of Opsumit for PAH, 14% were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
### Gender
There is no FDA guidance on the use of Macitentan with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Macitentan with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Macitentan in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Macitentan in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Females
- Pregnancy Testing: Female patients of reproductive potential must have a negative pregnancy test prior to starting treatment with Opsumit and monthly pregnancy tests during treatment with Opsumit. Advise patients to contact their health care provider if they become pregnant or suspect they may be pregnant. Perform a pregnancy test if pregnancy is suspected for any reason. For positive pregnancy tests, counsel patients on the potential risk to the fetus.
- Contraception: Female patients of reproductive potential must use acceptable methods of contraception during treatment with Opsumit and for 1 month after treatment with Opsumit. Patients may choose one highly effective form of contraception (intrauterine devices (IUD), contraceptive implants or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods). If a partner's vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method. Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling.
- Males
- Testicular effects: Like other endothelin receptor antagonists, Opsumit may have an adverse effect on spermatogenesis
### Immunocompromised Patients
There is no FDA guidance one the use of Macitentan in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Macitentan in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Macitentan in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Opsumit has been administered as a single dose of up to and including 600 mg to healthy subjects (60 times the approved dosage). Adverse reactions of headache, nausea and vomiting were observed.
### Management
- In the event of an overdose, standard supportive measures should be taken, as required. Dialysis is unlikely to be effective because macitentan is highly protein-bound.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Macitentan in the drug label.
# Pharmacology
## Mechanism of Action
- Endothelin (ET)-1 and its receptors (ETA and ETB) mediate a variety of deleterious effects, such as vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation. In disease conditions such as PAH, the local ET system is upregulated and is involved in vascular hypertrophy and in organ damage.
- Macitentan is an endothelin receptor antagonist that prevents the binding of ET-1 to both ETA and ETB receptors. Macitentan displays high affinity and sustained occupancy of the ET receptors in human pulmonary arterial smooth muscle cells. One of the metabolites of macitentan is also pharmacologically active at the ET receptors and is estimated to be about 20% as potent as the parent drug in vitro.
## Structure
- Opsumit (macitentan) is an endothelin receptor antagonist. The chemical name of macitentan is N-ethoxy]-4-pyrimidinyl]-N'-propylsulfamide. It has a molecular formula of C19H20Br2N6O4S and a molecular weight of 588.27. Macitentan is achiral and has the following structural formula:
- Macitentan is a crystalline powder that is insoluble in water. In the solid state macitentan is very stable, is not hygroscopic, and is not light sensitive.
- Opsumit is available as a 10 mg film-coated tablet for once daily oral administration. The tablets include the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone, and sodium starch glycolate Type A. The tablets are film-coated with a coating material containing polyvinyl alcohol, soya lecithin, talc, titanium dioxide, and xanthan gum.
## Pharmacodynamics
- Pulmonary Hemodynamics: The clinical efficacy study in patients with pulmonary arterial hypertension assessed hemodynamic parameters in a subset of patients after 6 months of treatment. Patients treated with Opsumit 10 mg (N=57) achieved a median reduction of 37% (95% CI 22-49) in pulmonary vascular resistance and an increase of 0.6 L/min/m2 (95% CI 0.3-0.9) in cardiac index compared to placebo (N=67).
- Cardiac Electrophysiology: In a randomized, placebo-controlled four-way crossover study with a positive control in healthy subjects, repeated doses of macitentan 10 and 30 mg (3 times the recommended dosage) had no significant effect on the QTc interval.
## Pharmacokinetics
- The pharmacokinetics of macitentan and its active metabolite have been studied primarily in healthy subjects. The pharmacokinetics of macitentan are dose proportional over a range from 1 mg to 30 mg after once daily administration.
- A cross study comparison shows that the exposures to macitentan and its active metabolite in patients with PAH are similar to those observed in healthy subjects.
- The maximum plasma concentration of macitentan is achieved about 8 hours after oral administration. The absolute bioavailability after oral administration is not known. In a study in healthy subjects, the exposure to macitentan and its active metabolite were unchanged after a high fat breakfast. Macitentan may therefore be taken with or without food.
- Macitentan and its active metabolite are highly bound to plasma proteins (>99%), primarily to albumin and to a lesser extent to alpha-1-acid glycoprotein. The apparent volumes of distribution (Vss/F) of macitentan and its active metabolite were about 50 L and 40 L respectively in healthy subjects.
- Following oral administration, the apparent elimination half-lives of macitentan and its active metabolite are approximately 16 hours and 48 hours, respectively. Macitentan is metabolized primarily by oxidative depropylation of the sulfamide to form the pharmacologically active metabolite. This reaction is dependent on the cytochrome P450 (CYP) system, mainly CYP3A4 with a minor contribution of CYP2C19. At steady state in PAH patients, the systemic exposure to the active metabolite is 3-times the exposure to macitentan and is expected to contribute approximately 40% of the total pharmacologic activity. In a study in healthy subjects with radiolabeled macitentan, approximately 50% of radioactive drug material was eliminated in urine but none was in the form of unchanged drug or the active metabolite. About 24% of the radioactive drug material was recovered from feces.
- There are no clinically relevant effects of age, sex, or race on the pharmacokinetics of macitentan and its active metabolite.
- Renal impairment: Exposure to macitentan and its active metabolite in patients with severe renal impairment (CrCl 15-29 mL/min) compared to healthy subjects was increased by 30% and 60%, respectively. This increase is not considered clinically relevant.
- Hepatic impairment: Exposure to macitentan was decreased by 21%, 34%, and 6% and exposure to the active metabolite was decreased by 20%, 25%, and 25% in subjects with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, and C), respectively. This decrease is not considered clinically relevant.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenesis: Carcinogenicity studies of 2 years' duration did not reveal any carcinogenic potential at exposures 75-fold and 140-fold the human exposure (based on AUC) in male and female mice, respectively, and 8.3- and 42-fold in male and female rats, respectively.
- Mutagenesis: Macitentan was not genotoxic in a standard battery of in vitro and in vivo assays that included a bacterial reverse mutation assay, an assay for gene mutations in mouse lymphoma cells, a chromosome aberration test in human lymphocytes, and an in vivo micronucleus test in rats.
- Impairment of Fertility: Treatment of juvenile rats from postnatal Day 4 to Day 114 led to reduced body weight gain and testicular tubular atrophy at exposures 7-fold the human exposure. Fertility was not affected.
- Reversible testicular tubular dilatation was observed in chronic toxicity studies at exposures greater than 7-fold and 23-fold the human exposure in rats and dogs, respectively. After 2 years of treatment, tubular atrophy was seen in rats at 4-fold the human exposure. Macitentan did not affect male or female fertility at exposures ranging from 19- to 44-fold the human exposure, respectively, and had no effect on sperm count, motility, and morphology in male rats. No testicular findings were noted in mice after treatment up to 2 years.
- Animal Toxicology
- In dogs, macitentan decreased blood pressure at exposures similar to the therapeutic human exposure. Intimal thickening of coronary arteries was observed at 17-fold the human exposure after 4 to 39 weeks of treatment. Due to the species-specific sensitivity and the safety margin, this finding is considered not relevant for humans.
- There were no adverse liver findings in long-term studies conducted in mice, rats, and dogs at exposures of 12- to 116-fold the human exposure.
# Clinical Studies
- Pulmonary Arterial Hypertension
- The effect of macitentan on progression of PAH was demonstrated in a multi-center, long-term (average duration of exposure approximately 2 years), placebo-controlled study in 742 patients with symptomatic PAH who were randomized to placebo (n=250), 3 mg macitentan (n=250), or 10 mg macitentan (n=242) once daily.
- The primary study endpoint was time to the first occurrence of death, a significant morbidity event, defined as atrial septostomy, lung transplantation, initiation of IV or subcutaneous (SC) prostanoids, or "other worsening of PAH" during double-blind treatment plus 7 days. Other worsening was defined as all of the following: 1) a sustained ≥15% decrease from baseline in 6 minute walk distance (6MWD), 2) worsening of PAH symptoms (worsening of WHO FC), and 3) need for additional treatment for PAH. All of these other worsening events were confirmed by an independent adjudication committee, blinded to treatment allocation. A critical secondary endpoint was time to PAH death or PAH hospitalization.
- The mean patient age was 46 years (14% were age 65 or above). Most patients were white (55%) or Asian (29%) and female (77%). Approximately 52%, 46%, and 2% of patients were in WHO FC II, III, and IV, respectively.
- Idiopathic or heritable PAH was the most common etiology in the study population (57%) followed by PAH caused by connective tissue disorders (31%), PAH caused by congenital heart disease with repaired shunts (8%), and PAH caused by other etiologies .
- At baseline, the majority of enrolled patients (64%) were being treated with a stable dose of specific therapy for PAH, either oral phosphodiesterase inhibitors (61%) and/or inhaled/oral prostanoids (6%).
- Study results are described for the placebo and Opsumit 10 mg groups. The median treatment durations were 101 and 118 weeks in the placebo and Opsumit 10 mg groups, respectively, up to a maximum of 188 weeks.
- Treatment with Opsumit 10 mg resulted in a 45% reduction (HR 0.55, 97.5% CI 0.39-0.76; logrank p<0.0001) in the occurrence of the primary endpoint up to end of double-blind treatment compared to placebo (Table 3 and Figure 2). The beneficial effect of Opsumit 10 mg was primarily attributable to a reduction in clinical worsening events (deterioration in 6MWD and worsening of PAH symptoms and need for additional PAH treatment).
- Subgroup analyses were performed to examine their influence on outcome as shown in Figure 3. Consistent efficacy of Opsumit 10 mg on the primary endpoint was seen across subgroups of age, sex, race, etiology, by monotherapy or in combination with another PAH therapy, baseline 6MWD, and baseline WHO FC.
- PAH related death or hospitalization for PAH was assessed as a secondary endpoint. The risk of PAH related death or hospitalization for PAH was reduced by 50% in patients receiving Opsumit 10 mg compared to placebo (HR 0.50, 97.5% CI 0.34-0.75; logrank p<0.0001) (Table 4 and Figure 4).
- Treatment with Opsumit 10 mg resulted in a placebo-corrected mean increase in 6MWD of 22 meters at Month 6 (97.5% CI 3-41; p=0.0078), with significant improvement in 6MWD by Month 3. 6MWD increased more in patients with worse baseline WHO Functional Class (37 meters and 12 meters placebo-corrected mean increase in WHO FC III/IV and FC I/II, respectively). The increase in 6MWD achieved with Opsumit was maintained for the duration of the study.
- Treatment with Opsumit 10 mg led to an improvement of at least one WHO Functional Class at Month 6 in 22% of patients compared to 13% of patients treated with placebo.
# How Supplied
- Opsumit tablets are 10 mg white, film-coated, bi-convex debossed with "10" on one side and supplied as follows:
- Store at 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F).
## Storage
There is limited information regarding Macitentan Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Macitentan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Opsumit®
# Look-Alike Drug Names
- N/A
# Drug Shortage Status
# Price | Macitentan
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi
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# Black Box Warning
# Overview
Macitentan is an endothelin receptor antagonist and antihypertensive that is FDA approved for the {{{indicationType}}} of pulmonary artery hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include anemia, influenza, headache, urinary tract infections, bronchitis, nasopharyngitis, and pharyngitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Opsumit® is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression. Disease progression included: death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment). Opsumit also reduced hospitalization for PAH.
- Effectiveness was established in a long-term study in PAH patients with predominantly WHO Functional Class II-III symptoms treated for an average of 2 years. Patients were treated with Opsumit monotherapy or in combination with phosphodiesterase-5 inhibitors or inhaled prostanoids. Patients had idiopathic and heritable PAH (57%), PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%).
- Dosing Information
- The recommended dosage of Opsumit is 10 mg once daily for oral administration. Doses higher than 10 mg once daily have not been studied in patients with PAH and are not recommended.
- Initiate treatment with Opsumit in females of reproductive potential only after a negative pregnancy test. Obtain monthly pregnancy test during treatment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Macitentan in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Macitentan in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Macitentan in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- The safety and efficacy of Opsumit in children have not been established.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Macitentan in pediatric patients.
# Contraindications
- Pregnancy
- Opsumit may cause fetal harm when administered to a pregnant woman. Opsumit is contraindicated in females who are pregnant. Opsumit was consistently shown to have teratogenic effects when administered to animals. If Opsumit is used during pregnancy, apprise the patient of the potential hazard to a fetus.
# Warnings
- Embryo-fetal Toxicity
- Opsumit may cause fetal harm when administered during pregnancy and is contraindicated for use in females who are pregnant. In females of reproductive potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable contraceptive methods and obtain monthly pregnancy tests.
- Opsumit is available for females through the Opsumit REMS Program, a restricted distribution program.
- Opsumit REMS Program
- For all females, Opsumit is available only through a restricted program called the Opsumit REMS Program, because of the risk of embryo-fetal toxicity.
- Notable requirements of the Opsumit REMS Program include the following:
- Prescribers must be certified with the program by enrolling and completing training.
- All females, regardless of reproductive potential, must enroll in the Opsumit REMS Program prior to initiating Opsumit. Male patients are not enrolled in the REMS.
- Females of reproductive potential must comply with the pregnancy testing and contraception requirements.
- Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive Opsumit.
- Further information is available at www.OpsumitREMS.com or 1-866-228-3546. Information on Opsumit certified pharmacies or wholesale distributors is available through Actelion Pathways at 1-866-228-3546.
- Hepatotoxicity
- Other ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure. The incidence of elevated aminotransferases in the study of Opsumit in PAH is shown in Table 1.
- In the placebo-controlled study of Opsumit, discontinuations for hepatic adverse events were 3.3% in the Opsumit 10 mg group vs. 1.6% for placebo. Obtain liver enzyme tests prior to initiation of Opsumit and repeat during treatment as clinically indicated.
- Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching). If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 × ULN, or by clinical symptoms of hepatotoxicity, discontinue Opsumit. Consider re-initiation of Opsumit when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity.
- Hemoglobin Decrease
- Decreases in hemoglobin concentration and hematocrit have occurred following administration of other ERAs and were observed in clinical studies with Opsumit. These decreases occurred early and stabilized thereafter. In the placebo-controlled study of Opsumit in PAH, Opsumit 10 mg caused a mean decrease in hemoglobin from baseline to up to 18 months of about 1.0 g/dL compared to no change in the placebo group. A decrease in hemoglobin to below 10.0 g/dL was reported in 8.7% of the Opsumit 10 mg group and in 3.4% of the placebo group. Decreases in hemoglobin seldom require transfusion. Initiation of Opsumit is not recommended in patients with severe anemia. Measure hemoglobin prior to initiation of treatment and repeat during treatment as clinically indicated.
- Pulmonary Edema with Pulmonary Veno-occlusive Disease (PVOD)
- Should signs of pulmonary edema occur, consider the possibility of associated PVOD. If confirmed, discontinue Opsumit.
- Decreased Sperm Counts
- Other ERAs have caused adverse effects on spermatogenesis. Counsel men about potential effects on fertility.
# 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 clinical practice.
- Safety data for Opsumit were obtained primarily from one placebo-controlled clinical study in 742 patients with PAH (SERAPHIN study). The exposure to Opsumit in this trial was up to 3.6 years with a median exposure of about 2 years (N=542 for 1 year; N=429 for 2 years; and N=98 for more than 3 years). The overall incidence of treatment discontinuations because of adverse events was similar across Opsumit 10 mg and placebo treatment groups (approximately 11%).
- Table 2 presents adverse reactions more frequent on Opsumit than on placebo by ≥3%.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Macitentan in the drug label.
# Drug Interactions
- Strong CYP3A4 Inducers
- Strong inducers of CYP3A4 such as rifampin significantly reduce macitentan exposure. Concomitant use of Opsumit with strong CYP3A4 inducers should be avoided.
- Strong CYP3A4 Inhibitors
- Concomitant use of strong CYP3A4 inhibitors like ketoconazole approximately double macitentan exposure. Many HIV drugs like ritonavir are strong inhibitors of CYP3A4. Avoid concomitant use of Opsumit with strong CYP3A4 inhibitors. Use other PAH treatment options when strong CYP3A4 inhibitors are needed as part of HIV treatment.
- At plasma levels obtained with dosing at 10 mg once daily, macitentan has no relevant inhibitory or inducing effects on CYP enzymes, and is neither a substrate nor an inhibitor of the multi-drug resistance protein (P-gp, MDR-1). Macitentan and its active metabolite are neither substrates nor inhibitors of the organic anion transporting polypeptides (OATP1B1 and OATP1B3) and do not significantly interact with proteins involved in hepatic bile salt transport, i.e., the bile salt export pump (BSEP) and the sodium-dependent taurocholate co-transporting polypeptide (NTCP).
- Effect of other drugs on macitentan: The effect of other drugs on macitentan and its active metabolite are studied in healthy subjects and are shown in Figure 1 below.
- Effects of other strong CYP3A4 inhibitors such as ritonavir on macitentan were not studied, but are likely to result in an increase in macitentan exposure at steady state similar to that seen with ketoconazole [see Drug Interactions (7.2)].
- Warfarin: Macitentan once daily dosing did not alter the exposure to R- and S-warfarin or their effect on international normalized ratio (INR).
- Sildenafil: At steady-state, the exposure to sildenafil 20 mg t.i.d. increased by 15% during concomitant administration of macitentan 10 mg once daily. This change is not considered clinically relevant.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category X
- Risk Summary
- Opsumit may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy. Macitentan was teratogenic in rabbits and rats at all doses tested. A no-effect dose was not established in either species. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential hazard to a fetus.
- Animal Data
- In both rabbits and rats, there were cardiovascular and mandibular arch fusion abnormalities. Administration of macitentan to female rats from late pregnancy through lactation caused reduced pup survival and impairment of the male fertility of the offspring at all dose levels tested.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Macitentan in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Macitentan during labor and delivery.
### Nursing Mothers
- It is not known whether Opsumit is present in human milk. Macitentan and its metabolites were present in the milk of lactating rats. Because many drugs are present in human milk and because of the potential for serious adverse reactions from macitentan in nursing infants, nursing mothers should discontinue nursing or discontinue Opsumit.
### Pediatric Use
- The safety and efficacy of Opsumit in children have not been established.
### Geriatic Use
- Of the total number of subjects in the clinical study of Opsumit for PAH, 14% were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
### Gender
There is no FDA guidance on the use of Macitentan with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Macitentan with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Macitentan in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Macitentan in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Females
- Pregnancy Testing: Female patients of reproductive potential must have a negative pregnancy test prior to starting treatment with Opsumit and monthly pregnancy tests during treatment with Opsumit. Advise patients to contact their health care provider if they become pregnant or suspect they may be pregnant. Perform a pregnancy test if pregnancy is suspected for any reason. For positive pregnancy tests, counsel patients on the potential risk to the fetus.
- Contraception: Female patients of reproductive potential must use acceptable methods of contraception during treatment with Opsumit and for 1 month after treatment with Opsumit. Patients may choose one highly effective form of contraception (intrauterine devices (IUD), contraceptive implants or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods). If a partner's vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method. Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling.
- Males
- Testicular effects: Like other endothelin receptor antagonists, Opsumit may have an adverse effect on spermatogenesis
### Immunocompromised Patients
There is no FDA guidance one the use of Macitentan in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Macitentan in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Macitentan in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Opsumit has been administered as a single dose of up to and including 600 mg to healthy subjects (60 times the approved dosage). Adverse reactions of headache, nausea and vomiting were observed.
### Management
- In the event of an overdose, standard supportive measures should be taken, as required. Dialysis is unlikely to be effective because macitentan is highly protein-bound.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Macitentan in the drug label.
# Pharmacology
## Mechanism of Action
- Endothelin (ET)-1 and its receptors (ETA and ETB) mediate a variety of deleterious effects, such as vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation. In disease conditions such as PAH, the local ET system is upregulated and is involved in vascular hypertrophy and in organ damage.
- Macitentan is an endothelin receptor antagonist that prevents the binding of ET-1 to both ETA and ETB receptors. Macitentan displays high affinity and sustained occupancy of the ET receptors in human pulmonary arterial smooth muscle cells. One of the metabolites of macitentan is also pharmacologically active at the ET receptors and is estimated to be about 20% as potent as the parent drug in vitro.
## Structure
- Opsumit (macitentan) is an endothelin receptor antagonist. The chemical name of macitentan is N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide. It has a molecular formula of C19H20Br2N6O4S and a molecular weight of 588.27. Macitentan is achiral and has the following structural formula:
- Macitentan is a crystalline powder that is insoluble in water. In the solid state macitentan is very stable, is not hygroscopic, and is not light sensitive.
- Opsumit is available as a 10 mg film-coated tablet for once daily oral administration. The tablets include the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone, and sodium starch glycolate Type A. The tablets are film-coated with a coating material containing polyvinyl alcohol, soya lecithin, talc, titanium dioxide, and xanthan gum.
## Pharmacodynamics
- Pulmonary Hemodynamics: The clinical efficacy study in patients with pulmonary arterial hypertension assessed hemodynamic parameters in a subset of patients after 6 months of treatment. Patients treated with Opsumit 10 mg (N=57) achieved a median reduction of 37% (95% CI 22-49) in pulmonary vascular resistance and an increase of 0.6 L/min/m2 (95% CI 0.3-0.9) in cardiac index compared to placebo (N=67).
- Cardiac Electrophysiology: In a randomized, placebo-controlled four-way crossover study with a positive control in healthy subjects, repeated doses of macitentan 10 and 30 mg (3 times the recommended dosage) had no significant effect on the QTc interval.
## Pharmacokinetics
- The pharmacokinetics of macitentan and its active metabolite have been studied primarily in healthy subjects. The pharmacokinetics of macitentan are dose proportional over a range from 1 mg to 30 mg after once daily administration.
- A cross study comparison shows that the exposures to macitentan and its active metabolite in patients with PAH are similar to those observed in healthy subjects.
- The maximum plasma concentration of macitentan is achieved about 8 hours after oral administration. The absolute bioavailability after oral administration is not known. In a study in healthy subjects, the exposure to macitentan and its active metabolite were unchanged after a high fat breakfast. Macitentan may therefore be taken with or without food.
- Macitentan and its active metabolite are highly bound to plasma proteins (>99%), primarily to albumin and to a lesser extent to alpha-1-acid glycoprotein. The apparent volumes of distribution (Vss/F) of macitentan and its active metabolite were about 50 L and 40 L respectively in healthy subjects.
- Following oral administration, the apparent elimination half-lives of macitentan and its active metabolite are approximately 16 hours and 48 hours, respectively. Macitentan is metabolized primarily by oxidative depropylation of the sulfamide to form the pharmacologically active metabolite. This reaction is dependent on the cytochrome P450 (CYP) system, mainly CYP3A4 with a minor contribution of CYP2C19. At steady state in PAH patients, the systemic exposure to the active metabolite is 3-times the exposure to macitentan and is expected to contribute approximately 40% of the total pharmacologic activity. In a study in healthy subjects with radiolabeled macitentan, approximately 50% of radioactive drug material was eliminated in urine but none was in the form of unchanged drug or the active metabolite. About 24% of the radioactive drug material was recovered from feces.
- There are no clinically relevant effects of age, sex, or race on the pharmacokinetics of macitentan and its active metabolite.
- Renal impairment: Exposure to macitentan and its active metabolite in patients with severe renal impairment (CrCl 15-29 mL/min) compared to healthy subjects was increased by 30% and 60%, respectively. This increase is not considered clinically relevant.
- Hepatic impairment: Exposure to macitentan was decreased by 21%, 34%, and 6% and exposure to the active metabolite was decreased by 20%, 25%, and 25% in subjects with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, and C), respectively. This decrease is not considered clinically relevant.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenesis: Carcinogenicity studies of 2 years' duration did not reveal any carcinogenic potential at exposures 75-fold and 140-fold the human exposure (based on AUC) in male and female mice, respectively, and 8.3- and 42-fold in male and female rats, respectively.
- Mutagenesis: Macitentan was not genotoxic in a standard battery of in vitro and in vivo assays that included a bacterial reverse mutation assay, an assay for gene mutations in mouse lymphoma cells, a chromosome aberration test in human lymphocytes, and an in vivo micronucleus test in rats.
- Impairment of Fertility: Treatment of juvenile rats from postnatal Day 4 to Day 114 led to reduced body weight gain and testicular tubular atrophy at exposures 7-fold the human exposure. Fertility was not affected.
- Reversible testicular tubular dilatation was observed in chronic toxicity studies at exposures greater than 7-fold and 23-fold the human exposure in rats and dogs, respectively. After 2 years of treatment, tubular atrophy was seen in rats at 4-fold the human exposure. Macitentan did not affect male or female fertility at exposures ranging from 19- to 44-fold the human exposure, respectively, and had no effect on sperm count, motility, and morphology in male rats. No testicular findings were noted in mice after treatment up to 2 years.
- Animal Toxicology
- In dogs, macitentan decreased blood pressure at exposures similar to the therapeutic human exposure. Intimal thickening of coronary arteries was observed at 17-fold the human exposure after 4 to 39 weeks of treatment. Due to the species-specific sensitivity and the safety margin, this finding is considered not relevant for humans.
- There were no adverse liver findings in long-term studies conducted in mice, rats, and dogs at exposures of 12- to 116-fold the human exposure.
# Clinical Studies
- Pulmonary Arterial Hypertension
- The effect of macitentan on progression of PAH was demonstrated in a multi-center, long-term (average duration of exposure approximately 2 years), placebo-controlled study in 742 patients with symptomatic [WHO functional class (FC) II-IV] PAH who were randomized to placebo (n=250), 3 mg macitentan (n=250), or 10 mg macitentan (n=242) once daily.
- The primary study endpoint was time to the first occurrence of death, a significant morbidity event, defined as atrial septostomy, lung transplantation, initiation of IV or subcutaneous (SC) prostanoids, or "other worsening of PAH" during double-blind treatment plus 7 days. Other worsening was defined as all of the following: 1) a sustained ≥15% decrease from baseline in 6 minute walk distance (6MWD), 2) worsening of PAH symptoms (worsening of WHO FC), and 3) need for additional treatment for PAH. All of these other worsening events were confirmed by an independent adjudication committee, blinded to treatment allocation. A critical secondary endpoint was time to PAH death or PAH hospitalization.
- The mean patient age was 46 years (14% were age 65 or above). Most patients were white (55%) or Asian (29%) and female (77%). Approximately 52%, 46%, and 2% of patients were in WHO FC II, III, and IV, respectively.
- Idiopathic or heritable PAH was the most common etiology in the study population (57%) followed by PAH caused by connective tissue disorders (31%), PAH caused by congenital heart disease with repaired shunts (8%), and PAH caused by other etiologies [drugs and toxins (3%) and HIV (1%)].
- At baseline, the majority of enrolled patients (64%) were being treated with a stable dose of specific therapy for PAH, either oral phosphodiesterase inhibitors (61%) and/or inhaled/oral prostanoids (6%).
- Study results are described for the placebo and Opsumit 10 mg groups. The median treatment durations were 101 and 118 weeks in the placebo and Opsumit 10 mg groups, respectively, up to a maximum of 188 weeks.
- Treatment with Opsumit 10 mg resulted in a 45% reduction (HR 0.55, 97.5% CI 0.39-0.76; logrank p<0.0001) in the occurrence of the primary endpoint up to end of double-blind treatment compared to placebo (Table 3 and Figure 2). The beneficial effect of Opsumit 10 mg was primarily attributable to a reduction in clinical worsening events (deterioration in 6MWD and worsening of PAH symptoms and need for additional PAH treatment).
- Subgroup analyses were performed to examine their influence on outcome as shown in Figure 3. Consistent efficacy of Opsumit 10 mg on the primary endpoint was seen across subgroups of age, sex, race, etiology, by monotherapy or in combination with another PAH therapy, baseline 6MWD, and baseline WHO FC.
- PAH related death or hospitalization for PAH was assessed as a secondary endpoint. The risk of PAH related death or hospitalization for PAH was reduced by 50% in patients receiving Opsumit 10 mg compared to placebo (HR 0.50, 97.5% CI 0.34-0.75; logrank p<0.0001) (Table 4 and Figure 4).
- Treatment with Opsumit 10 mg resulted in a placebo-corrected mean increase in 6MWD of 22 meters at Month 6 (97.5% CI 3-41; p=0.0078), with significant improvement in 6MWD by Month 3. 6MWD increased more in patients with worse baseline WHO Functional Class (37 meters and 12 meters placebo-corrected mean increase in WHO FC III/IV and FC I/II, respectively). The increase in 6MWD achieved with Opsumit was maintained for the duration of the study.
- Treatment with Opsumit 10 mg led to an improvement of at least one WHO Functional Class at Month 6 in 22% of patients compared to 13% of patients treated with placebo.
# How Supplied
- Opsumit tablets are 10 mg white, film-coated, bi-convex debossed with "10" on one side and supplied as follows:
- Store at 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F).
## Storage
There is limited information regarding Macitentan Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Macitentan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Opsumit®[1]
# Look-Alike Drug Names
- N/A[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Macitentan | |
4ecb4d891761aefa324fac9db9989b5d09a316ff | wikidoc | Macrocycle | Macrocycle
# Overview
A macrocycle is, as defined by IUPAC, "a cyclic macromolecule or a macromolecular cyclic portion of a molecule." In the chemical literature, organic chemists may consider any molecule containing a ring of seven, fifteen, or any arbitrarily large number of atoms to be macrocyclic.
# Macrocycle Effect
Coordination chemists study macrocycle with three or more potential donor atoms in rings of greater than nine atoms as these compounds often have strong and specific binding with metals. This property of coordinating macrocyclic molecules is the macrocycle effect. It is in essence a specific case of the chelation effect: complexes of bidentate and polydentate ligands are more stable than those with unidentate ligands of similar strength (or similar donor atoms). A macrocycle has donor atoms arranged in more fixed positions and thus there is less of an entropic effect in the binding energy of macrocycles than monodentate or bidentate ligands with an equal number of donor atoms. Thus the macrocycle effect states that complexes of macrocyclic ligands are more stable than those with linear polydentate ligands of similar strength (or similar donor atoms). The same can be said for multicyclic macrocycles, or cryptates, being stronger complexing agents (a cryptate effect).
# Synthesis
Macrocycles are generally synthesized from smaller, usually linear, molecules. To create a ring, either an intermolecular reaction, where two or more molecules come together in a reaction to form a ring, or an intramolecular reaction, where one molecule reacts with itself to form a ring, must occur. Because the formation of macrocycles uses the same chemistry that polymerization does, steps need to be taken to prevent polymerization from occurring.
Traditionally, this involved high dilution chemistry where large amounts of solvent and low concentrations were used to prevent molecules from reacting with other molecules. Also, the reagents frequently needed to be added slowly. At low concentration, the molecule is more likely to react with itself than with another molecule. This is generally inefficient, using large quantities of solvents and giving low yields.
To achieve high yields of macrocycles at high concentrations, a way to orient the reactive sites such that they readily undergo cyclization was needed. Transition metals, with their ability to gather & dispose of ligands in a given predictable geometry, can induce a “template effect.” By binding to the linear molecule, to influence its geometry, a metal "template" can accelerate either the intramolecular or the intermolecular reaction. Thus the judicious choice of a metal ion and the relative locations of donor atoms would allow a metal to control the cyclization process.
The template effect can be divided into two slightly more specific effects:
The kinetic template effect describes the directive influence of the metal ion controls the steric course of a sequence of stepwise reactions. In cases where the thermodynamic template effect operates, the metal ion perturbs an existing equilibrium in an organic system and the required product is produced often in high yield as a metal complex. In most cases, the kinetic template effect is operative, however an assignment cannot be made in all cases.
# Applications
- Removal of heavy metals from aqueous solution for water purification.
Chelation therapy whereby the use of chelating agents such as EDTA to remove heavy metals from the body.
- Chelation therapy whereby the use of chelating agents such as EDTA to remove heavy metals from the body.
- Molecular switches and linear motors for constructing artificial nanoscale machinery (rotaxanes)
- Chemical Sensors
- Mimicry of cellular receptors
- Molecular recognition
Recognition of peptides
Small molecules
- Recognition of peptides
- Small molecules
- Organic light-emitting diodes (OLEDs)
# Historical Uses
Macrocycles have been in use for several decades as synthetic dyes. Phthalocyanine is a porphyrin analogue, which is arguably the most useful, in uses as dyes and pigments since their discovery in 1928, due to their dark blue colour. There are however many other uses for them. Their name comes from their synthetic precursor, phthalodinitrile.
# Biological Macrocycles
- Heme, the active site in the hemoglobin (the protein in blood that transports oxygen) is a porphyrin containing iron.
- Chlorophyll, the green photosynthetic pigment found in plants contains a chlorin ring.
- Vitamin B12, contains a corrin ring.
# Related Molecular Categories
- Ligand: an atom, ion or functional group that is bonded to one or more central atoms or ions.
- Chelate: a multidentate ligand, containing more than one donor atom.
- Cryptand: a macrocycle with multiple loops (e.g. bicyclic).
- Rotaxane: macrocycle(s) stuck on a stick, generally freely rotating.
- Catenane: interlocked molecular rings (like a chain).
- Molecular knot: a molecule in the shape of a knot such as a trefoil knot. | Macrocycle
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A macrocycle is, as defined by IUPAC, "a cyclic macromolecule or a macromolecular cyclic portion of a molecule."[2] In the chemical literature, organic chemists may consider any molecule containing a ring of seven, fifteen, or any arbitrarily large number of atoms to be macrocyclic.
# Macrocycle Effect
Coordination chemists study macrocycle with three or more potential donor atoms in rings of greater than nine atoms as these compounds often have strong and specific binding with metals.[3] This property of coordinating macrocyclic molecules is the macrocycle effect. It is in essence a specific case of the chelation effect: complexes of bidentate and polydentate ligands are more stable than those with unidentate ligands of similar strength (or similar donor atoms). A macrocycle has donor atoms arranged in more fixed positions and thus there is less of an entropic effect in the binding energy of macrocycles than monodentate or bidentate ligands with an equal number of donor atoms. Thus the macrocycle effect states that complexes of macrocyclic ligands are more stable than those with linear polydentate ligands of similar strength (or similar donor atoms). The same can be said for multicyclic macrocycles, or cryptates, being stronger complexing agents (a cryptate effect).
# Synthesis
Macrocycles are generally synthesized from smaller, usually linear, molecules. To create a ring, either an intermolecular reaction, where two or more molecules come together in a reaction to form a ring, or an intramolecular reaction, where one molecule reacts with itself to form a ring, must occur. Because the formation of macrocycles uses the same chemistry that polymerization does, steps need to be taken to prevent polymerization from occurring.
Traditionally, this involved high dilution chemistry where large amounts of solvent and low concentrations were used to prevent molecules from reacting with other molecules. Also, the reagents frequently needed to be added slowly. At low concentration, the molecule is more likely to react with itself than with another molecule. This is generally inefficient, using large quantities of solvents and giving low yields.
To achieve high yields of macrocycles at high concentrations, a way to orient the reactive sites such that they readily undergo cyclization was needed. Transition metals, with their ability to gather & dispose of ligands in a given predictable geometry, can induce a “template effect.” By binding to the linear molecule, to influence its geometry, a metal "template" can accelerate either the intramolecular or the intermolecular reaction. Thus the judicious choice of a metal ion and the relative locations of donor atoms would allow a metal to control the cyclization process.
The template effect can be divided into two slightly more specific effects:
The kinetic template effect describes the directive influence of the metal ion controls the steric course of a sequence of stepwise reactions. In cases where the thermodynamic template effect operates, the metal ion perturbs an existing equilibrium in an organic system and the required product is produced often in high yield as a metal complex. In most cases, the kinetic template effect is operative, however an assignment cannot be made in all cases. [4]
# Applications
- Removal of heavy metals from aqueous solution for water purification.
Chelation therapy whereby the use of chelating agents such as EDTA to remove heavy metals from the body.
- Chelation therapy whereby the use of chelating agents such as EDTA to remove heavy metals from the body.
- Molecular switches and linear motors for constructing artificial nanoscale machinery (rotaxanes)
- Chemical Sensors
- Mimicry of cellular receptors
- Molecular recognition
Recognition of peptides[5]
Small molecules
- Recognition of peptides[5]
- Small molecules
- Organic light-emitting diodes (OLEDs)
# Historical Uses
Macrocycles have been in use for several decades as synthetic dyes. Phthalocyanine is a porphyrin analogue, which is arguably the most useful, in uses as dyes and pigments since their discovery in 1928, due to their dark blue colour. There are however many other uses for them. Their name comes from their synthetic precursor, phthalodinitrile.[6]
# Biological Macrocycles
- Heme, the active site in the hemoglobin (the protein in blood that transports oxygen) is a porphyrin containing iron.
- Chlorophyll, the green photosynthetic pigment found in plants contains a chlorin ring.
- Vitamin B12, contains a corrin ring.
# Related Molecular Categories
- Ligand: an atom, ion or functional group that is bonded to one or more central atoms or ions.
- Chelate: a multidentate ligand, containing more than one donor atom.
- Cryptand: a macrocycle with multiple loops (e.g. bicyclic).
- Rotaxane: macrocycle(s) stuck on a stick, generally freely rotating.
- Catenane: interlocked molecular rings (like a chain).
- Molecular knot: a molecule in the shape of a knot such as a trefoil knot. | https://www.wikidoc.org/index.php/Macrocycle | |
ea3096377f33978abab50e6daa9e5702a375c5b9 | wikidoc | Pegaptanib | Pegaptanib
# 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
Pegaptanib is a Ophthalmologic Agent that is FDA approved for the treatment of neovascular (wet) age-related macular degeneration. Common adverse reactions include anterior chamber inflammation, blurred vision, cataract, conjunctival hemorrhage, corneal edema, eye discharge, eye irritation, eye pain, hypertension, increased intraocular pressure (IOP), ocular discomfort, punctate keratitis, reduced visual acuity, visual disturbance, vitreous floaters, and vitreous opacities..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Macugen is indicated for the treatment of neovascular (wet) age-related macular degeneration.
### Dosage
- FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY.
- Macugen 0.3 mg should be administered once every six weeks by intravitreous injection into the eye to be treated.
- Macugen should be inspected visually for particulate matter and discoloration prior to administration. If visible particulates are observed and/or the liquid in the syringe is discolored, the syringe must not be used.
- Administration of the syringe contents involves assembly of the syringe with the administration needle. The injection procedure should be carried out under controlled aseptic conditions, which includes the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). When ready to assemble syringe and administer injection, carefully peel open pouches, remove contents, and place on sterile field. If upon opening the pouch, the plastic clip is missing or not attached to the syringe, the syringe should not be used.
- To avoid compromising the sterility of the product, do not pull back on the plunger.
- Remove the syringe from the plastic clip.
- Twist off cap.
- Attach the sterile BD® 30G 1/2" Precision Glide® administration needle (included) to the syringe by screwing it into the syringe tip.
--Another sterile BD® 30G 1/2" Precision Glide® administration needle may be used in lieu of the one included. Remove the plastic needle shield from the needle.
Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are bubbles, gently tap the syringe with your finger until the bubbles rise to the top of the syringe. SLOWLY depress the plunger to eliminate all the bubbles and to expel the excess drug so that the top edge of the 3rd rib on the plunger stopper aligns with the pre-printed black dosing line (See Figure 2, below).
Inject the entire contents of the syringe.
### DOSAGE FORMS AND STRENGTHS
- Single-use glass syringe pre-filled with 0.3 mg of Macugen® in a nominal 90 μL solution for intravitreal injection.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pegaptanib in adult patients.
### Non–Guideline-Supported Use
- Diabetic macular edema
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Pegaptanib in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pegaptanib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pegaptanib in pediatric patients.
# Contraindications
- Macugen is contraindicated in patients with ocular or periocular infections.
- Macugen is contraindicated in patients with known hypersensitivity to pegaptanib sodium or any other excipient in this product.
# Warnings
- Intravitreous injections, including those with Macugen, have been associated with endophthalmitis. Proper aseptic injection technique should always be utilized when administering Macugen. In addition, patients should be monitored during the week following the injection to permit early treatment, should an infection occur.
- Increases in intraocular pressure have been seen within 30 minutes of injection with Macugen. Therefore, intraocular pressure as well as the perfusion of the optic nerve head should be monitored and managed appropriately.
- Rare cases of anaphylaxis/anaphylactoid reactions, including angioedema, have been reported in the post-marketing experience following the Macugen intravitreal administration procedure
# Adverse Reactions
## Clinical Trials Experience
- Serious adverse events related to the injection procedure occurring in < 1% of intravitreous injections included endophthalmitis, retinal detachment, and iatrogenic traumatic cataract.
- The most frequently reported adverse events in patients treated with Macugen 0.3 mg for up to two years were anterior chamber inflammation, blurred vision, cataract, conjunctival hemorrhage, corneal edema, eye discharge, eye irritation, eye pain, hypertension, increased intraocular pressure (IOP), ocular discomfort, punctate keratitis, reduced visual acuity, visual disturbance, vitreous floaters, and vitreous opacities. These events occurred in approximately 10-40% of patients.
- The following events were reported in 6-10% of patients receiving Macugen 0.3 mg therapy:
- blepharitis, conjunctivitis, photopsia, vitreous disorder.
- bronchitis, diarrhea, dizziness, headache, nausea, urinary tract infection.
- The following events were reported in 1-5% of patients receiving Macugen 0.3 mg therapy:
- allergic conjunctivitis, conjunctival edema, corneal abrasion, corneal deposits, corneal epithelium disorder, endophthalmitis, eye inflammation, eye swelling, eyelid irritation, meibomianitis, mydriasis, periorbital hematoma, retinal edema, vitreous hemorrhage.
- arthritis, bone spur, carotid artery occlusion, cerebrovascular accident, chest pain, contact dermatitis, contusion, diabetes mellitus, dyspepsia, hearing loss, pleural effusion, transient ischemic attack, urinary retention, vertigo, vomiting.
## Postmarketing Experience
- Anaphylaxis/anaphylactoid reactions, including angioedema, have been identified during postapproval use of Macugen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure
# Drug Interactions
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Pegaptanib produced no maternal toxicity and no evidence of teratogenicity or fetal mortality in mice at intravenous doses of up to 40 mg/kg/day (about 7,000 times the recommended human monocular ophthalmic dose of 0.3 mg/eye). Pegaptanib crosses the placenta in mice.
- 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 Pegaptanib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pegaptanib during labor and delivery.
### Nursing Mothers
- It is not known whether pegaptanib is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Macugen is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness of Macugen in pediatric patients have not been established.
### Geriatic Use
- Approximately 94% (834/892) of the patients treated with Macugen were ≥ 65 years of age and approximately 62% (553/892) were ≥ 75 years of age. No difference in treatment effect or systemic exposure was seen with increasing age.
### Gender
There is no FDA guidance on the use of Pegaptanib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pegaptanib with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pegaptanib in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pegaptanib in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pegaptanib in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pegaptanib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY
- The injection procedure should be carried out under controlled aseptic conditions, which includes the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a broad-spectrum microbicide should be given prior to the injection.
- The patient's medical history for hypersensitivity reactions should be evaluated prior to performing the intravitreal procedure.
- Following the injection, patients should be monitored for elevation in intraocular pressure and for endophthalmitis. Monitoring may consist of a check for perfusion of the optic nerve head immediately after the injection, tonometry within 30 minutes following the injection, and monitoring during the week following the injection. Patients should be instructed to report any symptoms suggestive of endophthalmitis without delay.
- No special dosage modification is required for any of the populations that have been studied (i.e. gender, elderly).
- The safety and efficacy of Macugen therapy administered to both eyes concurrently have not been studied.
### Monitoring
There is limited information regarding Monitoring of Pegaptanib in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Pegaptanib in the drug label.
# Overdosage
- Doses of Macugen up to 10 times the recommended dosage of 0.3 mg have been studied. No additional adverse events have been noted but there is decreased efficacy with doses above 1 mg.
# Pharmacology
## Mechanism of Action
- Pegaptanib is a selective vascular endothelial growth factor (VEGF) antagonist. VEGF is a secreted protein that selectively binds and activates its receptors located primarily on the surface of vascular endothelial cells. VEGF induces angiogenesis, and increases vascular permeability and inflammation, all of which are thought to contribute to the progression of the neovascular (wet) form of age-related macular degeneration (AMD), a leading cause of blindness. VEGF has been implicated in blood retinal barrier breakdown and pathological ocular neovascularization.
- Pegaptanib is an aptamer, a pegylated modified oligonucleotide, which adopts a three-dimensional conformation that enables it to bind to extracellular VEGF. Under in vitro testing conditions, pegaptanib binds to the major pathological VEGF isoform, extracellular VEGF165, thereby inhibiting VEGF165 binding to its VEGF receptors. The inhibition of VEGF164, the rodent counterpart of human VEGF165, was effective at suppressing pathological neovascularization.
## Structure
- Macugen (pegaptanib sodium injection) is a sterile, aqueous solution containing pegaptanib sodium for intravitreous injection. Macugen is supplied in a single-dose, pre-filled syringe and is formulated as a 3.47 mg/mL solution, measured as the free acid form of the oligonucleotide. The active ingredient is 0.3 mg of the free acid form of the oligonucleotide without polyethylene glycol, in a nominal volume of 90 μL. This dose is equivalent to 1.6 mg of pegaptanib sodium (pegylated oligonucleotide) or 0.32 mg when expressed as the sodium salt form of the oligonucleotide moiety. The product is a sterile, clear, preservative-free solution containing sodium chloride, monobasic sodium phosphate monohydrate, dibasic sodium phosphate heptahydrate, hydrochloric acid, and/or sodium hydroxide to adjust the pH and water for injection.
- Pegaptanib sodium is a covalent conjugate of an oligonucleotide of twenty-eight nucleotides in length that terminates in a pentylamino linker, to which two 20-kilodalton monomethoxy polyethylene glycol (PEG) units are covalently attached via the two amino groups on a lysine residue.
- Pegaptanib sodium is represented by the following structural formula:
- The chemical name for pegaptanib sodium is as follows: RNA, ((2'-deoxy-2'-fluoro)C-Gm-Gm-A-A-(2'-deoxy-2'-fluoro)U-(2'-deoxy-2'-fluoro)C-Am-Gm-(2'-deoxy-2'-fluoro)U-Gm-Am-Am-(2'-deoxy-2'-fluoro)U-Gm-(2'-deoxy-2'-fluoro)C-(2'-deoxy-2'-fluoro)U-(2'-deoxy-2'-fluoro)U-Am-(2'-deoxy-2'-fluoro)U-Am-(2'-deoxy-2'-fluoro)C-Am-(2'-deoxy-2'-fluoro)U-(2'-deoxy-2'-fluoro)C-(2'-deoxy-2'-fluoro)C-Gm-(3'→3')-dT), 5'-ester with α,α'--3,13-dioxa-5,11-diaza-1,15-pentadecanediyl]bis, sodium salt.
- The molecular formula for pegaptanib sodium is C294H342F13N107Na28O188P28n (where n is approximately 900) and the molecular weight is approximately 50 kilodaltons.
- Macugen is formulated to have an osmolality of 280-360 mOsm/Kg, and a pH of 6-7.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Pegaptanib in the drug label.
## Pharmacokinetics
- In animals, pegaptanib is slowly absorbed into the systemic circulation from the eye after intravitreous administration. The rate of absorption from the eye is the rate limiting step in the disposition of pegaptanib in animals and is likely to be the rate limiting step in humans.
- In humans, a mean maximum plasma concentration of about 80 ng/mL occurs within 1 to 4 days after a 3 mg monocular dose (10 times the recommended dose). The mean area under the plasma concentration-time curve (AUC) is about 25 μghr/mL at this dose.
- Pegaptanib is metabolized by nucleases and is generally not affected by the cytochrome P450 system.
- Two early clinical studies conducted in patients who received Macugen alone and in combination with photodynamic therapy (PDT) revealed no apparent difference in the plasma pharmacokinetics of pegaptanib.
- Twenty-four hours after intravitreous administration of a radiolabeled dose of pegaptanib to both eyes of rabbits, radioactivity was mainly distributed in vitreous fluid, retina, and aqueous fluid. After intravitreous and intravenous administrations of radiolabeled pegaptanib to rabbits, the highest concentrations of radioactivity (excluding the eye for the intravitreous dose) were obtained in the kidney. In rabbits, the component nucleotide, 2'-fluorouridine is found in plasma and urine after single radiolabeled pegaptanib intravenous and intravitreous doses. In rabbits, pegaptanib is eliminated as parent drug and metabolites primarily in the urine.
- Based on preclinical data, pegaptanib is metabolized by endo- and exonucleases.
- In humans, after a 3 mg monocular dose (10 times the recommended dose), the average (± standard deviation) apparent plasma half-life of pegaptanib is 10 (±4) days.
- Plasma concentrations do not appear to be affected by age or gender, but have not been studied in patients under the age of 50.
## Nonclinical Toxicology
- Carcinogenicity studies with pegaptanib have not been conducted. No data are available to evaluate male or female mating or fertility indices.
- Pegaptanib and its monomer component nucleotides (2'-MA, 2'-MG, 2'-FU, 2'-FC) were evaluated for genotoxicity in a battery of in vitro and in vivo assay systems. Pegaptanib, 2'-O-methyladenosine (2'-MA), and 2'-O-methylguanosine (2'-MG) were negative in all assay systems evaluated. 2'-fluorouridine (2'-FU) and 2'-fluorocytidine (2'-FC) were nonclastogenic and were negative in all S. typhimurium tester strains, but produced a non-dose related increase in revertant frequency in a single E. coli tester strain. Pegaptanib, 2'-FU, and 2'-FC tested negative in cell transformation assays.
# Clinical Studies
- Macugen was studied in two controlled, double-masked, and identically designed randomized studies in patients with neovascular AMD. Patients were randomized to receive control (sham treatment) or 0.3 mg, 1 mg or 3 mg Macugen administered as intravitreous injections every 6 weeks for 48 weeks. A total of approximately 1200 patients were enrolled with 892 patients receiving Macugen and 298 receiving a sham injection. The median age of the patients was 77 years. Patients received a mean 8.5 treatments out of a possible 9 total treatments across all treatment arms. Patients were re-randomized between treatment and no treatment during the second year. Patients who continued treatment in year 2 received a mean of 16 treatments out of a possible total 17 overall.
- The two trials enrolled patients with neovascular AMD characteristics including classic, occult, and mixed lesions of up to 12 disc areas and baseline visual acuity in the study eye between 20/40 and 20/320. The primary efficacy endpoint was the proportion of patients losing less than 15 letters of visual acuity, from baseline up to 54 week assessment. Verteporfin PDT usage was permitted at the discretion of the investigators in patients with predominantly classic lesions.
- The groups treated with Macugen 0.3 mg exhibited a statistically significant result in both trials for the primary efficacy endpoint at 1 year: Study EOP1003, Macugen 73% vs. Sham 60%; Study EOP1004, Macugen 67% vs. Sham 53%. Concomitant use of PDT overall was low. More sham treated patients (75/296) received PDT than Macugen 0.3 mg treated patients (58/294).
- On average, Macugen 0.3 mg treated patients and sham treated patients continued to experience vision loss. However, the rate of vision decline in the Macugen treated group was slower than the rate in the patients who received sham treatment. See Figure 1.
- At the end of the first year (week 54), approximately 1050 of the original 1200 patients were re-randomized to either continue the same treatment or to discontinue treatment through week 102. See Figure 2.
- Macugen was less effective during the second year than during the first year. The percentage of patients losing less than 15 letters from baseline to week 102 was: Study EOP1003, Macugen 38/67 (57%); Sham 30/54 (56%); Study EOP1004, Macugen 40/66 (61%); Sham 18/53 (34%).
- Dose levels above 0.3 mg did not demonstrate any additional benefit.
- The safety or efficacy of Macugen beyond 2 years has not been demonstrated.
# How Supplied
- Macugen (pegaptanib sodium injection) is supplied in a sterile foil pouch as a single-use glass syringe pre-filled with 0.3 mg of Macugen® in a nominal 90 μL deliverable volume pack. A sterile packaged BD® single use 30G x 1/2" Precision Glide® Luer Lok® needle is supplied in a separate pouch. The foil pouch and needle are packaged together in a carton (NDC 68782-001-02).
## Storage
- Store in the refrigerator at 2° to 8°C (36° to 46°F). Do not freeze or shake vigorously.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
PRINCIPAL DISPLAY PANEL
NDC 68782-001-02
Rx only
Macugen®
(pegaptanib sodium injection)
For Intravitreous Injection
0.3 mg / 90 μL*
### Ingredients and Appearance
# Patient Counseling Information
- In the days following Macugen administration, patients are at risk for the development of endophthalmitis. If the eye becomes red, sensitive to light, painful or develops a change in vision, the patient should seek the immediate care with their ophthalmologist
# Precautions with Alcohol
- Alcohol-Pegaptanib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- MACUGEN®
# Look-Alike Drug Names
There is limited information regarding Pegaptanib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Pegaptanib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
# Disclaimer
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# Overview
Pegaptanib is a Ophthalmologic Agent that is FDA approved for the treatment of neovascular (wet) age-related macular degeneration. Common adverse reactions include anterior chamber inflammation, blurred vision, cataract, conjunctival hemorrhage, corneal edema, eye discharge, eye irritation, eye pain, hypertension, increased intraocular pressure (IOP), ocular discomfort, punctate keratitis, reduced visual acuity, visual disturbance, vitreous floaters, and vitreous opacities..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Macugen is indicated for the treatment of neovascular (wet) age-related macular degeneration.
### Dosage
- FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY.
- Macugen 0.3 mg should be administered once every six weeks by intravitreous injection into the eye to be treated.
- Macugen should be inspected visually for particulate matter and discoloration prior to administration. If visible particulates are observed and/or the liquid in the syringe is discolored, the syringe must not be used.
- Administration of the syringe contents involves assembly of the syringe with the administration needle. The injection procedure should be carried out under controlled aseptic conditions, which includes the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). When ready to assemble syringe and administer injection, carefully peel open pouches, remove contents, and place on sterile field. If upon opening the pouch, the plastic clip is missing or not attached to the syringe, the syringe should not be used.
- To avoid compromising the sterility of the product, do not pull back on the plunger.
- Remove the syringe from the plastic clip.
- Twist off cap.
- Attach the sterile BD® 30G 1/2" Precision Glide® administration needle (included) to the syringe by screwing it into the syringe tip.
--Another sterile BD® 30G 1/2" Precision Glide® administration needle may be used in lieu of the one included. Remove the plastic needle shield from the needle.
Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are bubbles, gently tap the syringe with your finger until the bubbles rise to the top of the syringe. SLOWLY depress the plunger to eliminate all the bubbles and to expel the excess drug so that the top edge of the 3rd rib on the plunger stopper aligns with the pre-printed black dosing line (See Figure 2, below).
Inject the entire contents of the syringe.
### DOSAGE FORMS AND STRENGTHS
- Single-use glass syringe pre-filled with 0.3 mg of Macugen® in a nominal 90 μL solution for intravitreal injection.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pegaptanib in adult patients.
### Non–Guideline-Supported Use
- Diabetic macular edema[1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Pegaptanib in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pegaptanib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pegaptanib in pediatric patients.
# Contraindications
- Macugen is contraindicated in patients with ocular or periocular infections.
- Macugen is contraindicated in patients with known hypersensitivity to pegaptanib sodium or any other excipient in this product.
# Warnings
- Intravitreous injections, including those with Macugen, have been associated with endophthalmitis. Proper aseptic injection technique should always be utilized when administering Macugen. In addition, patients should be monitored during the week following the injection to permit early treatment, should an infection occur.
- Increases in intraocular pressure have been seen within 30 minutes of injection with Macugen. Therefore, intraocular pressure as well as the perfusion of the optic nerve head should be monitored and managed appropriately.
- Rare cases of anaphylaxis/anaphylactoid reactions, including angioedema, have been reported in the post-marketing experience following the Macugen intravitreal administration procedure
# Adverse Reactions
## Clinical Trials Experience
- Serious adverse events related to the injection procedure occurring in < 1% of intravitreous injections included endophthalmitis, retinal detachment, and iatrogenic traumatic cataract.
- The most frequently reported adverse events in patients treated with Macugen 0.3 mg for up to two years were anterior chamber inflammation, blurred vision, cataract, conjunctival hemorrhage, corneal edema, eye discharge, eye irritation, eye pain, hypertension, increased intraocular pressure (IOP), ocular discomfort, punctate keratitis, reduced visual acuity, visual disturbance, vitreous floaters, and vitreous opacities. These events occurred in approximately 10-40% of patients.
- The following events were reported in 6-10% of patients receiving Macugen 0.3 mg therapy:
- blepharitis, conjunctivitis, photopsia, vitreous disorder.
- bronchitis, diarrhea, dizziness, headache, nausea, urinary tract infection.
- The following events were reported in 1-5% of patients receiving Macugen 0.3 mg therapy:
- allergic conjunctivitis, conjunctival edema, corneal abrasion, corneal deposits, corneal epithelium disorder, endophthalmitis, eye inflammation, eye swelling, eyelid irritation, meibomianitis, mydriasis, periorbital hematoma, retinal edema, vitreous hemorrhage.
- arthritis, bone spur, carotid artery occlusion, cerebrovascular accident, chest pain, contact dermatitis, contusion, diabetes mellitus, dyspepsia, hearing loss, pleural effusion, transient ischemic attack, urinary retention, vertigo, vomiting.
## Postmarketing Experience
- Anaphylaxis/anaphylactoid reactions, including angioedema, have been identified during postapproval use of Macugen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure
# Drug Interactions
-
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Pegaptanib produced no maternal toxicity and no evidence of teratogenicity or fetal mortality in mice at intravenous doses of up to 40 mg/kg/day (about 7,000 times the recommended human monocular ophthalmic dose of 0.3 mg/eye). Pegaptanib crosses the placenta in mice.
- 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 Pegaptanib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pegaptanib during labor and delivery.
### Nursing Mothers
- It is not known whether pegaptanib is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Macugen is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness of Macugen in pediatric patients have not been established.
### Geriatic Use
- Approximately 94% (834/892) of the patients treated with Macugen were ≥ 65 years of age and approximately 62% (553/892) were ≥ 75 years of age. No difference in treatment effect or systemic exposure was seen with increasing age.
### Gender
There is no FDA guidance on the use of Pegaptanib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pegaptanib with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pegaptanib in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pegaptanib in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pegaptanib in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pegaptanib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY
- The injection procedure should be carried out under controlled aseptic conditions, which includes the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a broad-spectrum microbicide should be given prior to the injection.
- The patient's medical history for hypersensitivity reactions should be evaluated prior to performing the intravitreal procedure.
- Following the injection, patients should be monitored for elevation in intraocular pressure and for endophthalmitis. Monitoring may consist of a check for perfusion of the optic nerve head immediately after the injection, tonometry within 30 minutes following the injection, and monitoring during the week following the injection. Patients should be instructed to report any symptoms suggestive of endophthalmitis without delay.
- No special dosage modification is required for any of the populations that have been studied (i.e. gender, elderly).
- The safety and efficacy of Macugen therapy administered to both eyes concurrently have not been studied.
### Monitoring
There is limited information regarding Monitoring of Pegaptanib in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Pegaptanib in the drug label.
# Overdosage
- Doses of Macugen up to 10 times the recommended dosage of 0.3 mg have been studied. No additional adverse events have been noted but there is decreased efficacy with doses above 1 mg.
# Pharmacology
## Mechanism of Action
- Pegaptanib is a selective vascular endothelial growth factor (VEGF) antagonist. VEGF is a secreted protein that selectively binds and activates its receptors located primarily on the surface of vascular endothelial cells. VEGF induces angiogenesis, and increases vascular permeability and inflammation, all of which are thought to contribute to the progression of the neovascular (wet) form of age-related macular degeneration (AMD), a leading cause of blindness. VEGF has been implicated in blood retinal barrier breakdown and pathological ocular neovascularization.
- Pegaptanib is an aptamer, a pegylated modified oligonucleotide, which adopts a three-dimensional conformation that enables it to bind to extracellular VEGF. Under in vitro testing conditions, pegaptanib binds to the major pathological VEGF isoform, extracellular VEGF165, thereby inhibiting VEGF165 binding to its VEGF receptors. The inhibition of VEGF164, the rodent counterpart of human VEGF165, was effective at suppressing pathological neovascularization.
## Structure
- Macugen (pegaptanib sodium injection) is a sterile, aqueous solution containing pegaptanib sodium for intravitreous injection. Macugen is supplied in a single-dose, pre-filled syringe and is formulated as a 3.47 mg/mL solution, measured as the free acid form of the oligonucleotide. The active ingredient is 0.3 mg of the free acid form of the oligonucleotide without polyethylene glycol, in a nominal volume of 90 μL. This dose is equivalent to 1.6 mg of pegaptanib sodium (pegylated oligonucleotide) or 0.32 mg when expressed as the sodium salt form of the oligonucleotide moiety. The product is a sterile, clear, preservative-free solution containing sodium chloride, monobasic sodium phosphate monohydrate, dibasic sodium phosphate heptahydrate, hydrochloric acid, and/or sodium hydroxide to adjust the pH and water for injection.
- Pegaptanib sodium is a covalent conjugate of an oligonucleotide of twenty-eight nucleotides in length that terminates in a pentylamino linker, to which two 20-kilodalton monomethoxy polyethylene glycol (PEG) units are covalently attached via the two amino groups on a lysine residue.
- Pegaptanib sodium is represented by the following structural formula:
- The chemical name for pegaptanib sodium is as follows: RNA, ((2'-deoxy-2'-fluoro)C-Gm-Gm-A-A-(2'-deoxy-2'-fluoro)U-(2'-deoxy-2'-fluoro)C-Am-Gm-(2'-deoxy-2'-fluoro)U-Gm-Am-Am-(2'-deoxy-2'-fluoro)U-Gm-(2'-deoxy-2'-fluoro)C-(2'-deoxy-2'-fluoro)U-(2'-deoxy-2'-fluoro)U-Am-(2'-deoxy-2'-fluoro)U-Am-(2'-deoxy-2'-fluoro)C-Am-(2'-deoxy-2'-fluoro)U-(2'-deoxy-2'-fluoro)C-(2'-deoxy-2'-fluoro)C-Gm-(3'→3')-dT), 5'-ester with α,α'-[4,12-dioxo-6-5-(phosphoonoxy)pentylamino carbonyl]-3,13-dioxa-5,11-diaza-1,15-pentadecanediyl]bis[ω-methoxypoly(oxy-1,2-ethanediyl)], sodium salt.
- The molecular formula for pegaptanib sodium is C294H342F13N107Na28O188P28[C2H4O]n (where n is approximately 900) and the molecular weight is approximately 50 kilodaltons.
- Macugen is formulated to have an osmolality of 280-360 mOsm/Kg, and a pH of 6-7.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Pegaptanib in the drug label.
## Pharmacokinetics
- In animals, pegaptanib is slowly absorbed into the systemic circulation from the eye after intravitreous administration. The rate of absorption from the eye is the rate limiting step in the disposition of pegaptanib in animals and is likely to be the rate limiting step in humans.
- In humans, a mean maximum plasma concentration of about 80 ng/mL occurs within 1 to 4 days after a 3 mg monocular dose (10 times the recommended dose). The mean area under the plasma concentration-time curve (AUC) is about 25 μg•hr/mL at this dose.
- Pegaptanib is metabolized by nucleases and is generally not affected by the cytochrome P450 system.
- Two early clinical studies conducted in patients who received Macugen alone and in combination with photodynamic therapy (PDT) revealed no apparent difference in the plasma pharmacokinetics of pegaptanib.
- Twenty-four hours after intravitreous administration of a radiolabeled dose of pegaptanib to both eyes of rabbits, radioactivity was mainly distributed in vitreous fluid, retina, and aqueous fluid. After intravitreous and intravenous administrations of radiolabeled pegaptanib to rabbits, the highest concentrations of radioactivity (excluding the eye for the intravitreous dose) were obtained in the kidney. In rabbits, the component nucleotide, 2'-fluorouridine is found in plasma and urine after single radiolabeled pegaptanib intravenous and intravitreous doses. In rabbits, pegaptanib is eliminated as parent drug and metabolites primarily in the urine.
- Based on preclinical data, pegaptanib is metabolized by endo- and exonucleases.
- In humans, after a 3 mg monocular dose (10 times the recommended dose), the average (± standard deviation) apparent plasma half-life of pegaptanib is 10 (±4) days.
- Plasma concentrations do not appear to be affected by age or gender, but have not been studied in patients under the age of 50.
## Nonclinical Toxicology
- Carcinogenicity studies with pegaptanib have not been conducted. No data are available to evaluate male or female mating or fertility indices.
- Pegaptanib and its monomer component nucleotides (2'-MA, 2'-MG, 2'-FU, 2'-FC) were evaluated for genotoxicity in a battery of in vitro and in vivo assay systems. Pegaptanib, 2'-O-methyladenosine (2'-MA), and 2'-O-methylguanosine (2'-MG) were negative in all assay systems evaluated. 2'-fluorouridine (2'-FU) and 2'-fluorocytidine (2'-FC) were nonclastogenic and were negative in all S. typhimurium tester strains, but produced a non-dose related increase in revertant frequency in a single E. coli tester strain. Pegaptanib, 2'-FU, and 2'-FC tested negative in cell transformation assays.
# Clinical Studies
- Macugen was studied in two controlled, double-masked, and identically designed randomized studies in patients with neovascular AMD. Patients were randomized to receive control (sham treatment) or 0.3 mg, 1 mg or 3 mg Macugen administered as intravitreous injections every 6 weeks for 48 weeks. A total of approximately 1200 patients were enrolled with 892 patients receiving Macugen and 298 receiving a sham injection. The median age of the patients was 77 years. Patients received a mean 8.5 treatments out of a possible 9 total treatments across all treatment arms. Patients were re-randomized between treatment and no treatment during the second year. Patients who continued treatment in year 2 received a mean of 16 treatments out of a possible total 17 overall.
- The two trials enrolled patients with neovascular AMD characteristics including classic, occult, and mixed lesions of up to 12 disc areas and baseline visual acuity in the study eye between 20/40 and 20/320. The primary efficacy endpoint was the proportion of patients losing less than 15 letters of visual acuity, from baseline up to 54 week assessment. Verteporfin PDT usage was permitted at the discretion of the investigators in patients with predominantly classic lesions.
- The groups treated with Macugen 0.3 mg exhibited a statistically significant result in both trials for the primary efficacy endpoint at 1 year: Study EOP1003, Macugen 73% vs. Sham 60%; Study EOP1004, Macugen 67% vs. Sham 53%. Concomitant use of PDT overall was low. More sham treated patients (75/296) received PDT than Macugen 0.3 mg treated patients (58/294).
- On average, Macugen 0.3 mg treated patients and sham treated patients continued to experience vision loss. However, the rate of vision decline in the Macugen treated group was slower than the rate in the patients who received sham treatment. See Figure 1.
- At the end of the first year (week 54), approximately 1050 of the original 1200 patients were re-randomized to either continue the same treatment or to discontinue treatment through week 102. See Figure 2.
- Macugen was less effective during the second year than during the first year. The percentage of patients losing less than 15 letters from baseline to week 102 was: Study EOP1003, Macugen 38/67 (57%); Sham 30/54 (56%); Study EOP1004, Macugen 40/66 (61%); Sham 18/53 (34%).
- Dose levels above 0.3 mg did not demonstrate any additional benefit.
- The safety or efficacy of Macugen beyond 2 years has not been demonstrated.
# How Supplied
- Macugen (pegaptanib sodium injection) is supplied in a sterile foil pouch as a single-use glass syringe pre-filled with 0.3 mg of Macugen® in a nominal 90 μL deliverable volume pack. A sterile packaged BD® single use 30G x 1/2" Precision Glide® Luer Lok® needle is supplied in a separate pouch. The foil pouch and needle are packaged together in a carton (NDC 68782-001-02).
## Storage
- Store in the refrigerator at 2° to 8°C (36° to 46°F). Do not freeze or shake vigorously.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
PRINCIPAL DISPLAY PANEL
NDC 68782-001-02
Rx only
Macugen®
(pegaptanib sodium injection)
For Intravitreous Injection
0.3 mg / 90 μL*
### Ingredients and Appearance
# Patient Counseling Information
- In the days following Macugen administration, patients are at risk for the development of endophthalmitis. If the eye becomes red, sensitive to light, painful or develops a change in vision, the patient should seek the immediate care with their ophthalmologist
# Precautions with Alcohol
- Alcohol-Pegaptanib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- MACUGEN®[3]
# Look-Alike Drug Names
There is limited information regarding Pegaptanib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Macugen | |
5ee672c2af9098312a3a7f96c68bdef1996a950a | wikidoc | Malassezia | Malassezia
Synonyms and keywords: Pityrosporum.
# Overview
Malassezia (formerly known as Pityrosporum) is a genus of fungi. Malassezia is naturally found on the skin surfaces of many animals, including humans. In occasional opportunistic infections,
some species can cause hypopigmentation on the trunk and other locations in humans. Allergy tests for this fungus are available.
# Nomenclature
Due to progressive changes in their nomenclature, some confusion exists about the naming and classification of Malassezia yeast species. Work on these yeasts has been complicated because they are extremely difficult to propagate in laboratory culture.
Malassezia were originally identified by the French scientist Louis-Charles Malassez in the late 19th century. Raymond Sabouraud identified a dandruff-causing organism in 1904 and called it "Pityrosporum malassez", honoring Malassez, but at the species level as opposed to the genus level. When it was determined that the organisms were the same, the term "Malassezia" was judged to possess priority.
In the mid-20th century, it was reclassified into two species:
- Pityrosporum (Malassezia) ovale, which is lipid-dependent and found only on humans. P. ovale was later divided into two species, P. ovale and P. orbiculare, but current sources consider these terms to refer to a single species of fungus, with M. furfur the preferred name.
- Pityrosporum (Malassezia) pachydermatis, which is lipophilic but not lipid-dependent, is found on the skin of most animals.
In the mid-1990s, scientists at the Pasteur Institute in Paris, France, discovered additional species.
Currently there are 10 recognized species:
- M. dermatis Sugita et al. 2002
- M. furfur
- M. globosa
- M. japonica Sugita et al. 2002
- M. nana
- M. obtusa
- M. pachydermatis
- M. restricta
- M. slooffiae
- M. sympodialis
- M. yamatoensis
Thomas Frieden once said his favorite disease was Malassezia furfur because "it's a rash that doesn't cause any harm; it sounds great."
# Role in human diseases
Identification of Malassezia on skin has been aided by the application of molecular or DNA-based techniques. These investigations show that the Malassezia species causing most skin disease in humans, including the most common cause of dandruff and seborrhoeic dermatitis, is M. globosa (though M. restricta is also involved). The skin rash of tinea versicolor (pityriasis versicolor) is also due to infection by this fungus.
As the fungus requires fat to grow, it is most common in areas with many sebaceous glands: on the scalp, face, and upper part of the body. When the fungus grows too rapidly, the natural renewal of cells is disturbed and dandruff appears with itching (a similar process may also occur with other fungi or bacteria).
A project in 2007 has sequenced the genome of dandruff-causing Malassezia globosa and found it to have 4,285 genes. M. globosa uses eight different types of lipase, along with three phospholipases, to break down the oils on the scalp. Any of these 11 proteins would be a suitable target for dandruff medications.
M. globosa has been predicted to have the ability to reproduce sexually, but this has not been observed.
# Numbers
The number of specimens of M. globosa on a human head can be up to ten million.
# Physical Examination
## Trunk
- Malassezia. Adapted from Atlas"Dermatology Atlas"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Malassezia. Adapted from Atlas"Dermatology Atlas".
- Malassezia. Adapted from Atlas"Dermatology Atlas".
- Malassezia. Adapted from Atlas"Dermatology Atlas". | Malassezia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Jesus Rosario Hernandez, M.D. [2].
Synonyms and keywords: Pityrosporum.
# Overview
Malassezia (formerly known as Pityrosporum) is a genus of fungi. Malassezia is naturally found on the skin surfaces of many animals, including humans. In occasional opportunistic infections,
some species can cause hypopigmentation on the trunk and other locations in humans. Allergy tests for this fungus are available.
# Nomenclature
Due to progressive changes in their nomenclature, some confusion exists about the naming and classification of Malassezia yeast species. Work on these yeasts has been complicated because they are extremely difficult to propagate in laboratory culture.
Malassezia were originally identified by the French scientist Louis-Charles Malassez in the late 19th century. Raymond Sabouraud identified a dandruff-causing organism in 1904 and called it "Pityrosporum malassez", honoring Malassez, but at the species level as opposed to the genus level. When it was determined that the organisms were the same, the term "Malassezia" was judged to possess priority.[1]
In the mid-20th century, it was reclassified into two species:
- Pityrosporum (Malassezia) ovale, which is lipid-dependent and found only on humans. P. ovale was later divided into two species, P. ovale and P. orbiculare, but current sources consider these terms to refer to a single species of fungus, with M. furfur the preferred name.[2]
- Pityrosporum (Malassezia) pachydermatis, which is lipophilic but not lipid-dependent, is found on the skin of most animals.
In the mid-1990s, scientists at the Pasteur Institute in Paris, France, discovered additional species.[3]
Currently there are 10 recognized species:
- M. dermatis Sugita et al. 2002[4]
- M. furfur
- M. globosa[5]
- M. japonica Sugita et al. 2002 [6]
- M. nana[7]
- M. obtusa
- M. pachydermatis[8]
- M. restricta[9]
- M. slooffiae[10]
- M. sympodialis[11]
- M. yamatoensis[12]
Thomas Frieden once said his favorite disease was Malassezia furfur because "it's a rash that doesn't cause any harm; it sounds great." [13]
# Role in human diseases
Identification of Malassezia on skin has been aided by the application of molecular or DNA-based techniques. These investigations show that the Malassezia species causing most skin disease in humans, including the most common cause of dandruff and seborrhoeic dermatitis, is M. globosa (though M. restricta is also involved).[5] The skin rash of tinea versicolor (pityriasis versicolor) is also due to infection by this fungus.
As the fungus requires fat to grow, it is most common in areas with many sebaceous glands: on the scalp,[14] face, and upper part of the body. When the fungus grows too rapidly, the natural renewal of cells is disturbed and dandruff appears with itching (a similar process may also occur with other fungi or bacteria).
A project in 2007 has sequenced the genome of dandruff-causing Malassezia globosa and found it to have 4,285 genes.[15] M. globosa uses eight different types of lipase, along with three phospholipases, to break down the oils on the scalp. Any of these 11 proteins would be a suitable target for dandruff medications.
M. globosa has been predicted to have the ability to reproduce sexually,[16] but this has not been observed.
# Numbers
The number of specimens of M. globosa on a human head can be up to ten million.[citation needed]
# Physical Examination
## Trunk
- Malassezia. Adapted from Atlas<ref name="www.atlasdermatologico.com.br">"Dermatology Atlas"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Malassezia. Adapted from Atlas<ref name="www.atlasdermatologico.com.br">"Dermatology Atlas".
- Malassezia. Adapted from Atlas<ref name="www.atlasdermatologico.com.br">"Dermatology Atlas".
- Malassezia. Adapted from Atlas<ref name="www.atlasdermatologico.com.br">"Dermatology Atlas". | https://www.wikidoc.org/index.php/Malassezia | |
95af41e51e846a47aae0e9a178b28eda165fe521 | wikidoc | Malic acid | Malic acid
# Overview
Malic acid is a tart-tasting organic dicarboxylic acid that plays a role in many sour or tart foods. The salts and esters of malic acid are known as malates. Malate anion is an intermediate in the citric acid cycle along with fumarate. It can also be formed from pyruvate as one of the anaplerotic reactions.
# History
Malic acid was first isolated from apple juice by Carl Wilhelm Scheele in 1785. Antoine Lavoisier in 1787 proposed the name acide malique which is derived from the latin word for apple, malum.
# Biology
Malate is an important chemical compound in biochemistry. In biological sources, malic acid is homochiral and only exists as the (-)-malic acid enantiomer. In the C4 carbon fixation process, malate is a source of CO2 in the Calvin cycle.
In the citric acid cycle, (S)-malate is an intermediate formed by the addition of an -OH group on the si face of fumarate; it can also be formed from pyruvate via anaplerotic reactions. Malate dehydrogenase catalyzes the reversible conversion of malate into oxaloacetate using NAD as a cofactor.
Malate is also produced from starch in guard cells of plant leaves. A build up of malate leads to a low water potential. Water then flows into the guard cells causing the stoma to open. However, this process does not always induce the opening of stomas.
Apples contain malic acid, which contributes to the sourness of a green apple. Malic acid can make a wine taste tart, although the amount decreases with increasing fruit ripeness. The process of malolactic fermentation converts malic acid to much milder lactic acid.
# As a food additive
Malic acid, when added to food products, is denoted by E number E296. Malic acid is the source of extreme tartness in so called "extreme candy", for example Mega Warheads. It is also used with or in place of the less sour citric acid in sour candies such as Jolly Ranchers, SweeTarts and Jimmy Johns Salt & Vinegar potato chips. These candies are sometimes labeled with a warning that excessive consumption can cause irritation of the mouth.
# Chemistry
Malic acid stars in the discovery of the Walden inversion and the Walden cycle in which (-)-malic acid first is converted into (+)-chlorosuccinic acid by action of phosphorus pentachloride. Wet silver oxide then takes the chlorine compound to (+)-malic acid which then reacts with PCl5 to the (-)-chlorosuccinic acid. The cycle is completed when silver oxide takes this compound back to (-)-malic acid.
Self-condensation of malic acid with fuming sulfuric acid gives the pyrone coumalic acid: | Malic acid
Template:Chembox new
# Overview
Malic acid is a tart-tasting organic dicarboxylic acid that plays a role in many sour or tart foods. The salts and esters of malic acid are known as malates. Malate anion is an intermediate in the citric acid cycle along with fumarate. It can also be formed from pyruvate as one of the anaplerotic reactions.
# History
Malic acid was first isolated from apple juice by Carl Wilhelm Scheele in 1785. Antoine Lavoisier in 1787 proposed the name acide malique which is derived from the latin word for apple, malum.[1]
# Biology
Malate is an important chemical compound in biochemistry. In biological sources, malic acid is homochiral and only exists as the (-)-malic acid enantiomer. In the C4 carbon fixation process, malate is a source of CO2 in the Calvin cycle.
In the citric acid cycle, (S)-malate is an intermediate formed by the addition of an -OH group on the si face of fumarate; it can also be formed from pyruvate via anaplerotic reactions. Malate dehydrogenase catalyzes the reversible conversion of malate into oxaloacetate using NAD as a cofactor.
Malate is also produced from starch in guard cells of plant leaves. A build up of malate leads to a low water potential. Water then flows into the guard cells causing the stoma to open. However, this process does not always induce the opening of stomas.
Apples contain malic acid, which contributes to the sourness of a green apple. Malic acid can make a wine taste tart, although the amount decreases with increasing fruit ripeness. The process of malolactic fermentation converts malic acid to much milder lactic acid.
# As a food additive
Malic acid, when added to food products, is denoted by E number E296. Malic acid is the source of extreme tartness in so called "extreme candy", for example Mega Warheads. It is also used with or in place of the less sour citric acid in sour candies such as Jolly Ranchers, SweeTarts and Jimmy Johns Salt & Vinegar potato chips. These candies are sometimes labeled with a warning that excessive consumption can cause irritation of the mouth.
# Chemistry
Malic acid stars in the discovery of the Walden inversion and the Walden cycle in which (-)-malic acid first is converted into (+)-chlorosuccinic acid by action of phosphorus pentachloride. Wet silver oxide then takes the chlorine compound to (+)-malic acid which then reacts with PCl5 to the (-)-chlorosuccinic acid. The cycle is completed when silver oxide takes this compound back to (-)-malic acid.
Self-condensation of malic acid with fuming sulfuric acid gives the pyrone coumalic acid:[2] | https://www.wikidoc.org/index.php/Malic_acid | |
1053b309324aeab53dbbaeedbbb2dc6c32efdf9e | wikidoc | Mastectomy | Mastectomy
In medicine, mastectomy is the medical term for the surgical removal of one or both breasts, partially or completely. Mastectomy is usually done to treat breast cancer; in some cases, women and some men believed to be at high risk of breast cancer have the operation prophylactically, that is, to prevent cancer rather than treat it. It is also the medical procedure carried out to remove breast cancer (tissue) in males. Alternatively, certain patients can choose to have a wide local excision (also called a lumpectomy), an operation in which a small volume of breast tissue containing the tumor and some surrounding healthy tissue is removed to conserve the breast. Both mastectomy and lumpectomy are what are referred to as "local therapies" for breast cancer, targeting the area of the tumor, as opposed to systemic therapies such as chemotherapy, hormonal therapy, or immunotherapy.
Traditionally, in the case of breast cancer, the whole breast was removed. Currently the decision to do the mastectomy is based on various factors including breast size, number of lesions, biologic aggressiveness of a breast cancer, the availability of adjuvant radiation, and the willingness of the patient to accept higher rates of tumor recurrences after lumpectomy and radiation. Outcome studies comparing mastectomy to lumpectomy with radiation have suggested that routine radical mastectomy surgeries will not always prevent later distant secondary tumors arising from micro-metastases prior to discovery, diagnosis, and operation.
Mastectomy rates vary tremendously world-wide, as was documented by the 2004 'Intergroup Exemestane Study', an analysis of surgical techniques used in an international trial of adjuvant treatment among 4,700 women with early breast cancer in 37 countries. The mastectomy rate was highest in central and eastern Europe at 77%. The USA had the second highest rate of mastectomy with 56%, western and northern Europe averaged 46%, southern Europe 42% and Australia and New Zealand 34%.
# Mastectomy Indications
Despite the increased ability to offer breast-conservation techniques to patients with breast cancer, there exist certain groups who may be better served by traditional mastectomy procedures including:
- women who have already had radiation therapy to the affected breast
- women with 2 or more areas of cancer in the same breast that are too far apart to be removed through 1 surgical incision, while keeping the appearance of the breast satisfactory
- women whose initial lumpectomy along with (one or more) re-excisions has not completely removed the cancer
- women with certain serious connective tissue diseases such as scleroderma, which make them especially sensitive to the side effects of radiation therapy
- pregnant women who would require radiation while still pregnant (risking harm to the fetus)
- women with a tumor larger than 5 cm (2 inches) that doesn't shrink very much with neoadjuvant chemotherapy
- women with a cancer that is large relative to her breast size
- male breast cancer patients
# Types of Mastectomy
There are a variety of types of mastectomy in use, and the type that a patient decides to undergo (or whether he or she will decide instead to have a lumpectomy) depends on factors such as size, location, and behavior of the tumor (if there is one), whether or not the surgery is prophylactic, and whether or not the patient intends to undergo reconstructive surgery.
- Simple mastectomy (or "total mastectomy"): In this procedure, the entire breast tissue is removed, but axillary contents are undisturbed. Sometimes the "sentinel lymph node"--that is, the first axillary lymph node that the would be expected to drain into--is removed. This surgery is sometimes done bilaterally (on both breasts) on patients who wish to undergo mastectomy as a cancer-preventative measure. Patients who undergo simple mastectomy can usually leave the hospital after a brief stay. Frequently, a drainage tube is inserted during surgery in their chest and attached to a small suction device to remove subcutaneous fluid. These are usually removed several days after surgery as drainage decrease to less than 20-30 ml per day. illustration
- Modified radical mastectomy: The entire breast tissue is removed along with the axillary contents (fatty tissue and lymph nodes). illustration
- Radical mastectomy (or "Halsted mastectomy"): First performed in 1882, this procedure involves removing the entire breast, the axillary lymph nodes, and the pectoral tissue behind the breast. This procedure is more disfiguring than a modified radical mastectomy and provides no survival benefit for most tumors. This operation is now reserved for tumors involving the pectoralis major muscle or recurrent breast cancer involving the chest wall. illustration
- Skin-sparing mastectomy: In this surgery, the breast tissue is removed through a conservative incision made around the areola (the dark part surrounding the nipple). The increased amount of skin preserved as compared to traditional mastecomy resections serves to facilitate breast reconstruction procedures. Patients with cancers that involve the skin, such as inflammatory cancer, are not candidates for skin-sparing mastectomy. illustration
- Quadrantectomy, or partial mastectomy: Like a lumpectomy, this is considered a form of breast conservation therapy. However, a quadrantectomy involves removal of more breast tissue than a lumpectomy--up to a quarter of the breast may be removed, whereas a lumpectomy removes only the tumor and a margin of surrounding tissue.
- Subcutaneous mastectomy: Breast tissue is removed, but the nipple-areola complex is preserved. This procedure was historically done only prophylactically or with mastecomy for benign disease over fear of increased cancer development in retained areolar ductal tissue. Recent series suggest that it may be an oncologically sound procedure for tumors not in the subareolar position | Mastectomy
In medicine, mastectomy is the medical term for the surgical removal of one or both breasts, partially or completely. Mastectomy is usually done to treat breast cancer; in some cases, women and some men believed to be at high risk of breast cancer have the operation prophylactically, that is, to prevent cancer rather than treat it. It is also the medical procedure carried out to remove breast cancer (tissue) in males. Alternatively, certain patients can choose to have a wide local excision (also called a lumpectomy), an operation in which a small volume of breast tissue containing the tumor and some surrounding healthy tissue is removed to conserve the breast. Both mastectomy and lumpectomy are what are referred to as "local therapies" for breast cancer, targeting the area of the tumor, as opposed to systemic therapies such as chemotherapy, hormonal therapy, or immunotherapy.
Traditionally, in the case of breast cancer, the whole breast was removed. Currently the decision to do the mastectomy is based on various factors including breast size, number of lesions, biologic aggressiveness of a breast cancer, the availability of adjuvant radiation, and the willingness of the patient to accept higher rates of tumor recurrences after lumpectomy and radiation. Outcome studies comparing mastectomy to lumpectomy with radiation have suggested that routine radical mastectomy surgeries will not always prevent later distant secondary tumors arising from micro-metastases prior to discovery, diagnosis, and operation.
Mastectomy rates vary tremendously world-wide, as was documented by the 2004 'Intergroup Exemestane Study'[1], an analysis of surgical techniques used in an international trial of adjuvant treatment among 4,700 women with early breast cancer in 37 countries. The mastectomy rate was highest in central and eastern Europe at 77%. The USA had the second highest rate of mastectomy with 56%, western and northern Europe averaged 46%, southern Europe 42% and Australia and New Zealand 34%.
# Mastectomy Indications
Despite the increased ability to offer breast-conservation techniques to patients with breast cancer, there exist certain groups who may be better served by traditional mastectomy procedures including:
- women who have already had radiation therapy to the affected breast
- women with 2 or more areas of cancer in the same breast that are too far apart to be removed through 1 surgical incision, while keeping the appearance of the breast satisfactory
- women whose initial lumpectomy along with (one or more) re-excisions has not completely removed the cancer
- women with certain serious connective tissue diseases such as scleroderma, which make them especially sensitive to the side effects of radiation therapy
- pregnant women who would require radiation while still pregnant (risking harm to the fetus)
- women with a tumor larger than 5 cm (2 inches) that doesn't shrink very much with neoadjuvant chemotherapy
- women with a cancer that is large relative to her breast size
- male breast cancer patients
# Types of Mastectomy
There are a variety of types of mastectomy in use, and the type that a patient decides to undergo (or whether he or she will decide instead to have a lumpectomy) depends on factors such as size, location, and behavior of the tumor (if there is one), whether or not the surgery is prophylactic, and whether or not the patient intends to undergo reconstructive surgery.
- Simple mastectomy (or "total mastectomy"): In this procedure, the entire breast tissue is removed, but axillary contents are undisturbed. Sometimes the "sentinel lymph node"--that is, the first axillary lymph node that the would be expected to drain into--is removed. This surgery is sometimes done bilaterally (on both breasts) on patients who wish to undergo mastectomy as a cancer-preventative measure. Patients who undergo simple mastectomy can usually leave the hospital after a brief stay. Frequently, a drainage tube is inserted during surgery in their chest and attached to a small suction device to remove subcutaneous fluid. These are usually removed several days after surgery as drainage decrease to less than 20-30 ml per day. illustration
- Modified radical mastectomy: The entire breast tissue is removed along with the axillary contents (fatty tissue and lymph nodes). illustration
- Radical mastectomy (or "Halsted mastectomy"): First performed in 1882, this procedure involves removing the entire breast, the axillary lymph nodes, and the pectoral tissue behind the breast. This procedure is more disfiguring than a modified radical mastectomy and provides no survival benefit for most tumors. This operation is now reserved for tumors involving the pectoralis major muscle or recurrent breast cancer involving the chest wall. illustration
- Skin-sparing mastectomy: In this surgery, the breast tissue is removed through a conservative incision made around the areola (the dark part surrounding the nipple). The increased amount of skin preserved as compared to traditional mastecomy resections serves to facilitate breast reconstruction procedures. Patients with cancers that involve the skin, such as inflammatory cancer, are not candidates for skin-sparing mastectomy. illustration
- Quadrantectomy, or partial mastectomy: Like a lumpectomy, this is considered a form of breast conservation therapy. However, a quadrantectomy involves removal of more breast tissue than a lumpectomy--up to a quarter of the breast may be removed, whereas a lumpectomy removes only the tumor and a margin of surrounding tissue.
- Subcutaneous mastectomy: Breast tissue is removed, but the nipple-areola complex is preserved. This procedure was historically done only prophylactically or with mastecomy for benign disease over fear of increased cancer development in retained areolar ductal tissue. Recent series suggest that it may be an oncologically sound procedure for tumors not in the subareolar position [PMID 12832974] [PMID 17269590] [PMID 17084333] | https://www.wikidoc.org/index.php/Mastectomy | |
7c9728e51b4d812693475c9199549f5e6513f428 | wikidoc | Masterwort | Masterwort
Masterwort typically refers to the plant Peucedanum ostruthium or Imperatoria ostruthium in the family Apiaceae, and not to be confused with great masterwort, Astrantia major, in the same family.
# Habitat
Woodland gardens and meadows, in semi-shady areas.
# Medicinal uses
The roots, collected in the spring of fall, have been known to hold many medicinal proprieties such as tonic, antiseptic, emmenagogue and diuretic.
They are used for flatulence problems, asthma, kidney and bladder stones and water retention. Masterwort tea can help in relieving migraines and stimulating the immune system.
de:Meisterwurz | Masterwort
Masterwort typically refers to the plant Peucedanum ostruthium or Imperatoria ostruthium in the family Apiaceae, and not to be confused with great masterwort, Astrantia major, in the same family.
# Habitat
Woodland gardens and meadows, in semi-shady areas.
# Medicinal uses
The roots, collected in the spring of fall, have been known to hold many medicinal proprieties such as tonic, antiseptic, emmenagogue and diuretic.
They are used for flatulence problems, asthma, kidney and bladder stones and water retention. Masterwort tea can help in relieving migraines and stimulating the immune system.
Template:Apiales-stub
de:Meisterwurz
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Masterwort | |
676fc7cdf0ffa99ad4c9d34ce49f5c595b4e5d55 | wikidoc | Matricaria | Matricaria
Matricaria is a genus of flowering plants in the sunflower family (Asteraceae). Some of the species have the common name of "mayweed," but this name also refers to plants not in this genus.
Most are very common in the temperate regions of Europe, Asia, and America, as well as in northern and southern Africa, and some are naturalised in Australia. M. occidentalis is native to North America; other species have been introduced there.
These are hardy, pleasantly aromatic annuals, growing along roadsides in ruderal communities and in fallow land rich in nutrients. Though many are considered nuisance weeds, they are suitable for rock gardens and herb gardens, and as border plants.
Their many-branched stems are prostrate to erect, glabrous, and very leafy. Their bipinnate leaves have numerous linear, narrowly lobed leaflets.
The flowers are radially symmetrical. The greenish-yellow capitula are semi-spherical. The white ray florets can be present (M. recutita) or lacking (M. discoidea). The disc florets are 4- to 5-dentate. The receptacle is 2–3 times as high as wide. The pappus may be crown-shaped and short, or lacking.
Matricaria species are used as food plants by the larvae of some Lepidoptera species (caterpillars) including Lime-speck Pug.
The extract of German chamomile (M. recutita) is taken as a strong tea. It has been used in herbal medicine as a carminative and anti-inflammatory. It is also used in ointments and lotions, and as a mouthwash against infections of mouth and gums. Aromatherapy uses two essential oils of chamomile: the "true chamomile" oil (or german chamomile oil, from M. recutita) and the Roman chamomile oil (from Anthemis nobilis).
The taxonomy of Matricaria is controversial and very confused. Several species are classified either in Tripleurospermum or Matricaria depending on the interpretation of the author. The distinction is made according to the number of the seed ribs: Tripleurospermum has one adaxial and two lateral seed ribs, while Matricaria has four or five adaxial seed ribs. | Matricaria
Matricaria is a genus of flowering plants in the sunflower family (Asteraceae). Some of the species have the common name of "mayweed," but this name also refers to plants not in this genus.
Most are very common in the temperate regions of Europe, Asia, and America, as well as in northern and southern Africa, and some are naturalised in Australia. M. occidentalis is native to North America; other species have been introduced there.
These are hardy, pleasantly aromatic annuals, growing along roadsides in ruderal communities and in fallow land rich in nutrients. Though many are considered nuisance weeds, they are suitable for rock gardens and herb gardens, and as border plants.
Their many-branched stems are prostrate to erect, glabrous, and very leafy. Their bipinnate leaves have numerous linear, narrowly lobed leaflets.
The flowers are radially symmetrical. The greenish-yellow capitula are semi-spherical. The white ray florets can be present (M. recutita) or lacking (M. discoidea). The disc florets are 4- to 5-dentate. The receptacle is 2–3 times as high as wide. The pappus may be crown-shaped and short, or lacking.
Matricaria species are used as food plants by the larvae of some Lepidoptera species (caterpillars) including Lime-speck Pug.
The extract of German chamomile (M. recutita) is taken as a strong tea. It has been used in herbal medicine as a carminative and anti-inflammatory. It is also used in ointments and lotions, and as a mouthwash against infections of mouth and gums. Aromatherapy uses two essential oils of chamomile: the "true chamomile" oil (or german chamomile oil, from M. recutita) and the Roman chamomile oil (from Anthemis nobilis).
The taxonomy of Matricaria is controversial and very confused. Several species are classified either in Tripleurospermum or Matricaria depending on the interpretation of the author. The distinction is made according to the number of the seed ribs: Tripleurospermum has one adaxial and two lateral seed ribs, while Matricaria has four or five adaxial seed ribs.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Matricaria | |
a9ee6ddd36653d1f7a87fe6677ade213e4c240ff | wikidoc | Max Perutz | Max Perutz
Max Ferdinand Perutz, OM (May 19 1914 – February 6 2002) was an Austrian-British molecular biologist.
He was born in Vienna in 1914. In 1936 he became a research student at the Cavendish Laboratory in a crystallography group directed by J.D. Bernal, and remained in Cambridge.
During World War II, he was asked to find a way to improve the structural qualities of ice for Project Habakkuk (a secret project to build an aircraft carrier made of ice) and investigated the recently invented mixture of ice and woodpulp known as pykrete.
In 1953 Perutz showed that the diffracted X-rays from protein crystals could be phased by comparing the patterns from crystals of the protein with and without heavy atoms attached. In 1959 he determined the molecular structure of the protein hemoglobin, which transports oxygen in the blood, using this method. In 1962 he received the Nobel Prize for Chemistry, with John Kendrew.
In the history of science, Perutz is also known as the supervisor of James D. Watson and Francis Crick during the early 1950's, during which time Watson and Crick determined the structure of deoxyribonucleic acid (DNA). Watson and Crick made use of information from unpublished X-ray diffraction images of Franklin's (shown at meetings and shared by Wilkins), and preliminary accounts of Franklin's detailed analysis of the X-ray images that were included in a written progress report for the King's College laboratory of John Randall from late 1952. The report was given to Watson and Crick by Perutz and lead to criticism of him for doing so; Sir John Randall of King's College London was said to be angry over the report's disclosure to Crick and Watson.
It is a matter of debate whether Watson and Crick should have had access to Franklin's results without her knowledge or permission and before she had a chance to formally publish the results of her detailed analysis of her X-ray diffraction data that were included in the progress report. In an effort to clarify this issue, Perutz later published what had been in the progress report, and suggested that nothing was in the report that Franklin herself had not said in her talk (attended by Watson) in late 1951. Further, Perutz explained that the report was to a Medical Research Council committee that had been created in order to "establish contact between the different groups of people working for the Council". Randall's and Perutz's labs were both MRC funded laboratories. It is also not clear how important Franklin's unpublished results from the progress report actually were for the model building done by Watson and Crick.
Perutz established the MRC Laboratory of Molecular Biology, Cambridge, England in 1962 and was chairman until 1979. He remained active in research to the end of his life. From the mid-1980s on he was a regular reviewer/essayist for The New York Review of Books on biomedical subjects.
Perutz's flair for writing was a late development. Leo Perutz, the distinguished writer and a relative, once told Max when he was a boy that he would never be a writer, and so one of his most cherished awards was one for scientific writing. "I wish I had made you angry earlier" (Cold Spring Harbor Laboratory Press; 1998) contains a selection of his essays on science, scientists and humanity.
Max Perutz and his wife Gisela's son, Robin Perutz, is a professor of chemistry at the University of York in England; their daughter Vivien Perutz has edited a selection of Max Perutz's letters for publication by Cold Spring Harbor Laboratory Press.
An Italian biography of Max Perutz entitled "Piccole Visioni - La Grande Storia di una Molecola" was written by Marta Paterlini and published by Codice Edizioni, Turin, in May 2006; another biography (in English) by Georgina Ferry was published by Chatto & Windus in July 2007.
Max Perutz's major contribution to molecular biology in Cambridge is also well documented in The History of the University of Cambridge: Volume 4 (1870 to 1990) published by CUP in 1992.
Max Perutz was acknowledged as one of the foremost scientists of the 20th century and as the architect of arguably the most famous and successful research laboratory now in existence, the Medical Research Council Laboratory of Molecular Biology in Cambridge. He was seen at least weekly in his College in Cambridge, Peterhouse, until just before his death; he took a keen interest in the Junior Members, and was a regular and most popular speaker at the Kelvin Club, the College's scientific society. He matriculated in 1936 and was an Honorary Fellow from 1962 to 2002.
# Books
- Is Science Necessary: Essays on Science and Scientists
- I Wish I'd Made You Angry Earlier: Essays on Science, Science, Scientists, and Humanity
- Proteins and nucleic acids: structure and function.
- Science is Not a Quiet Life: Unravelling the Atomic Mechanism of Haemoglobin
- Glutamine Repeats and Neurodegenerative Diseases: Molecular Aspects
- Le molecole dei viventi, Di Renzo Editore, Roma, ISBN: 8886044917
- Protein Structure: A User's Guide | Max Perutz
Template:Infobox Scientist
Max Ferdinand Perutz, OM (May 19 1914 – February 6 2002) was an Austrian-British molecular biologist.
He was born in Vienna in 1914. In 1936 he became a research student at the Cavendish Laboratory in a crystallography group directed by J.D. Bernal, and remained in Cambridge.
During World War II, he was asked to find a way to improve the structural qualities of ice for Project Habakkuk (a secret project to build an aircraft carrier made of ice) and investigated the recently invented mixture of ice and woodpulp known as pykrete.
In 1953 Perutz showed that the diffracted X-rays from protein crystals could be phased by comparing the patterns from crystals of the protein with and without heavy atoms attached. In 1959 he determined the molecular structure of the protein hemoglobin, which transports oxygen in the blood, using this method. In 1962 he received the Nobel Prize for Chemistry, with John Kendrew.
In the history of science, Perutz is also known as the supervisor of James D. Watson and Francis Crick during the early 1950's, during which time Watson and Crick determined the structure of deoxyribonucleic acid (DNA). Watson and Crick made use of information from unpublished X-ray diffraction images of Franklin's (shown at meetings and shared by Wilkins), and preliminary accounts of Franklin's detailed analysis of the X-ray images that were included in a written progress report for the King's College laboratory of John Randall from late 1952. The report was given to Watson and Crick by Perutz and lead to criticism of him for doing so; Sir John Randall of King's College London was said to be angry over the report's disclosure to Crick and Watson.
It is a matter of debate whether Watson and Crick should have had access to Franklin's results without her knowledge or permission and before she had a chance to formally publish the results of her detailed analysis of her X-ray diffraction data that were included in the progress report. In an effort to clarify this issue, Perutz later published what had been in the progress report, and suggested that nothing was in the report that Franklin herself had not said in her talk (attended by Watson) in late 1951. Further, Perutz explained that the report was to a Medical Research Council committee that had been created in order to "establish contact between the different groups of people working for the Council". Randall's and Perutz's labs were both MRC funded laboratories. It is also not clear how important Franklin's unpublished results from the progress report actually were for the model building done by Watson and Crick.
Perutz established the MRC Laboratory of Molecular Biology, Cambridge, England in 1962 and was chairman until 1979. He remained active in research to the end of his life. From the mid-1980s on he was a regular reviewer/essayist for The New York Review of Books on biomedical subjects.
Perutz's flair for writing was a late development. Leo Perutz, the distinguished writer and a relative, once told Max when he was a boy that he would never be a writer, and so one of his most cherished awards was one for scientific writing. "I wish I had made you angry earlier" (Cold Spring Harbor Laboratory Press; 1998) contains a selection of his essays on science, scientists and humanity. [1]
Max Perutz and his wife Gisela's son, Robin Perutz, is a professor of chemistry at the University of York in England; their daughter Vivien Perutz has edited a selection of Max Perutz's letters for publication by Cold Spring Harbor Laboratory Press.
An Italian biography of Max Perutz entitled "Piccole Visioni - La Grande Storia di una Molecola" was written by Marta Paterlini and published by Codice Edizioni, Turin, in May 2006; another biography (in English) by Georgina Ferry was published by Chatto & Windus in July 2007.
Max Perutz's major contribution to molecular biology in Cambridge is also well documented in The History of the University of Cambridge: Volume 4 (1870 to 1990) published by CUP in 1992.
Max Perutz was acknowledged as one of the foremost scientists of the 20th century and as the architect of arguably the most famous and successful research laboratory now in existence, the Medical Research Council Laboratory of Molecular Biology in Cambridge. He was seen at least weekly in his College in Cambridge, Peterhouse, until just before his death; he took a keen interest in the Junior Members, and was a regular and most popular speaker at the Kelvin Club, the College's scientific society. He matriculated in 1936 and was an Honorary Fellow from 1962 to 2002.
# Books
- Is Science Necessary: Essays on Science and Scientists
- I Wish I'd Made You Angry Earlier: Essays on Science, Science, Scientists, and Humanity
- Proteins and nucleic acids: structure and function.
- Science is Not a Quiet Life: Unravelling the Atomic Mechanism of Haemoglobin
- Glutamine Repeats and Neurodegenerative Diseases: Molecular Aspects
- Le molecole dei viventi, Di Renzo Editore, Roma, ISBN: 8886044917
- Protein Structure: A User's Guide | https://www.wikidoc.org/index.php/Max_Perutz | |
ec3eff31c9c78b220b402ef778243078c747a984 | wikidoc | Max Planck | Max Planck
Max Karl Ernst Ludwig Planck (April 23 1858 – October 4 1947) was a German physicist. He is considered to be the founder of quantum theory, and one of the most important physicists of the twentieth century.
# Biography
Planck came from a traditional, intellectual family. His paternal great-grandfather and grandfather were both theology professors in Göttingen, his father was a law professor in Kiel and Munich, and his paternal uncle was a judge.
Planck was born in Kiel, Holstein, to Johann Julius Wilhelm Planck and his second wife, Emma Patzig. He was the sixth child in the family, though two of his siblings were from his father's first marriage. Among his earliest memories was the marching of Prussian and Austrian troops into Kiel during the Danish-Prussian war of 1864. In 1867 the family moved to Munich, and Planck enrolled in the Maximilians gymnasium school, where he came under the tutelage of Hermann Müller, a mathematician who took an interest in the youth, and taught him astronomy and mechanics as well as mathematics. It was from Müller that Planck first learned the principle of conservation of energy. Planck graduated early, at age 17. This is how Planck first came in contact with the field of physics.
Planck was gifted when it came to music. He took singing lessons and played piano, organ and cello, and composed songs and operas. However, instead of music he chose to study physics.
The Munich physics professor Philipp von Jolly advised Planck against going into physics, saying, "in this field, almost everything is already discovered, and all that remains is to fill a few holes." Planck replied that he did not wish to discover new things, only to understand the known fundamentals of the field, and began his studies in 1874 at the University of Munich. Under Jolly's supervision, Planck performed the only experiments of his scientific career, studying the diffusion of hydrogen through heated platinum, but transferred to theoretical physics.
In 1877 he went to Berlin for a year of study with physicists Hermann von Helmholtz and Gustav Kirchhoff and the mathematician Karl Weierstrass. He wrote that Helmholtz was never quite prepared, spoke slowly, miscalculated endlessly, and bored his listeners, while Kirchhoff spoke in carefully prepared lectures which were dry and monotonous. He soon became close friends with Helmholtz. While there he undertook a program of mostly self-study of Clausius's writings, which led him to choose heat theory as his field.
In October 1878 Planck passed his qualifying exams and in February 1879 defended his dissertation, Über den zweiten Hauptsatz der mechanischen Wärmetheorie (On the second fundamental theorem of the mechanical theory of heat). He briefly taught mathematics and physics at his former school in Munich.
In June 1880 he presented his habilitation thesis, Gleichgewichtszustände isotroper Körper in verschiedenen Temperaturen (Equilibrium states of isotropic bodies at different temperatures).
## Academic career
With the completion of his habilitation thesis, Planck became an unpaid private lecturer in Munich, waiting until he was offered an academic position. Although he was initially ignored by the academic community, he furthered his work on the field of heat theory and discovered one after another the same thermodynamical formalism as Gibbs without realizing it. Clausius's ideas on entropy occupied a central role in his work.
In April 1885 the University of Kiel appointed Planck as associate professor of theoretical physics. Further work on entropy and its treatment, especially as applied in physical chemistry, followed. He proposed a thermodynamic basis for Arrhenius's theory of electrolytic dissociation.
Within four years he was named the successor to Kirchhoff's position at the University of Berlin — presumably thanks to Helmholtz's intercession — and by 1892 became a full professor. In 1907 Planck was offered Boltzmann's position in Vienna, but turned it down to stay in Berlin. During 1909 he was the Ernest Kempton Adams Lecturer in Theoretical Physics at Columbia University in New York City. He retired from Berlin on 10 January, 1926, and was succeeded by Erwin Schrödinger.
## Family
In March 1887 Planck married Marie Merck (1861-1909), sister of a school fellow, and moved with her into a sublet apartment in Kiel. They had four children: Karl (1888-1916), the twins Emma (1889-1919) and Grete (1889-1917), and Erwin (1893-1945).
After the appointment to Berlin, the Planck family lived in a villa in Berlin-Grunewald, Wangenheimstraße 21. Several other professors of Berlin University lived nearby, among them theologian Adolf von Harnack, who became a close friend of Planck. Soon the Planck home became a social and cultural centre. Numerous well-known scientists, such as Albert Einstein, Otto Hahn and Lise Meitner were frequent visitors. The tradition of jointly performing music had already been established in the home of Helmholtz.
After several happy years the Planck family was struck by a series of disasters. In July 1909 Marie Planck died, possibly from tuberculosis. In March 1911 Planck married his second wife, Marga von Hoesslin (1882-1948); in December his third son Hermann was born.
During the First World War Planck's oldest son, Karl, was killed in action at Verdun, and Erwin was taken prisoner by the French in 1914. Grete died in 1917 while giving birth to her first child. Her sister died two years later the same way, after marrying Grete's widower. Both granddaughters survived and were named after their mothers. Planck endured these losses stoically.
In January 1945 his second son, Erwin, to whom he had been particularly close, was sentenced to death by the Volksgerichtshof because of his participation in the failed attempt to assassinate Hitler in July 1944. Erwin was hanged on 23 January 1945.
- Wives: Marie Merck (m. 1887), Marga von Hoesslin (m. 1910)
- Children: Karl (1888-1916), twins Emma (1889-1919) and Grete (1889-1917), Erwin (1893-1945), Hermann (b. 1911)
## Professor at Berlin University
In Berlin, Max Planck joined the local Physical Society. He later wrote about this time: "In those days I was essentially the only theoretical physicist there, whence things were not so easy for me, because I started mentioning entropy, but this was not quite fashionable, since it was regarded as a mathematical spook". Thanks to his initiative, the various local Physical Societies of Germany merged in 1898 to form the German Physical Society (Deutsche Physikalische Gesellschaft, DPG); from 1905 to 1909 Planck was the president.
Planck started a six-semester course of lectures on theoretical physics, "dry, somewhat impersonal" according to Lise Meitner, "using no notes, never making mistakes, never faltering; the best lecturer I ever heard" according to an English participant, James R. Partington, who continues: "There were always many standing around the room. As the lecture-room was well heated and rather close, some of the listeners would from time to time drop to the floor, but this did not disturb the lecture". Planck did not establish an actual "school", the number of his graduate students was only about 20, among them:
## Black-body radiation
In 1894 Planck turned his attention to the problem of black-body radiation. He had been commissioned by electric companies to create maximum light from lightbulbs with minimum energy. The problem had been stated by Kirchhoff in 1859: how does the intensity of the electromagnetic radiation emitted by a black body (a perfect absorber, also known as a cavity radiator) depend on the frequency of the radiation (e.g., the color of the light) and the temperature of the body? The question had been explored experimentally, but no theoretical treatment agreed with experimental values. Wilhelm Wien proposed Wien's law, which correctly predicted the behaviour at high frequencies, but failed at low frequencies. The Rayleigh-Jeans law, another approach to the problem, created what was later known as the "ultraviolet catastrophe", but contrary to many textbooks this was not a motivation for Planck.
Planck's first proposed solution to the problem in 1899 followed from what Planck called the "principle of elementary disorder", which allowed him to derive Wien's law from a number of assumptions about the entropy of an ideal oscillator, creating what was referred to as the Wien-Planck law. Soon it was found that experimental evidence did not confirm the new law at all, to Planck's frustration. Planck revised his approach, deriving the first version of the famous Planck black-body radiation law, which described the experimentally observed black-body spectrum well. It was first proposed in a meeting of the DPG on 19 October, 1900 and published in 1901. This first derivation did not include energy quantization, and did not use statistical mechanics, to which he held an aversion. In November 1900, Planck revised this first approach, relying on Boltzmann's statistical interpretation of the second law of thermodynamics as a way of gaining a more fundamental understanding of the principles behind his radiation law. As Planck was deeply suspicious of the philosophical and physical implications of such an interpretation of Boltzmann's approach, his recourse to them was, as he later put it, "an act of despair ... I was ready to sacrifice any of my previous convictions about physics."
The central assumption behind his new derivation, presented to the DPG on 14 December 1900, was the supposition that the electromagnetic energy could be emitted only in quantized form, in other words, the energy could only be a multiple of an elementary unit E = h \nu, where h is Planck's constant, also known as Planck's action quantum (introduced already in 1899), and \nu is the frequency of the radiation.
At first Planck considered that the quantisation was only as "a purely formal assumption ... actually I did not think much about it..."; nowadays this assumption, incompatible with classical physics, is regarded as the birth of quantum physics and the greatest intellectual accomplishment of Planck's career (Ludwig Boltzmann had been discussing in a theoretical paper in 1877 the possibility that the energy states of a physical system could be discrete). The full interpretation of the radical implications of Planck's work was advanced by Albert Einstein in 1905—for this reason, the philosopher and historian of science Thomas Kuhn argued that Einstein should be given credit for quantum theory more so than Planck, since Planck did not understand in a deep sense that he was "introducing the quantum" as a real physical entity. It was in recognition of his monumental accomplishment that Planck was awarded the Nobel Prize in Physics in 1918.
The discovery of Planck's constant enabled him to define a new universal set of physical units (such as the Planck length and the Planck mass), all based on fundamental physical constants.
Subsequently, Planck tried to grasp the meaning of the energy quanta, but to no avail. "My unavailing attempts to somehow reintegrate the action quantum into classical theory extended over several years and caused me much trouble." Even several years later, other physicists like Rayleigh, Jeans, and Lorentz set Planck's constant to zero in order to align with classical physics, but Planck knew well that this constant had a precise nonzero value. "I am unable to understand Jeans' stubbornness — he is an example of a theoretician as should never be existing, the same as Hegel was for philosophy. So much the worse for the facts, if they are wrong."
Max Born wrote about Planck: "He was by nature and by the tradition of his family conservative, averse to revolutionary novelties and skeptical towards speculations. But his belief in the imperative power of logical thinking based on facts was so strong that he did not hesitate to express a claim contradicting to all tradition, because he had convinced himself that no other resort was possible."
## Einstein and the theory of relativity
In 1905 the three epochal papers of the hitherto completely unknown Albert Einstein were published in the journal Annalen der Physik. Planck was among the few who immediately recognized the significance of the special theory of relativity. Thanks to his influence this theory was soon widely accepted in Germany. Planck also contributed considerably to extend the special theory of relativity.
Einstein's hypothesis of light quanta (photons), based on Philipp Lenard's 1902 discovery of the photoelectric effect, was initially rejected by Planck. He was unwilling to discard completely Maxwell's theory of electrodynamics. "The theory of light would be thrown back not by decades, but by centuries, into the age when Christian Huygens dared to fight against the mighty emission theory of Isaac Newton ..."
In 1910 Einstein pointed out the anomalous behavior of specific heat at low temperatures as another example of a phenomenon which defies explanation by classical physics. Planck and Nernst, seeking to clarify the increasing number of contradictions, organized the First Solvay Conference (Brussels 1911). At this meeting Einstein was able to convince Planck.
Meanwhile Planck had been appointed dean of Berlin University, whereby it was possible for him to call Einstein to Berlin and establish a new professorship for him (1914). Soon the two scientists became close friends and met frequently to play music together.
## World War and Weimar Republic
At the onset of the First World War Planck was not immune to the general excitement of the public: "... besides of much horrible also much unexpectedly great and beautiful: the swift solution of the most difficult issues of domestic policy through arrangement of all parties... the higher esteem for all that is brave and truthful..." Admittedly, he refrained from the extremes of nationalism. He voted successfully for a scientific paper from Italy receiving a prize from the Prussian Academy of Sciences in 1915 (Planck was one of its four permanent presidents), although at that time Italy was about to join the Allies. The infamous "Manifesto of the 93 intellectuals", a polemic pamphlet of war propaganda, was also signed by Planck, while Einstein retained a strictly pacifistic attitude which almost led to his imprisonment (he was saved by his Swiss citizenship). But already in 1915 Planck revoked (after several meetings with Dutch physicist Lorentz) parts of the Manifesto, and in 1916 he signed a declaration against German annexationism.
In the turbulent post-war years, Planck, now the highest authority of German physics, issued the slogan "persevere and continue working" to his colleagues. In October 1920 he and Fritz Haber established the Notgemeinschaft der Deutschen Wissenschaft (Emergency Organization of German Science), aimed at providing support for destitute scientific research. A considerable portion of the money they distributed was raised abroad. In this time Planck held leading positions also at Berlin University, the Prussian Academy of Sciences, the German Physical Society and the Kaiser-Wilhelm-Gesellschaft (which in 1948 became the Max-Planck-Gesellschaft). Under such conditions he was hardly able to conduct research.
He became a member of the Deutsche Volks-Partei (German People's Party), the party of Nobel Peace Prize laureate Gustav Stresemann, which aspired to liberal aims for domestic policy and rather revisionistic aims for international politics. He disagreed with the introduction of universal suffrage and later expressed the view that the Nazi dictatorship resulted from "the ascent of the rule of the crowds".
## Quantum mechanics
At the end of the 1920s Bohr, Heisenberg and Pauli had worked out the Copenhagen interpretation of quantum mechanics, but it was rejected by Planck, as well as Schrödinger, Laue, and Einstein. Planck expected that wave mechanics would soon render quantum theory—his own child—unnecessary. This was not to be the case, however. Further work only cemented quantum theory, even against his and Einstein's philosophical revulsions. Planck experienced the truth of his own earlier observation from his struggle with the older views in his younger years: "A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die, and a new generation grows up that is familiar with it."
## Nazi dictatorship and Second World War
When the Nazis seized power in 1933, Planck was 74. He witnessed many Jewish friends and colleagues expelled from their positions and humiliated, and hundreds of scientists emigrated from Germany. Again he tried the "persevere and continue working" slogan and asked scientists who were considering emigration to remain in Germany.
He hoped the crisis would abate soon and the political situation would improve. There was also a deeper argument against emigration. Emigrating German non-Jewish scientists would need to look for academic positions abroad, but these positions better served Jewish scientists, who had no chance of continuing to work in Germany.
Hahn asked Planck to gather well-known German professors in order to issue a public proclamation against the treatment of Jewish professors, but Planck replied, "If you are able to gather today 30 such gentlemen, then tomorrow 150 others will come and speak against it, because they are eager to take over the positions of the others." Under Planck's leadership, the Kaiser-Wilhelm-Gesellschaft (KWG) avoided open conflict with the Nazi regime, except concerning Fritz Haber. Planck tried to discuss the issue with Adolf Hitler but was unsuccessful. In the following year, 1934, Haber died in exile.
One year later, Planck, having been the president of the KWG since 1930, organized in a somewhat provocative style an official commemorative meeting for Haber. He also succeeded in secretly enabling a number of Jewish scientists to continue working in institutes of the KWG for several years. In 1936, his term as president of the KWG ended, and the Nazi government pressured him to refrain from seeking another term.
As the political climate in Germany gradually became more hostile, Johannes Stark, prominent exponent of Deutsche Physik ("German Physics", also called "Aryan Physics") attacked Planck, Sommerfeld and Heisenberg for continuing to teach the theories of Einstein, calling them "white Jews." The "Hauptamt Wissenschaft" (Nazi government office for science) started an investigation of Planck's ancestry, but all they could find out was that he was "1/16 Jewish."
In 1938 Planck celebrated his 80th birthday. The DPG held a celebration, during which the Max-Planck medal (founded as the highest medal by the DPG in 1928) was awarded to French physicist Louis de Broglie. At the end of 1938 the Prussian Academy lost its remaining independence and was taken over by Nazis (Gleichschaltung). Planck protested by resigning his presidency. He continued to travel frequently, giving numerous public talks, such as his famous talk on Religion and Science, and five years later he was sufficiently fit to climb 3,000-meter peaks in the Alps.
During the Second World War, the increasing number of Allied bombing campaigns against Berlin forced Planck and his wife to leave the city temporarily and live in the countryside. In 1942 he wrote: "In me an ardent desire has grown to persevere this crisis and live long enough to be able to witness the turning point, the beginning of a new rise." In February 1944 his home in Berlin was completely destroyed by an air raid, annihilating all his scientific records and correspondence. Finally, he got into a dangerous situation in his rural retreat due to the rapid advance of the Allied armies from both sides. After the end of the war he was brought to a relative in Göttingen.
Planck endured many personal tragedies after the age of 50. In 1909, his first wife died after 22 years of marriage, leaving him with two sons and twin daughters. Planck's oldest son, Karl, was killed in action in 1916. His daughter Margarete died in childbirth in 1917, and another daughter, Emma, married her late sister's husband and then also died in childbirth, in 1919. During World War II, Planck's house in Berlin was completely destroyed by bombs in 1944 and his youngest son, Erwin, was implicated in the attempt made on Hitler's life in the July 20 plot. Consequently, Erwin died a horrible death at the hands of the Gestapo in 1945. Erwin's death destroyed Planck's will to live. By the end of the war, Planck, his second wife and his son by her, moved to Göttingen where he died on October 4, 1947.
# Religious view
Max Planck was a devoted and persistent adherent of Christianity from early life to death, but he was very tolerant towards alternate views and religions, and so was discontented with the church organizations' demands for unquestioning belief.
The God in which Max Planck believed was an almighty, all-knowing, benevolent but unintelligible God that permeated everything, manifest by symbols, including physical laws. His view may have been motivated by an opposition like Einstein's and Schrödinger's against the positivist, statistical subjective quantum mechanics universe of Bohr, Heisenberg and others. Planck was interested in truth and Universe beyond observation, and objected to atheism as an obsession with symbols.
Planck regarded the scientist as a man of imagination and faith, "faith" interpreted as being similar to "having a working hypothesis". For example the causality principle isn't true or false, it is an act of faith. Thereby Planck may have indicated a view that points toward Imre Lakatos' research programs process descriptions, where falsification is mostly tolerable, in faith of its future removal.
# Honours and awards
- "Pour le Mérite" for Science and Arts 1915 (in 1930 he became chancellor of this order)
- Nobel Prize in Physics 1918 (awarded 1919)
- Lorentz Medal 1927
- Adlerschild des Deutschen Reiches (1928), an award from the German Reich President
- Max Planck medal (1929, together with Einstein)
- Copley Medal (1929)
- Planck received honorary doctorates from the universities of Frankfurt, Munich (TH), Rostock, Berlin (TH), Graz, Athens, Cambridge, London, and Glasgow.
- The asteroid 1069 was named "Stella Planckia" by the International Astronomical Union (1938) | Max Planck
Template:Infobox Scientist
Max Karl Ernst Ludwig Planck [1] (April 23 1858 – October 4 1947) was a German physicist. He is considered to be the founder of quantum theory, and one of the most important physicists of the twentieth century.
# Biography
Planck came from a traditional, intellectual family. His paternal great-grandfather and grandfather were both theology professors in Göttingen, his father was a law professor in Kiel and Munich, and his paternal uncle was a judge.
Planck was born in Kiel, Holstein, to Johann Julius Wilhelm Planck and his second wife, Emma Patzig. He was the sixth child in the family, though two of his siblings were from his father's first marriage. Among his earliest memories was the marching of Prussian and Austrian troops into Kiel during the Danish-Prussian war of 1864. In 1867 the family moved to Munich, and Planck enrolled in the Maximilians gymnasium school, where he came under the tutelage of Hermann Müller, a mathematician who took an interest in the youth, and taught him astronomy and mechanics as well as mathematics. It was from Müller that Planck first learned the principle of conservation of energy. Planck graduated early, at age 17.[2] This is how Planck first came in contact with the field of physics.
Planck was gifted when it came to music. He took singing lessons and played piano, organ and cello, and composed songs and operas. However, instead of music he chose to study physics.
The Munich physics professor Philipp von Jolly advised Planck against going into physics, saying, "in this field, almost everything is already discovered, and all that remains is to fill a few holes." Planck replied that he did not wish to discover new things, only to understand the known fundamentals of the field, and began his studies in 1874 at the University of Munich. Under Jolly's supervision, Planck performed the only experiments of his scientific career, studying the diffusion of hydrogen through heated platinum, but transferred to theoretical physics.
In 1877 he went to Berlin for a year of study with physicists Hermann von Helmholtz and Gustav Kirchhoff and the mathematician Karl Weierstrass. He wrote that Helmholtz was never quite prepared, spoke slowly, miscalculated endlessly, and bored his listeners, while Kirchhoff spoke in carefully prepared lectures which were dry and monotonous. He soon became close friends with Helmholtz. While there he undertook a program of mostly self-study of Clausius's writings, which led him to choose heat theory as his field.
In October 1878 Planck passed his qualifying exams and in February 1879 defended his dissertation, Über den zweiten Hauptsatz der mechanischen Wärmetheorie (On the second fundamental theorem of the mechanical theory of heat). He briefly taught mathematics and physics at his former school in Munich.
In June 1880 he presented his habilitation thesis, Gleichgewichtszustände isotroper Körper in verschiedenen Temperaturen (Equilibrium states of isotropic bodies at different temperatures).
## Academic career
With the completion of his habilitation thesis, Planck became an unpaid private lecturer in Munich, waiting until he was offered an academic position. Although he was initially ignored by the academic community, he furthered his work on the field of heat theory and discovered one after another the same thermodynamical formalism as Gibbs without realizing it. Clausius's ideas on entropy occupied a central role in his work.
In April 1885 the University of Kiel appointed Planck as associate professor of theoretical physics. Further work on entropy and its treatment, especially as applied in physical chemistry, followed. He proposed a thermodynamic basis for Arrhenius's theory of electrolytic dissociation.
Within four years he was named the successor to Kirchhoff's position at the University of Berlin — presumably thanks to Helmholtz's intercession — and by 1892 became a full professor. In 1907 Planck was offered Boltzmann's position in Vienna, but turned it down to stay in Berlin. During 1909 he was the Ernest Kempton Adams Lecturer in Theoretical Physics at Columbia University in New York City. He retired from Berlin on 10 January, 1926, and was succeeded by Erwin Schrödinger.
## Family
In March 1887 Planck married Marie Merck (1861-1909), sister of a school fellow, and moved with her into a sublet apartment in Kiel. They had four children: Karl (1888-1916), the twins Emma (1889-1919) and Grete (1889-1917), and Erwin (1893-1945).
After the appointment to Berlin, the Planck family lived in a villa in Berlin-Grunewald, Wangenheimstraße 21. Several other professors of Berlin University lived nearby, among them theologian Adolf von Harnack, who became a close friend of Planck. Soon the Planck home became a social and cultural centre. Numerous well-known scientists, such as Albert Einstein, Otto Hahn and Lise Meitner were frequent visitors. The tradition of jointly performing music had already been established in the home of Helmholtz.
After several happy years the Planck family was struck by a series of disasters. In July 1909 Marie Planck died, possibly from tuberculosis. In March 1911 Planck married his second wife, Marga von Hoesslin (1882-1948); in December his third son Hermann was born.
During the First World War Planck's oldest son, Karl, was killed in action at Verdun, and Erwin was taken prisoner by the French in 1914. Grete died in 1917 while giving birth to her first child. Her sister died two years later the same way, after marrying Grete's widower. Both granddaughters survived and were named after their mothers. Planck endured these losses stoically.
In January 1945 his second son, Erwin, to whom he had been particularly close, was sentenced to death by the Volksgerichtshof because of his participation in the failed attempt to assassinate Hitler in July 1944. Erwin was hanged on 23 January 1945.
- Wives: Marie Merck (m. 1887), Marga von Hoesslin (m. 1910)
- Children: Karl (1888-1916), twins Emma (1889-1919) and Grete (1889-1917), Erwin (1893-1945), Hermann (b. 1911)
## Professor at Berlin University
In Berlin, Max Planck joined the local Physical Society. He later wrote about this time: "In those days I was essentially the only theoretical physicist there, whence things were not so easy for me, because I started mentioning entropy, but this was not quite fashionable, since it was regarded as a mathematical spook".[citation needed] Thanks to his initiative, the various local Physical Societies of Germany merged in 1898 to form the German Physical Society (Deutsche Physikalische Gesellschaft, DPG); from 1905 to 1909 Planck was the president.
Planck started a six-semester course of lectures on theoretical physics, "dry, somewhat impersonal" according to Lise Meitner, "using no notes, never making mistakes, never faltering; the best lecturer I ever heard" according to an English participant, James R. Partington, who continues: "There were always many standing around the room. As the lecture-room was well heated and rather close, some of the listeners would from time to time drop to the floor, but this did not disturb the lecture". Planck did not establish an actual "school", the number of his graduate students was only about 20, among them:
## Black-body radiation
In 1894 Planck turned his attention to the problem of black-body radiation. He had been commissioned by electric companies to create maximum light from lightbulbs with minimum energy. The problem had been stated by Kirchhoff in 1859: how does the intensity of the electromagnetic radiation emitted by a black body (a perfect absorber, also known as a cavity radiator) depend on the frequency of the radiation (e.g., the color of the light) and the temperature of the body? The question had been explored experimentally, but no theoretical treatment agreed with experimental values. Wilhelm Wien proposed Wien's law, which correctly predicted the behaviour at high frequencies, but failed at low frequencies. The Rayleigh-Jeans law, another approach to the problem, created what was later known as the "ultraviolet catastrophe", but contrary to many textbooks this was not a motivation for Planck.[3]
Planck's first proposed solution to the problem in 1899 followed from what Planck called the "principle of elementary disorder", which allowed him to derive Wien's law from a number of assumptions about the entropy of an ideal oscillator, creating what was referred to as the Wien-Planck law. Soon it was found that experimental evidence did not confirm the new law at all, to Planck's frustration. Planck revised his approach, deriving the first version of the famous Planck black-body radiation law, which described the experimentally observed black-body spectrum well. It was first proposed in a meeting of the DPG on 19 October, 1900 and published in 1901. This first derivation did not include energy quantization, and did not use statistical mechanics, to which he held an aversion. In November 1900, Planck revised this first approach, relying on Boltzmann's statistical interpretation of the second law of thermodynamics as a way of gaining a more fundamental understanding of the principles behind his radiation law. As Planck was deeply suspicious of the philosophical and physical implications of such an interpretation of Boltzmann's approach, his recourse to them was, as he later put it, "an act of despair ... I was ready to sacrifice any of my previous convictions about physics."[3]
The central assumption behind his new derivation, presented to the DPG on 14 December 1900, was the supposition that the electromagnetic energy could be emitted only in quantized form, in other words, the energy could only be a multiple of an elementary unit <math>E = h \nu</math>, where <math>h</math> is Planck's constant, also known as Planck's action quantum (introduced already in 1899), and <math>\nu</math> is the frequency of the radiation.
At first Planck considered that the quantisation was only as "a purely formal assumption ... actually I did not think much about it..."; nowadays this assumption, incompatible with classical physics, is regarded as the birth of quantum physics and the greatest intellectual accomplishment of Planck's career (Ludwig Boltzmann had been discussing in a theoretical paper in 1877 the possibility that the energy states of a physical system could be discrete). The full interpretation of the radical implications of Planck's work was advanced by Albert Einstein in 1905—for this reason, the philosopher and historian of science Thomas Kuhn argued that Einstein should be given credit for quantum theory more so than Planck, since Planck did not understand in a deep sense that he was "introducing the quantum" as a real physical entity.[4] It was in recognition of his monumental accomplishment that Planck was awarded the Nobel Prize in Physics in 1918.
The discovery of Planck's constant enabled him to define a new universal set of physical units (such as the Planck length and the Planck mass), all based on fundamental physical constants.
Subsequently, Planck tried to grasp the meaning of the energy quanta, but to no avail. "My unavailing attempts to somehow reintegrate the action quantum into classical theory extended over several years and caused me much trouble." Even several years later, other physicists like Rayleigh, Jeans, and Lorentz set Planck's constant to zero in order to align with classical physics, but Planck knew well that this constant had a precise nonzero value. "I am unable to understand Jeans' stubbornness — he is an example of a theoretician as should never be existing, the same as Hegel was for philosophy. So much the worse for the facts, if they are wrong."[citation needed]
Max Born wrote about Planck: "He was by nature and by the tradition of his family conservative, averse to revolutionary novelties and skeptical towards speculations. But his belief in the imperative power of logical thinking based on facts was so strong that he did not hesitate to express a claim contradicting to all tradition, because he had convinced himself that no other resort was possible."[citation needed]
## Einstein and the theory of relativity
In 1905 the three epochal papers of the hitherto completely unknown Albert Einstein were published in the journal Annalen der Physik. Planck was among the few who immediately recognized the significance of the special theory of relativity. Thanks to his influence this theory was soon widely accepted in Germany. Planck also contributed considerably to extend the special theory of relativity.
Einstein's hypothesis of light quanta (photons), based on Philipp Lenard's 1902 discovery of the photoelectric effect, was initially rejected by Planck. He was unwilling to discard completely Maxwell's theory of electrodynamics. "The theory of light would be thrown back not by decades, but by centuries, into the age when Christian Huygens dared to fight against the mighty emission theory of Isaac Newton ..."
In 1910 Einstein pointed out the anomalous behavior of specific heat at low temperatures as another example of a phenomenon which defies explanation by classical physics. Planck and Nernst, seeking to clarify the increasing number of contradictions, organized the First Solvay Conference (Brussels 1911). At this meeting Einstein was able to convince Planck.
Meanwhile Planck had been appointed dean of Berlin University, whereby it was possible for him to call Einstein to Berlin and establish a new professorship for him (1914). Soon the two scientists became close friends and met frequently to play music together.
## World War and Weimar Republic
At the onset of the First World War Planck was not immune to the general excitement of the public: "... besides of much horrible also much unexpectedly great and beautiful: the swift solution of the most difficult issues of domestic policy through arrangement of all parties... the higher esteem for all that is brave and truthful..." Admittedly, he refrained from the extremes of nationalism. He voted successfully for a scientific paper from Italy receiving a prize from the Prussian Academy of Sciences in 1915 (Planck was one of its four permanent presidents), although at that time Italy was about to join the Allies. The infamous "Manifesto of the 93 intellectuals", a polemic pamphlet of war propaganda, was also signed by Planck, while Einstein retained a strictly pacifistic attitude which almost led to his imprisonment (he was saved by his Swiss citizenship). But already in 1915 Planck revoked (after several meetings with Dutch physicist Lorentz) parts of the Manifesto, and in 1916 he signed a declaration against German annexationism.
In the turbulent post-war years, Planck, now the highest authority of German physics, issued the slogan "persevere and continue working" to his colleagues. In October 1920 he and Fritz Haber established the Notgemeinschaft der Deutschen Wissenschaft (Emergency Organization of German Science), aimed at providing support for destitute scientific research. A considerable portion of the money they distributed was raised abroad. In this time Planck held leading positions also at Berlin University, the Prussian Academy of Sciences, the German Physical Society and the Kaiser-Wilhelm-Gesellschaft (which in 1948 became the Max-Planck-Gesellschaft). Under such conditions he was hardly able to conduct research.
He became a member of the Deutsche Volks-Partei (German People's Party), the party of Nobel Peace Prize laureate Gustav Stresemann, which aspired to liberal aims for domestic policy and rather revisionistic aims for international politics. He disagreed with the introduction of universal suffrage and later expressed the view that the Nazi dictatorship resulted from "the ascent of the rule of the crowds".
## Quantum mechanics
At the end of the 1920s Bohr, Heisenberg and Pauli had worked out the Copenhagen interpretation of quantum mechanics, but it was rejected by Planck, as well as Schrödinger, Laue, and Einstein. Planck expected that wave mechanics would soon render quantum theory—his own child—unnecessary. This was not to be the case, however. Further work only cemented quantum theory, even against his and Einstein's philosophical revulsions. Planck experienced the truth of his own earlier observation from his struggle with the older views in his younger years: "A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die, and a new generation grows up that is familiar with it."[5]
## Nazi dictatorship and Second World War
When the Nazis seized power in 1933, Planck was 74. He witnessed many Jewish friends and colleagues expelled from their positions and humiliated, and hundreds of scientists emigrated from Germany. Again he tried the "persevere and continue working" slogan and asked scientists who were considering emigration to remain in Germany.
He hoped the crisis would abate soon and the political situation would improve. There was also a deeper argument against emigration. Emigrating German non-Jewish scientists would need to look for academic positions abroad, but these positions better served Jewish scientists, who had no chance of continuing to work in Germany.
Hahn asked Planck to gather well-known German professors in order to issue a public proclamation against the treatment of Jewish professors, but Planck replied, "If you are able to gather today 30 such gentlemen, then tomorrow 150 others will come and speak against it, because they are eager to take over the positions of the others."[6] Under Planck's leadership, the Kaiser-Wilhelm-Gesellschaft (KWG) avoided open conflict with the Nazi regime, except concerning Fritz Haber. Planck tried to discuss the issue with Adolf Hitler but was unsuccessful. In the following year, 1934, Haber died in exile.
One year later, Planck, having been the president of the KWG since 1930, organized in a somewhat provocative style an official commemorative meeting for Haber. He also succeeded in secretly enabling a number of Jewish scientists to continue working in institutes of the KWG for several years. In 1936, his term as president of the KWG ended, and the Nazi government pressured him to refrain from seeking another term.
As the political climate in Germany gradually became more hostile, Johannes Stark, prominent exponent of Deutsche Physik ("German Physics", also called "Aryan Physics") attacked Planck, Sommerfeld and Heisenberg for continuing to teach the theories of Einstein, calling them "white Jews." The "Hauptamt Wissenschaft" (Nazi government office for science) started an investigation of Planck's ancestry, but all they could find out was that he was "1/16 Jewish."
In 1938 Planck celebrated his 80th birthday. The DPG held a celebration, during which the Max-Planck medal (founded as the highest medal by the DPG in 1928) was awarded to French physicist Louis de Broglie. At the end of 1938 the Prussian Academy lost its remaining independence and was taken over by Nazis (Gleichschaltung). Planck protested by resigning his presidency. He continued to travel frequently, giving numerous public talks, such as his famous talk on Religion and Science, and five years later he was sufficiently fit to climb 3,000-meter peaks in the Alps.
During the Second World War, the increasing number of Allied bombing campaigns against Berlin forced Planck and his wife to leave the city temporarily and live in the countryside. In 1942 he wrote: "In me an ardent desire has grown to persevere this crisis and live long enough to be able to witness the turning point, the beginning of a new rise." In February 1944 his home in Berlin was completely destroyed by an air raid, annihilating all his scientific records and correspondence. Finally, he got into a dangerous situation in his rural retreat due to the rapid advance of the Allied armies from both sides. After the end of the war he was brought to a relative in Göttingen.
Planck endured many personal tragedies after the age of 50. In 1909, his first wife died after 22 years of marriage, leaving him with two sons and twin daughters. Planck's oldest son, Karl, was killed in action in 1916. His daughter Margarete died in childbirth in 1917, and another daughter, Emma, married her late sister's husband and then also died in childbirth, in 1919. During World War II, Planck's house in Berlin was completely destroyed by bombs in 1944 and his youngest son, Erwin, was implicated in the attempt made on Hitler's life in the July 20 plot. Consequently, Erwin died a horrible death at the hands of the Gestapo in 1945. Erwin's death destroyed Planck's will to live[citation needed]. By the end of the war, Planck, his second wife and his son by her, moved to Göttingen where he died on October 4, 1947.
# Religious view
Max Planck was a devoted and persistent adherent of Christianity from early life to death, but he was very tolerant towards alternate views and religions, and so was discontented with the church organizations' demands for unquestioning belief.
The God in which Max Planck believed was an almighty, all-knowing, benevolent but unintelligible God that permeated everything, manifest by symbols, including physical laws. His view may have been motivated by an opposition like Einstein's and Schrödinger's against the positivist, statistical subjective quantum mechanics universe of Bohr, Heisenberg and others. Planck was interested in truth and Universe beyond observation, and objected to atheism as an obsession with symbols.
Planck regarded the scientist as a man of imagination and faith, "faith" interpreted as being similar to "having a working hypothesis". For example the causality principle isn't true or false, it is an act of faith. Thereby Planck may have indicated a view that points toward Imre Lakatos' research programs process descriptions, where falsification is mostly tolerable, in faith of its future removal. [7]
# Honours and awards
- "Pour le Mérite" for Science and Arts 1915 (in 1930 he became chancellor of this order)
- Nobel Prize in Physics 1918 (awarded 1919)
- Lorentz Medal 1927
- Adlerschild des Deutschen Reiches (1928), an award from the German Reich President
- Max Planck medal (1929, together with Einstein)
- Copley Medal (1929)
- Planck received honorary doctorates from the universities of Frankfurt, Munich (TH), Rostock, Berlin (TH), Graz, Athens, Cambridge, London, and Glasgow.
- The asteroid 1069 was named "Stella Planckia" by the International Astronomical Union (1938) | https://www.wikidoc.org/index.php/Max_Planck | |
e701ba769625ba4e92e35f5b2dfe5f23fd5fcd16 | wikidoc | Pirbuterol | Pirbuterol
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# Overview
Pirbuterol is a Beta-2 Adrenergic Agonist that is FDA approved for the treatment of of bronchospasm in patients 12 years of age and older with reversible bronchospasm including asthma.. Common adverse reactions include nervousness, tremor.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- MAXAIR Inhaler is indicated for the prevention and reversal of bronchospasm in patients 12 years of age and older with reversible bronchospasm including asthma. It may be used with or without concurrent theophylline and/or corticosteroid therapy.
### Dosage
- The usual dose for adults and children 12 years and older is two inhalations (400 mcg) repeated every 4-6 hours. One inhalation (200 mcg) repeated every 4-6 hours may be sufficient for some patients.
- A total daily dose of 12 inhalations should not be exceeded. If a previously effective dosage regimen fails to provide the usual relief, medical advice should be sought immediately as this is often a sign of seriously worsening asthma which would require reassessment of therapy.
- As with all aerosol medications, it is recommended to prime (test) MAXAIR Inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks. Prime by releasing three “test sprays” into the air away from yourself and other people.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pirbuterol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pirbuterol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Dosage
- The usual dose for adults and children 12 years and older is two inhalations (400 mcg) repeated every 4-6 hours. One inhalation (200 mcg) repeated every 4-6 hours may be sufficient for some patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pirbuterol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pirbuterol in pediatric patients.
# Contraindications
- MAXAIR Inhaler is contraindicated in patients with a history of hypersensitivity to pirbuterol or any of its ingredients.
# Warnings
- MAXAIR Inhaler, like other inhaled beta-adrenergic agonists, can produce a clinically significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of MAXAIR Inhaler at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, MAXAIR Inhaler, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
- MAXAIR Inhaler can produce paradoxical bronchospasm, which can be life threatening. If paradoxical bronchospasm occurs, MAXAIR Inhaler should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister or vial.
- The use of beta adrenergic agonist bronchodilators alone may not be adequate to control asthma in many patients. Early consideration should be given to adding anti-inflammatory agents, e.g., corticosteroids.
- Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient needs more doses of MAXAIR Inhaler than usual, this may be a marker of destabilization of asthma and requires reevaluation of the patient and the treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids.
### Precautions
- Since pirbuterol is a sympathomimetic amine, it should be used with caution in patients with cardiovascular disorders, including ischemic heart disease, hypertension, or cardiac arrhythmias, in patients with hyperthyroidism or diabetes mellitus, and in patients who are unusually responsive to sympathomimetic amines or who have convulsive disorders. Significant changes in systolic and diastolic blood pressure could be expected to occur in some patients after use of any beta adrenergic aerosol bronchodilator.
- Beta adrenergic agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation.
# Adverse Reactions
## Clinical Trials Experience
- The following rates of adverse reactions to pirbuterol are based on single- and multiple-dose clinical trials involving 761 patients, 400 of whom received multiple doses (mean duration of treatment was 2.5 months and maximum was 19 months).
- The following were the adverse reactions reported more frequently than 1 in 100 patients:
- nervousness (6.9%), tremor (6.0%), headache (2.0%), dizziness (1.2%).
- palpitations (1.7%), tachycardia (1.2%).
- cough (1.2%).
- nausea (1.7%).
- The following adverse reactions occurred less frequently than 1 in 100 patients and there may be a causal relationship with pirbuterol:
- depression, anxiety, confusion, insomnia, weakness, hyperkinesia, syncope.
- hypotension, skipped beats, chest pain.
- dry mouth, glossitis, abdominal pain/cramps, anorexia, diarrhea, stomatitis, nausea and vomiting.
- smell/taste changes, sore throat.
- rash, pruritus.
- numbness in extremities, alopecia, bruising, fatigue, edema, weight gain, flushing.
- Other adverse reactions were reported with a frequency of less than 1 in 100 patients but a causal relationship between pirbuterol and the reaction could not be determined: migraine, productive cough, wheezing, and dermatitis.
- The following rates of adverse reactions during three-month controlled clinical trials involving 310 patients are noted. The table does not include mild reactions.
- Electrocardiograms, obtained during a randomized, double-blind, cross-over study in 57 patients, showed no observations or findings considered clinically significant, or related to drug administration. Most electrocardiographic observations, obtained during a randomized, double blind, cross-over study in 40 patients, were judged not clinically significant or related to drug administration. One patient was noted to have some changes on the one hour postdose electrocardiogram consisting of ST and T wave abnormality suggesting possible inferior ischemia. This abnormality was not observed on the predose or the six hours postdose ECG. A treadmill was subsequently performed and all the findings were normal.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Pirbuterol in the drug label.
# Drug Interactions
- Other short-acting beta adrenergic aerosol bronchodilators should not be used concomitantly with MAXAIR Inhaler because they may have additive effects.
- Pirbuterol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of pirbuterol on the vascular system may be potentiated.
- Beta adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists, such as MAXAIR Inhaler, but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with beta blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta blockers could be considered, although they should be administered with caution.
- The ECG changes and/or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non-potassium sparing diuretics.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Pirbuterol was not teratogenic in rats administered oral doses of 30, 100, and 300 mg/kg (approximately 100, 340, and 1000 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis). Pirbuterol was not teratogenic in rabbits administered oral doses of 30 and 100 mg/kg (approximately 200 and 680 times the maximum recommended inhalation dose for adults on a mg/m2 basis). However, pirbuterol at an oral dose of 300 mg/kg (approximately 2000 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis) caused abortions and fetal death.
- There are no adequate and well-controlled studies in pregnant women. Pirbuterol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pirbuterol in women who are pregnant.
### Labor and Delivery
- Because of the potential for beta-agonist interference with uterine contractility, use of MAXAIR Inhaler for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.
### Nursing Mothers
- It is not known whether pirbuterol is excreted in human milk. Therefore, MAXAIR Inhaler should be used during nursing only if the potential benefit justifies the possible risk to the newborn.
### Pediatric Use
- MAXAIR Inhaler is not recommended for patients under the age of 12 years because of insufficient clinical data to establish safety and effectiveness.
### Geriatic Use
There is no FDA guidance on the use of Pirbuterol with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Pirbuterol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pirbuterol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pirbuterol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pirbuterol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pirbuterol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pirbuterol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Inhalation
### Monitoring
There is limited information regarding Monitoring of Pirbuterol in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Pirbuterol in the drug label.
# Overdosage
- The expected symptoms with overdosage are those of excessive beta-stimulation and/or any of the symptoms listed under ADVERSE REACTIONS, e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats per minute, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. Hypokalemia may also occur. As with all sympathomimetic aerosol medication, cardiac arrest and even death may be associated with abuse of MAXAIR Inhaler.
- Treatment consists of discontinuation of pirbuterol together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage.
- The oral median lethal dose of pirbuterol dihydrochloride in mice and rats is greater than 2000 mg/kg (approximately 3400 and 6800 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis).
# Pharmacology
## Mechanism of Action
- The pharmacologic effects of beta adrenergic agonist drugs, including pirbuterol, are at least in part attributable to stimulation through beta adrenergic receptors of intracellular adenyl cyclase, the enzyme which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (c-AMP). Increased c-AMP levels are associated with relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.
- In vitro studies and in vivo pharmacologic studies have demonstrated that pirbuterol has a preferential effect on beta-2 adrenergic receptors compared with isoproterenol. While it is recognized that beta-2 adrenergic receptors are the predominant receptors in bronchial smooth muscle, data indicate that there is a population of beta-2 receptors in the human heart, existing in a concentration between 10-50%. The precise function of these receptors has not been established
- Bronchodilator activity of pirbuterol was manifested clinically by an improvement in various pulmonary function parameters (FEV1, MMF, PEFR, airway resistance and conductance ).
## Structure
- The active component of MAXAIR Inhaler (pirbuterol acetate) is (R,S)a6-{ methyl}-3-hydroxy-2,6-pyridine-dimethanol monoacetate salt, a beta-2 adrenergic bronchodilator, having the following chemical structure:
- Pirbuterol acetate is a white, crystalline racemic mixture of two optically active isomers. It is a powder, freely soluble in water, with a molecular weight of 300.3 and empirical formula of C12H20N2O3C2H4O2.
- MAXAIR Inhaler is a pressurized metered-dose aerosol unit for oral inhalation. It provides a fine-particle suspension of pirbuterol acetate in the propellant mixture of trichloromonofluoromethane and dichlorodifluoromethane, with sorbitan trioleate. Each actuation delivers 256 mcg of pirbuterol (as pirbuterol acetate) from the valve and 200 mcg of pirbuterol (as pirbuterol acetate) from the mouthpiece. Each canister provides 300 inhalations.
- As with all aerosol medications, it is recommended to prime (test) MAXAIR Inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks. Prime by releasing three “test sprays” into the air away from yourself and other people.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Pirbuterol in the drug label.
## Pharmacokinetics
- As expected by extrapolation from oral data, systemic blood levels of pirbuterol are below the limit of assay sensitivity (2-5 ng/ml) following inhalation of doses up to 800 mcg (twice the maximum recommended dose). A mean of 51% of the dose is recovered in urine as pirbuterol plus its sulfate conjugate following administration by aerosol. Pirbuterol is not metabolized by catechol-O-methyltransferase. The percent of administered dose recovered as pirbuterol plus its sulfate conjugate does not change significantly over the dose range of 400 mcg to 800 mcg and is not significantly different from that after oral administration of pirbuterol. The plasma half-life measured after oral administration is about two hours.
## Nonclinical Toxicology
- In a 2-year study in Sprague-Dawley rats, pirbuterol hydrochloride administered at dietary doses of 1.0, 3.0, and 10 mg/kg (approximately 3, 10, and 35 times the maximum recommended daily inhalation dose for adults and children on a mg/m2 basis) showed no evidence of carcinogenicity. In an 18-month study in mice at dietary doses of 1.0, 3.0, and 10 mg/kg (approximately 2, 5, and 15 times the maximum recommended daily inhalation dose for adults and children on a mg/m2 basis) no evidence of tumorigenicity was seen. Reproduction studies in rats administered pirbuterol hydrochloride at oral doses of 1, 3, and 10 mg/kg (approximately 3, 10, and 35 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis) revealed no evidence of impaired fertility.
- Pirbuterol dihydrochloride showed no evidence of mutagenicity in in vitro assays and host-mediated microbial (Ames) assays for point mutations and in vivo tests for somatic or germ cell effects following acute and subchronic treatment in mice (cytogenicity assays).
# Clinical Studies
- In controlled, double-blind, single-dose clinical trials, the onset of improvement in pulmonary function occurred within 5 minutes in most patients as determined by forced expiratory volume in one second (FEV1). FEV1 and MMF measurements also showed that maximum improvement in pulmonary function generally occurred 30-60 minutes following one (1) or two (2) inhalations of pirbuterol (200-400 mcg). The duration of action of pirbuterol is maintained for 5 hours (the time at which the last observations were made) in a substantial number of patients, based on a 15% or greater increase in FEV1. In controlled repetitive-dose studies of 12 weeks' duration, 74% of 156 patients on pirbuterol and 62% of 141 patients on metaproterenol showed a clinically significant improvement based on a 15% or greater increase in FEV1 on at least half of the days. Onset and duration were equivalent to that seen in single-dose studies. Continued effectiveness was demonstrated over the 12-week period in the majority (94%) of responding patients; however, chronic dosing was associated with the development of tachyphylaxis (tolerance) to the bronchodilator effect in some patients in both treatment groups.
- A placebo-controlled, double-blind, single-dose study (24 patients per treatment group), utilizing continuous Holter monitoring for 5 hours after drug administration, showed no significant difference in ectopic activity between the placebo control group and pirbuterol at the recommended dose (200-400 mcg), and twice the recommended dose (800 mcg). As with other inhaled beta adrenergic agonists, supraventricular and ventricular ectopic beats have been seen with pirbuterol (see WARNINGS).
- Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines were administered concurrently. The clinical significance of these findings when applied to humans is unknown.
# How Supplied
- MAXAIR Inhaler, box of one, is supplied in a pressurized aluminum canister with a light blue plastic actuator and attached white mouthpiece. Each actuation delivers pirbuterol acetate equivalent to 256 mcg of pirbuterol (as pirbuterol acetate) from the valve and 200 mcg of pirbuterol (as pirbuterol acetate) from the mouthpiece.
- Net content weight 25.6 g, 300 metered inhalations (NDC 0089-0790-21).
- The correct amount of medication in each canister cannot be assured after 300 actuations even though the canister is not completely empty. The canister should be discarded when the labeled number of actuations has been used.
- Note: The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFC's).
- WARNING: Contains trichloromonofluoromethane and dichlorodifluoromethane, substances which harm public health and environment by destroying ozone in the upper atmosphere.
- A notice similar to the above WARNING has been placed in the “PATIENT'S INSTRUCTIONS FOR USE” portion of this package insert under the Environmental Protection - Agency's (EPA's) regulations. The patient's warning states that the patient should consult his or her physician if there are questions about alternatives.
Rx only
## Storage
- Store between 15° and 30°C (59° to 86°F). Failure to use this product within this temperature range may result in improper dosing. For optimal results, the canister should be at room temperature before use. Shake well before using.
- The contents of MAXAIR Inhaler are under pressure. Do not puncture. Do not use or store near heat or open flame. Exposure to temperature above 120°F may cause bursting. Never throw container into fire or incinerator. Keep out of reach of children. Avoid spraying in eyes.
- The light blue plastic actuator supplied with MAXAIR Inhaler should not be used with any other product canisters, and actuators from other products should not be used with MAXAIR Inhaler canister.
# Images
## Drug Images
## Package and Label Display Panel
### Ingredients and Appearance
# Patient Counseling Information
- Information for Patients: The action of MAXAIR Inhaler should last up to five hours or longer. MAXAIR Inhaler should not be used more frequently than recommended. Do not increase the dose or frequency of MAXAIR Inhaler without consulting your physician. If you find that treatment with MAXAIR Inhaler becomes less effective for symptomatic relief, or your symptoms become worse, and/or you need to use the product more frequently than usual, you should seek medical attention immediately. While you are using MAXAIR Inhaler, other inhaled drugs and asthma medications should be taken only as directed by your physician. Common adverse effects include palpitations, chest pain, rapid heart rate, tremor or nervousness. If you are pregnant or nursing, contact your physician about use of MAXAIR Inhaler. Effective and safe use includes an understanding of the way the medication should be administered. As with all aerosol medications, it is recommended to prime (test) MAXAIR Inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks. Prime by releasing three “test sprays” into the air away from yourself and other people.
### SUPPLEMENTAL PATIENT MATERIAL
MAXAIR™ Inhaler
pirbuterol acetate inhalation aerosol
- Before using your MAXAIR Inhaler, read the following instructions carefully.
- NOTE: Your MAXAIR Inhaler is assembled with a special one-piece light blue plastic actuator and attached white mouthpiece/cap that protects your Inhaler from dust during shipping and in between use (see FIGURE A).
- Cleanse the Inhaler thoroughly at least once a day. Remove the canister and rinse the mouthpiece/cap section with warm running water. If soap is used, rinse thoroughly with plain water. Allow the actuator to dry before reuse (do not expose to excessive heat; see CAUTION below), then reassemble.
Dosage: Use only as directed by your physician. The correct amount of medication in each canister cannot be assured after 300 actuations even though the canister is not completely empty. You should keep track of the number of actuations used from each MAXAIR Inhaler and discard the canister after 300 actuations. The canister should be discarded when the labeled number of actuations has been used. Before you reach the specified number of actuations, you should consult your physician to determine whether a refill is needed. Just as you should not take extra doses without consulting your physician, you should not stop using MAXAIR Inhaler without consulting your physician.
- WARNINGS: The effects of MAXAIR Inhaler may last up to five hours or longer. Therefore, it should not be used more frequently than recommended. Do not increase the number or frequency of doses without speaking with the prescribing physician. If the recommended dosage does not provide relief of symptoms, or your symptoms get worse, speak with your physician. While taking MAXAIR Inhaler, other inhaled medicines should not be used unless prescribed.
- Note: The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFC's).
- This product contains trichloromonofluoromethane and dichlorodifluoromethane, substances which harm the environment by destroying ozone in the upper atmosphere.
Your physician has determined that this product is likely to help your personal health. USE THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE BY YOUR PHYSICIAN. If you have any questions about alternatives, consult with your physician.
- Caution: CONTENTS UNDER PRESSURE. Do not puncture. Do not use or store near heat or open flame. Exposure to temperature above 120°F may cause bursting. Never throw canister into fire or incinerator. Avoid spraying in eyes. KEEP OUT OF REACH OF CHILDREN.
- Store between 15° and 30°C (59° to 86°F). Failure to use this product within this temperature range may result in improper dosing. For optimal results, the canister should be at room temperature before use. Shake well before using.
# Precautions with Alcohol
- Alcohol-Pirbuterol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Maxair®
# Look-Alike Drug Names
There is limited information regarding Pirbuterol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Pirbuterol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Pirbuterol is a Beta-2 Adrenergic Agonist that is FDA approved for the treatment of of bronchospasm in patients 12 years of age and older with reversible bronchospasm including asthma.. Common adverse reactions include nervousness, tremor.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- MAXAIR Inhaler is indicated for the prevention and reversal of bronchospasm in patients 12 years of age and older with reversible bronchospasm including asthma. It may be used with or without concurrent theophylline and/or corticosteroid therapy.
### Dosage
- The usual dose for adults and children 12 years and older is two inhalations (400 mcg) repeated every 4-6 hours. One inhalation (200 mcg) repeated every 4-6 hours may be sufficient for some patients.
- A total daily dose of 12 inhalations should not be exceeded. If a previously effective dosage regimen fails to provide the usual relief, medical advice should be sought immediately as this is often a sign of seriously worsening asthma which would require reassessment of therapy.
- As with all aerosol medications, it is recommended to prime (test) MAXAIR Inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks. Prime by releasing three “test sprays” into the air away from yourself and other people.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pirbuterol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pirbuterol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Dosage
- The usual dose for adults and children 12 years and older is two inhalations (400 mcg) repeated every 4-6 hours. One inhalation (200 mcg) repeated every 4-6 hours may be sufficient for some patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pirbuterol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pirbuterol in pediatric patients.
# Contraindications
- MAXAIR Inhaler is contraindicated in patients with a history of hypersensitivity to pirbuterol or any of its ingredients.
# Warnings
- MAXAIR Inhaler, like other inhaled beta-adrenergic agonists, can produce a clinically significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of MAXAIR Inhaler at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, MAXAIR Inhaler, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
- MAXAIR Inhaler can produce paradoxical bronchospasm, which can be life threatening. If paradoxical bronchospasm occurs, MAXAIR Inhaler should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister or vial.
- The use of beta adrenergic agonist bronchodilators alone may not be adequate to control asthma in many patients. Early consideration should be given to adding anti-inflammatory agents, e.g., corticosteroids.
- Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient needs more doses of MAXAIR Inhaler than usual, this may be a marker of destabilization of asthma and requires reevaluation of the patient and the treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids.
### Precautions
- Since pirbuterol is a sympathomimetic amine, it should be used with caution in patients with cardiovascular disorders, including ischemic heart disease, hypertension, or cardiac arrhythmias, in patients with hyperthyroidism or diabetes mellitus, and in patients who are unusually responsive to sympathomimetic amines or who have convulsive disorders. Significant changes in systolic and diastolic blood pressure could be expected to occur in some patients after use of any beta adrenergic aerosol bronchodilator.
- Beta adrenergic agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation.
# Adverse Reactions
## Clinical Trials Experience
- The following rates of adverse reactions to pirbuterol are based on single- and multiple-dose clinical trials involving 761 patients, 400 of whom received multiple doses (mean duration of treatment was 2.5 months and maximum was 19 months).
- The following were the adverse reactions reported more frequently than 1 in 100 patients:
- nervousness (6.9%), tremor (6.0%), headache (2.0%), dizziness (1.2%).
- palpitations (1.7%), tachycardia (1.2%).
- cough (1.2%).
- nausea (1.7%).
- The following adverse reactions occurred less frequently than 1 in 100 patients and there may be a causal relationship with pirbuterol:
- depression, anxiety, confusion, insomnia, weakness, hyperkinesia, syncope.
- hypotension, skipped beats, chest pain.
- dry mouth, glossitis, abdominal pain/cramps, anorexia, diarrhea, stomatitis, nausea and vomiting.
- smell/taste changes, sore throat.
- rash, pruritus.
- numbness in extremities, alopecia, bruising, fatigue, edema, weight gain, flushing.
- Other adverse reactions were reported with a frequency of less than 1 in 100 patients but a causal relationship between pirbuterol and the reaction could not be determined: migraine, productive cough, wheezing, and dermatitis.
- The following rates of adverse reactions during three-month controlled clinical trials involving 310 patients are noted. The table does not include mild reactions.
- Electrocardiograms, obtained during a randomized, double-blind, cross-over study in 57 patients, showed no observations or findings considered clinically significant, or related to drug administration. Most electrocardiographic observations, obtained during a randomized, double blind, cross-over study in 40 patients, were judged not clinically significant or related to drug administration. One patient was noted to have some changes on the one hour postdose electrocardiogram consisting of ST and T wave abnormality suggesting possible inferior ischemia. This abnormality was not observed on the predose or the six hours postdose ECG. A treadmill was subsequently performed and all the findings were normal.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Pirbuterol in the drug label.
# Drug Interactions
- Other short-acting beta adrenergic aerosol bronchodilators should not be used concomitantly with MAXAIR Inhaler because they may have additive effects.
- Pirbuterol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of pirbuterol on the vascular system may be potentiated.
- Beta adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists, such as MAXAIR Inhaler, but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with beta blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta blockers could be considered, although they should be administered with caution.
- The ECG changes and/or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non-potassium sparing diuretics.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Pirbuterol was not teratogenic in rats administered oral doses of 30, 100, and 300 mg/kg (approximately 100, 340, and 1000 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis). Pirbuterol was not teratogenic in rabbits administered oral doses of 30 and 100 mg/kg (approximately 200 and 680 times the maximum recommended inhalation dose for adults on a mg/m2 basis). However, pirbuterol at an oral dose of 300 mg/kg (approximately 2000 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis) caused abortions and fetal death.
- There are no adequate and well-controlled studies in pregnant women. Pirbuterol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pirbuterol in women who are pregnant.
### Labor and Delivery
- Because of the potential for beta-agonist interference with uterine contractility, use of MAXAIR Inhaler for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.
### Nursing Mothers
- It is not known whether pirbuterol is excreted in human milk. Therefore, MAXAIR Inhaler should be used during nursing only if the potential benefit justifies the possible risk to the newborn.
### Pediatric Use
- MAXAIR Inhaler is not recommended for patients under the age of 12 years because of insufficient clinical data to establish safety and effectiveness.
### Geriatic Use
There is no FDA guidance on the use of Pirbuterol with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Pirbuterol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pirbuterol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pirbuterol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pirbuterol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pirbuterol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pirbuterol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Inhalation
### Monitoring
There is limited information regarding Monitoring of Pirbuterol in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Pirbuterol in the drug label.
# Overdosage
- The expected symptoms with overdosage are those of excessive beta-stimulation and/or any of the symptoms listed under ADVERSE REACTIONS, e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats per minute, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. Hypokalemia may also occur. As with all sympathomimetic aerosol medication, cardiac arrest and even death may be associated with abuse of MAXAIR Inhaler.
- Treatment consists of discontinuation of pirbuterol together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage.
- The oral median lethal dose of pirbuterol dihydrochloride in mice and rats is greater than 2000 mg/kg (approximately 3400 and 6800 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis).
# Pharmacology
## Mechanism of Action
- The pharmacologic effects of beta adrenergic agonist drugs, including pirbuterol, are at least in part attributable to stimulation through beta adrenergic receptors of intracellular adenyl cyclase, the enzyme which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (c-AMP). Increased c-AMP levels are associated with relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.
- In vitro studies and in vivo pharmacologic studies have demonstrated that pirbuterol has a preferential effect on beta-2 adrenergic receptors compared with isoproterenol. While it is recognized that beta-2 adrenergic receptors are the predominant receptors in bronchial smooth muscle, data indicate that there is a population of beta-2 receptors in the human heart, existing in a concentration between 10-50%. The precise function of these receptors has not been established
- Bronchodilator activity of pirbuterol was manifested clinically by an improvement in various pulmonary function parameters (FEV1, MMF, PEFR, airway resistance [RAW] and conductance [GA/Vtg]).
## Structure
- The active component of MAXAIR Inhaler (pirbuterol acetate) is (R,S)a6-{ [(1,1-dimethylethyl)amino]methyl}-3-hydroxy-2,6-pyridine-dimethanol monoacetate salt, a beta-2 adrenergic bronchodilator, having the following chemical structure:
- Pirbuterol acetate is a white, crystalline racemic mixture of two optically active isomers. It is a powder, freely soluble in water, with a molecular weight of 300.3 and empirical formula of C12H20N2O3•C2H4O2.
- MAXAIR Inhaler is a pressurized metered-dose aerosol unit for oral inhalation. It provides a fine-particle suspension of pirbuterol acetate in the propellant mixture of trichloromonofluoromethane and dichlorodifluoromethane, with sorbitan trioleate. Each actuation delivers 256 mcg of pirbuterol (as pirbuterol acetate) from the valve and 200 mcg of pirbuterol (as pirbuterol acetate) from the mouthpiece. Each canister provides 300 inhalations.
- As with all aerosol medications, it is recommended to prime (test) MAXAIR Inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks. Prime by releasing three “test sprays” into the air away from yourself and other people.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Pirbuterol in the drug label.
## Pharmacokinetics
- As expected by extrapolation from oral data, systemic blood levels of pirbuterol are below the limit of assay sensitivity (2-5 ng/ml) following inhalation of doses up to 800 mcg (twice the maximum recommended dose). A mean of 51% of the dose is recovered in urine as pirbuterol plus its sulfate conjugate following administration by aerosol. Pirbuterol is not metabolized by catechol-O-methyltransferase. The percent of administered dose recovered as pirbuterol plus its sulfate conjugate does not change significantly over the dose range of 400 mcg to 800 mcg and is not significantly different from that after oral administration of pirbuterol. The plasma half-life measured after oral administration is about two hours.
## Nonclinical Toxicology
- In a 2-year study in Sprague-Dawley rats, pirbuterol hydrochloride administered at dietary doses of 1.0, 3.0, and 10 mg/kg (approximately 3, 10, and 35 times the maximum recommended daily inhalation dose for adults and children on a mg/m2 basis) showed no evidence of carcinogenicity. In an 18-month study in mice at dietary doses of 1.0, 3.0, and 10 mg/kg (approximately 2, 5, and 15 times the maximum recommended daily inhalation dose for adults and children on a mg/m2 basis) no evidence of tumorigenicity was seen. Reproduction studies in rats administered pirbuterol hydrochloride at oral doses of 1, 3, and 10 mg/kg (approximately 3, 10, and 35 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis) revealed no evidence of impaired fertility.
- Pirbuterol dihydrochloride showed no evidence of mutagenicity in in vitro assays and host-mediated microbial (Ames) assays for point mutations and in vivo tests for somatic or germ cell effects following acute and subchronic treatment in mice (cytogenicity assays).
# Clinical Studies
- In controlled, double-blind, single-dose clinical trials, the onset of improvement in pulmonary function occurred within 5 minutes in most patients as determined by forced expiratory volume in one second (FEV1). FEV1 and MMF measurements also showed that maximum improvement in pulmonary function generally occurred 30-60 minutes following one (1) or two (2) inhalations of pirbuterol (200-400 mcg). The duration of action of pirbuterol is maintained for 5 hours (the time at which the last observations were made) in a substantial number of patients, based on a 15% or greater increase in FEV1. In controlled repetitive-dose studies of 12 weeks' duration, 74% of 156 patients on pirbuterol and 62% of 141 patients on metaproterenol showed a clinically significant improvement based on a 15% or greater increase in FEV1 on at least half of the days. Onset and duration were equivalent to that seen in single-dose studies. Continued effectiveness was demonstrated over the 12-week period in the majority (94%) of responding patients; however, chronic dosing was associated with the development of tachyphylaxis (tolerance) to the bronchodilator effect in some patients in both treatment groups.
- A placebo-controlled, double-blind, single-dose study (24 patients per treatment group), utilizing continuous Holter monitoring for 5 hours after drug administration, showed no significant difference in ectopic activity between the placebo control group and pirbuterol at the recommended dose (200-400 mcg), and twice the recommended dose (800 mcg). As with other inhaled beta adrenergic agonists, supraventricular and ventricular ectopic beats have been seen with pirbuterol (see WARNINGS).
- Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines were administered concurrently. The clinical significance of these findings when applied to humans is unknown.
# How Supplied
- MAXAIR Inhaler, box of one, is supplied in a pressurized aluminum canister with a light blue plastic actuator and attached white mouthpiece. Each actuation delivers pirbuterol acetate equivalent to 256 mcg of pirbuterol (as pirbuterol acetate) from the valve and 200 mcg of pirbuterol (as pirbuterol acetate) from the mouthpiece.
- Net content weight 25.6 g, 300 metered inhalations (NDC 0089-0790-21).
- The correct amount of medication in each canister cannot be assured after 300 actuations even though the canister is not completely empty. The canister should be discarded when the labeled number of actuations has been used.
- Note: The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFC's).
- WARNING: Contains trichloromonofluoromethane and dichlorodifluoromethane, substances which harm public health and environment by destroying ozone in the upper atmosphere.
- A notice similar to the above WARNING has been placed in the “PATIENT'S INSTRUCTIONS FOR USE” portion of this package insert under the Environmental Protection * Agency's (EPA's) regulations. The patient's warning states that the patient should consult his or her physician if there are questions about alternatives.
Rx only
## Storage
- Store between 15° and 30°C (59° to 86°F). Failure to use this product within this temperature range may result in improper dosing. For optimal results, the canister should be at room temperature before use. Shake well before using.
- The contents of MAXAIR Inhaler are under pressure. Do not puncture. Do not use or store near heat or open flame. Exposure to temperature above 120°F may cause bursting. Never throw container into fire or incinerator. Keep out of reach of children. Avoid spraying in eyes.
- The light blue plastic actuator supplied with MAXAIR Inhaler should not be used with any other product canisters, and actuators from other products should not be used with MAXAIR Inhaler canister.
# Images
## Drug Images
## Package and Label Display Panel
### Ingredients and Appearance
# Patient Counseling Information
- Information for Patients: The action of MAXAIR Inhaler should last up to five hours or longer. MAXAIR Inhaler should not be used more frequently than recommended. Do not increase the dose or frequency of MAXAIR Inhaler without consulting your physician. If you find that treatment with MAXAIR Inhaler becomes less effective for symptomatic relief, or your symptoms become worse, and/or you need to use the product more frequently than usual, you should seek medical attention immediately. While you are using MAXAIR Inhaler, other inhaled drugs and asthma medications should be taken only as directed by your physician. Common adverse effects include palpitations, chest pain, rapid heart rate, tremor or nervousness. If you are pregnant or nursing, contact your physician about use of MAXAIR Inhaler. Effective and safe use includes an understanding of the way the medication should be administered. As with all aerosol medications, it is recommended to prime (test) MAXAIR Inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks. Prime by releasing three “test sprays” into the air away from yourself and other people.
### SUPPLEMENTAL PATIENT MATERIAL
MAXAIR™ Inhaler
pirbuterol acetate inhalation aerosol
- Before using your MAXAIR Inhaler, read the following instructions carefully.
- NOTE: Your MAXAIR Inhaler is assembled with a special one-piece light blue plastic actuator and attached white mouthpiece/cap that protects your Inhaler from dust during shipping and in between use (see FIGURE A).
- Cleanse the Inhaler thoroughly at least once a day. Remove the canister and rinse the mouthpiece/cap section with warm running water. If soap is used, rinse thoroughly with plain water. Allow the actuator to dry before reuse (do not expose to excessive heat; see CAUTION below), then reassemble.
Dosage: Use only as directed by your physician. The correct amount of medication in each canister cannot be assured after 300 actuations even though the canister is not completely empty. You should keep track of the number of actuations used from each MAXAIR Inhaler and discard the canister after 300 actuations. The canister should be discarded when the labeled number of actuations has been used. Before you reach the specified number of actuations, you should consult your physician to determine whether a refill is needed. Just as you should not take extra doses without consulting your physician, you should not stop using MAXAIR Inhaler without consulting your physician.
- WARNINGS: The effects of MAXAIR Inhaler may last up to five hours or longer. Therefore, it should not be used more frequently than recommended. Do not increase the number or frequency of doses without speaking with the prescribing physician. If the recommended dosage does not provide relief of symptoms, or your symptoms get worse, speak with your physician. While taking MAXAIR Inhaler, other inhaled medicines should not be used unless prescribed.
- Note: The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFC's).
- This product contains trichloromonofluoromethane and dichlorodifluoromethane, substances which harm the environment by destroying ozone in the upper atmosphere.
Your physician has determined that this product is likely to help your personal health. USE THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE BY YOUR PHYSICIAN. If you have any questions about alternatives, consult with your physician.
- Caution: CONTENTS UNDER PRESSURE. Do not puncture. Do not use or store near heat or open flame. Exposure to temperature above 120°F may cause bursting. Never throw canister into fire or incinerator. Avoid spraying in eyes. KEEP OUT OF REACH OF CHILDREN.
- Store between 15° and 30°C (59° to 86°F). Failure to use this product within this temperature range may result in improper dosing. For optimal results, the canister should be at room temperature before use. Shake well before using.
# Precautions with Alcohol
- Alcohol-Pirbuterol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Maxair®[1]
# Look-Alike Drug Names
There is limited information regarding Pirbuterol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Maxair | |
467c0c8453e40dfeec7508aac45a23e1027665de | wikidoc | Mayonnaise | Mayonnaise
Mayonnaise (often abbreviated mayo) is a thick condiment made primarily from vegetable oil and egg yolks. Whitish-yellow in color, it is a stable emulsion formed from the oil and the yolks and is generally flavored with lemon juice and/or vinegar, salt, and sometimes mustard. Numerous other sauces can be created from it by adding additional seasonings (see below).
# History and etymology
One explanation of the origin of the name is that the idea was brought back to France from Mahon, Spain, after Louis-François-Armand du Plessis de Richelieu's victory over the British at the city's port in 1756. Later, Marie-Antoine Carême made it lighter by blending the vegetable oil and egg yolks into an emulsion; his recipe then became famous throughout Europe. If this history is correct, allioli (the Balearic version of aïoli) would seem to have been the inspiration.
The name mayonnaise is generally said to have been derived either from Mahon (giving mahonnaise), or from the French word manier (meaning to stir or to blend, giving magnonnaise).
The Larousse Gastronomique 1961 suggests another explanation: "However logical Carême's justification for the exclusive use of the term magnonaise may seem, we are not by any means convinced that it should take the place of the usual form, mayonnaise. Mayonnaise, in our view, is a popular corruption of moyeunaise, derived from the very old French word moyeu, which means yolk of egg. For, when all is said, this sauce is nothing but an emulsion of egg yolks and oil."
Since the name's real origin is unknown, several other explanations exist:
- The sauce may have been christened mayennaise after Charles de Lorraine, duke of Mayenne, because he took the time to finish his meal of chicken with cold sauce before being defeated in the Battle of Arques. Though, this suggestion was first made by the nineteenth-century culinary writer Pierre Lacam.
According to the Oxford English Dictionary, mayonnaise made its English language debut in a cookbook of 1841.
Ambrose Bierce said in his Devil's Dictionary that mayonnaise is "One of the sauces which serve the French in place of a state religion."
# Making mayonnaise
Mayonnaise can be made with an electric mixer, an electric blender, or a food processor, or by hand with a whisk or fork. Mayonnaise is made by slowly adding oil to an egg yolk, while whisking vigorously to disperse the oil. The oil and the water in yolks form a base of the emulsion, while the lecithin from the yolks acts as the emulsifier that stabilizes it. Additionally, a bit of a mustard may also be added to further stabilize the emulsion. Small particles of the mustard serve as nucleation sites for the droplets forming the mayonnaise.
## Traditional recipe
The traditional French recipe is essentially the same as the basic one described above, but it uses top-quality olive oil and sometimes vinegar or lemon juice. Some nouvelle cuisine recipes specify safflower oil. It is considered essential to constantly beat the mayonnaise using a whisk while adding the olive oil a drop at a time, fully incorporating the oil before adding the next tablespoon. Experienced cooks can judge when the mayonnaise is done by the emulsion's resistance to the beating action. Mayonnaise made this way may taste too strong or sharp to people accustomed to commercial products.
Overworking the olive oil can make mayonaisse bitter. Therefore, it is common to use safflower oil to create the initial emulsion, then add olive oil, working it in with a wooden spoon rather than a whisk.
## Vegan mayonnaise
Several brands of soy-based vegan mayonnaises are available, such as Nayonaise and Vegenaise. Vegan mayonnaise can also safely be made at home.
## Composition
Homemade mayonnaise can approach 85% fat before the emulsion breaks down; commercial mayonnaises are more typically 70-80% fat. "Low fat" mayonnaise products contain starches, cellulose gel, or other ingredients to simulate the texture of real mayonnaise.
Some homemade recipes use the whole egg, including the white. It can also be made using solely egg whites, with no yolks at all, if it is done at high speed in a food processor. The resulting texture appears to be the same, and—if seasoned, for example, with salt, pepper, mustard, lemon juice, vinegar, and a little paprika—the taste is similar to traditional mayonnaise made with egg yolks.
Commercial producers either pasteurize the yolks, freeze them and substitute water for most of their liquid, or use other emulsifiers. For homemade mayonnaise it is recommended using the freshest eggs possible. Some stores sell pasteurized eggs for home use. The eggs can also be coddled in 170°F (77°C) water, after which the hot yolks, now slightly cooked, are removed from the whites. Homemade mayonnaise will generally only keep under refrigeration for three to four days.
Mayonnaise has a pH between 3.8 and 4.6, making it an acidic food. There is a misconception that foods like potato salad can make a person sick if left out in the sun, due to the mayonnaise spoiling. This is false; the pH of mayonnaise prevents harmful bacteria from growing in it. Left out of refrigeration, mayonnaise will develop an unappetizing taste and smell, due to other types of bacteria and molds that can spoil it; but will not make one sick.
# Use of mayonnaise
Worldwide, mayonnaise is most commonly served in a sandwich, or with salad such as potato salad or canned tuna ("tuna mayo" or tuna salad). Regional uses are listed below:
## In the United States
Commercial mayonnaise sold in jars originated in New York City, in Manhattan's Upper West Side. In 1905, the first ready-made mayonnaise was sold at Richard Hellmann's delicatessen on Columbus Avenue, between 83rd and 84th Streets. In 1912, Mrs. Hellmann's mayonnaise was mass marketed and called Hellmann's Blue Ribbon Mayonnaise.
At about the same time that Hellmann's Mayonnaise was thriving on the East Coast of the United States, a California company, Best Foods, introduced their own mayonnaise, which turned out to be very popular in the western United States. Head-to-head competition between the two brands was averted when, in 1932, Best Foods bought out the Hellmann's brand. By then both mayonnaises had such commanding market shares in their own half of the country that it was decided that both brands be preserved.
In the Southeastern part of the United States, Mrs. Eugenia Duke of Greenville, South Carolina, founded the Duke Sandwich Company in 1917 to sell sandwiches to soldiers training at nearby Fort Sevier. Her homemade mayonnaise became so popular that her company began to focus exclusively on producing and selling the mayonnaise, eventually selling out to the C.F. Sauer Company of Richmond, Virginia, in 1929. Duke's Mayonnaise, still made to the original recipe, remains a popular brand of mayonnaise in the Southeast, although it is not generally available in other markets.
Reily Foods Company of New Orleans, LA, produces Blue Plate Mayonnaise, an extremely popular mayonnaise in the Southern United States. Formerly owned by Hunt-Wesson and manufactured in New Orleans, LA, Blue Plate Mayonnaise is now produced in Knoxville, TN.
Professional athletes have used mayonnaise as a home remedy for aching joints and an ache blocker. When applied direct to the aching joint it acts as a natural lubricator for overly tense muscle areas.
## Europe
In northern Europe, mayonnaise is often served with French fries, especially in the The Netherlands, Belgium and Germany, as well as increasingly in the United Kingdom, France and Spain. It is also served with cold chicken or hard-boiled eggs in The Netherlands, France, Poland, Ukraine and the UK.
Guidelines issued in September 1991 by Europe's Federation of the Condiment Sauce Industries recommend that oil and liquid egg yolk levels in mayonnaise should be at least 70% and 5% respectively, although this is not legislated. Most available brands easily exceed this target.
## Japan
Japanese mayonnaise is typically made with apple cider vinegar or rice vinegar and a small amount of MSG, which gives it a different flavor profile from mayonnaise made from distilled vinegar. It is most often sold in soft plastic squeeze bottles. Its texture is thinner than most Western commercial mayonnaises. A variety containing karashi (Japanese mustard) is also common.
Apart from salads, it is popular with dishes such as okonomiyaki, takoyaki and yakisoba. It is sometimes served with cooked vegetables, or mixed with soy sauce or wasabi and used as dips. In the Tōkai region, it is a frequent condiment on hiyashi chuka (cold noodle salad).
Kewpie (Q.P.) is the most popular brand of Japanese mayonnaise, advertised with a Kewpie doll logo.
People who are known to like mayonnaise are commonly called mayoler (マヨラー) by their friends.
## Russia
Mayonnaise is very popular in Russia where it is made with sunflower seed oil which gives it a very distinctive flavor. A 2004 study showed that Russia is the only market in Europe where more mayonnaise is sold than ketchup by volume. Leading brands are Calve (marketed by Unilever) and Sloboda (marketed by Efko).
Furthermore, in many Russian speaking countries, one can find different commercial flavors of mayonnaise, such as olive, quail-egg, and lemon.
## Chile
Chile is the world's third major per capita consumer of mayonnaise and first in Latin America. Since mayonnaise became widely accessible in the 1980s Chileans have used it on locos, hot dogs, French fries, and on boiled potatoes.
## As a base for other sauces
Mayonnaise is the base for many other chilled sauces and salad dressings. For example:
- Aïoli is often made as an olive-oil mayonnaise with garlic.
- Rouille is aïoli with added red pepper or paprika.
- Tartar sauce is mayonnaise spiced with pickled cucumbers and onion. Capers, olives, and crushed hardboiled eggs are sometimes included. A simpler recipe calls for sweet pickle relish and more lemon juice.
- Some types of Russian dressing (also known as Marie Rose sauce in Europe) combine mayonnaise with tomato sauce or ketchup and yoghurt or heavy cream. In North America, however, most homemade varieties and all commercial brands of Russian dressing use little or no mayonnaise as a base. They are very dark red and sweet dressings made with vegetable oil, tomato paste, vinegar, sugar, and a variety of herbs and spices (often including mustard).
- Thousand Island dressing is a salmon-pink dressing that combines tomato sauce and/or tomato ketchup or ketchup-based chili sauce, minced sweet pickles or sweet pickle relish, assorted herbs and spices (usually including mustard), and sometimes including chopped hard-boiled egg—all thoroughly blended into a mayonnaise base.
- Fry sauce is a mixture of mayonnaise, ketchup or another red sauce (e.g., Tabasco sauce, Buffalo wing sauce, or one of many smokey barbecue sauces popular in the Northwest states), spices, and sometimes a strong tasting salty liquid (such as worchestershire or soy sauce) is added to balance out the sweeter red sauces. Commonly eaten on french fries in Utah, Idaho, eastern Washington and rural Oregon.
- Mayonesa is a lime-flavored mayonnaise, usually found in Mexican or Spanish grocers in North America.
- Sauce rémoulade, in classic French cuisine is mayonnaise to which has been added mustard, gherkins, capers, parsley, chervil, tarragon, and possibly anchovy essence. An industrially made variety is popular in Denmark with french fries and fried fish. It is quite different from most of the remoulade sauces that are frequently found in Louisiana and generally do not have a mayonnaise base.
- Ranch dressing is made of buttermilk or sour cream, mayonnaise, and minced green onion, along with other seasonings.
# Notes
- ↑ "Mayonnaise is an emulsion of oil droplets suspended in a base composed of egg yolk, lemon juice or vinegar, water, and often mustard, which provide both flavor and stabilizing particles and carbohydrates." On Food and Cooking, Harold McGee, Scribner, New York, 2004.
- ↑ David, E. (1960). "French Provincial Cooking" (1999 edition) p.120
- ↑ A more usual definition of moyeu, from Mallarme.net: "Partie centrale de la roue où s’emboîtent les rais, et par où passe l’essieu. "Mais de ce que les moyeux des roues de votre carrosse auront pris feu, s’ensuit-il que votre carrosse n’ait pas été fait expressément pour vous porter d’un lieu à un autre?" Voltaire, Dictionnaire Philosophique, "Causes finales." Translation: "Central part of the wheel, where the spokes are housed, through which the axle passes." A fourteenthth-century surgeon, Guy de Chauliac, did use moyeu to mean yolk of the egg: "Oeufs sont tempérez : toutes fois l'aulbin tire à froideur, et le moyeu à la chaleur, avec sédation." ("Eggs are tempered, for albumen tends to "cooling" and the yolk tends to "heating", in the Four humours theory. The word moyeu would have been pronounced quite close to "mayo".
- ↑ The page reference has not been identified; the passage appeared either in Lacam's Mémorial historique et géographie de la pâtisserie (privately printed, Paris 1908), in his Nouveau pâtissier glacier français et étranger (1865) or his Glacier classique et artistique en France et en Italie, (1893).
- ↑ Egg-Free Vegan Mayonnaise Recipe
- ↑ Happy Birthday, Dear Mayo - We Hold You Dear : NPR
- ↑ See, for example, Larousse Gastronomique, 2003, ISBN 0 600 60863 8, page 1054. | Mayonnaise
Mayonnaise (often abbreviated mayo) is a thick condiment made primarily from vegetable oil and egg yolks.[1] Whitish-yellow in color, it is a stable emulsion formed from the oil and the yolks and is generally flavored with lemon juice and/or vinegar, salt, and sometimes mustard. Numerous other sauces can be created from it by adding additional seasonings (see below).
# History and etymology
One explanation of the origin of the name is that the idea was brought back to France from Mahon, Spain, after Louis-François-Armand du Plessis de Richelieu's victory over the British at the city's port in 1756.[2] Later, Marie-Antoine Carême made it lighter by blending the vegetable oil and egg yolks into an emulsion; his recipe then became famous throughout Europe.[citation needed] If this history is correct, allioli (the Balearic version of aïoli) would seem to have been the inspiration.
The name mayonnaise is generally said to have been derived either from Mahon (giving mahonnaise), or from the French word manier (meaning to stir or to blend, giving magnonnaise).
The Larousse Gastronomique 1961 suggests another explanation: "However logical Carême's justification for the exclusive use of the term magnonaise may seem, we are not by any means convinced that it should take the place of the usual form, mayonnaise. Mayonnaise, in our view, is a popular corruption of moyeunaise, derived from the very old French word moyeu[3], which means yolk of egg. For, when all is said, this sauce is nothing but an emulsion of egg yolks and oil."
Since the name's real origin is unknown, several other explanations exist:
- The sauce may have been christened mayennaise after Charles de Lorraine, duke of Mayenne, because he took the time to finish his meal of chicken with cold sauce before being defeated in the Battle of Arques. Though, this suggestion was first made by the nineteenth-century culinary writer Pierre Lacam[4].
According to the Oxford English Dictionary, mayonnaise made its English language debut in a cookbook of 1841.
Ambrose Bierce said in his Devil's Dictionary that mayonnaise is "One of the sauces which serve the French in place of a state religion."
# Making mayonnaise
Mayonnaise can be made with an electric mixer, an electric blender, or a food processor, or by hand with a whisk or fork. Mayonnaise is made by slowly adding oil to an egg yolk, while whisking vigorously to disperse the oil. The oil and the water in yolks form a base of the emulsion, while the lecithin from the yolks acts as the emulsifier that stabilizes it. Additionally, a bit of a mustard may also be added to further stabilize the emulsion. Small particles of the mustard serve as nucleation sites for the droplets forming the mayonnaise.
## Traditional recipe
The traditional French recipe is essentially the same as the basic one described above, but it uses top-quality olive oil and sometimes vinegar or lemon juice. Some nouvelle cuisine recipes specify safflower oil. It is considered essential to constantly beat the mayonnaise using a whisk while adding the olive oil a drop at a time, fully incorporating the oil before adding the next tablespoon. Experienced cooks can judge when the mayonnaise is done by the emulsion's resistance to the beating action. Mayonnaise made this way may taste too strong or sharp to people accustomed to commercial products.
Overworking the olive oil can make mayonaisse bitter. Therefore, it is common to use safflower oil to create the initial emulsion, then add olive oil, working it in with a wooden spoon rather than a whisk.
## Vegan mayonnaise
Several brands of soy-based vegan mayonnaises are available, such as Nayonaise and Vegenaise. Vegan mayonnaise can also safely be made at home.[5]
## Composition
Homemade mayonnaise can approach 85% fat before the emulsion breaks down; commercial mayonnaises are more typically 70-80% fat. "Low fat" mayonnaise products contain starches, cellulose gel, or other ingredients to simulate the texture of real mayonnaise.
Some homemade recipes use the whole egg, including the white. It can also be made using solely egg whites, with no yolks at all, if it is done at high speed in a food processor. The resulting texture appears to be the same, and—if seasoned, for example, with salt, pepper, mustard, lemon juice, vinegar, and a little paprika—the taste is similar to traditional mayonnaise made with egg yolks.
Commercial producers either pasteurize the yolks, freeze them and substitute water for most of their liquid, or use other emulsifiers. For homemade mayonnaise it is recommended using the freshest eggs possible. Some stores sell pasteurized eggs for home use. The eggs can also be coddled in 170°F (77°C) water, after which the hot yolks, now slightly cooked, are removed from the whites. Homemade mayonnaise will generally only keep under refrigeration for three to four days.
Mayonnaise has a pH between 3.8 and 4.6, making it an acidic food. There is a misconception that foods like potato salad can make a person sick if left out in the sun, due to the mayonnaise spoiling. This is false; the pH of mayonnaise prevents harmful bacteria from growing in it. Left out of refrigeration, mayonnaise will develop an unappetizing taste and smell, due to other types of bacteria and molds that can spoil it; but will not make one sick. [6]
# Use of mayonnaise
Worldwide, mayonnaise is most commonly served in a sandwich, or with salad such as potato salad or canned tuna ("tuna mayo" or tuna salad). Regional uses are listed below:
## In the United States
Commercial mayonnaise sold in jars originated in New York City, in Manhattan's Upper West Side. In 1905, the first ready-made mayonnaise was sold at Richard Hellmann's delicatessen on Columbus Avenue, between 83rd and 84th Streets. In 1912, Mrs. Hellmann's mayonnaise was mass marketed and called Hellmann's Blue Ribbon Mayonnaise.
At about the same time that Hellmann's Mayonnaise was thriving on the East Coast of the United States, a California company, Best Foods, introduced their own mayonnaise, which turned out to be very popular in the western United States. Head-to-head competition between the two brands was averted when, in 1932, Best Foods bought out the Hellmann's brand. By then both mayonnaises had such commanding market shares in their own half of the country that it was decided that both brands be preserved.
In the Southeastern part of the United States, Mrs. Eugenia Duke of Greenville, South Carolina, founded the Duke Sandwich Company in 1917 to sell sandwiches to soldiers training at nearby Fort Sevier. Her homemade mayonnaise became so popular that her company began to focus exclusively on producing and selling the mayonnaise, eventually selling out to the C.F. Sauer Company of Richmond, Virginia, in 1929. Duke's Mayonnaise, still made to the original recipe, remains a popular brand of mayonnaise in the Southeast, although it is not generally available in other markets.
Reily Foods Company of New Orleans, LA, produces Blue Plate Mayonnaise, an extremely popular mayonnaise in the Southern United States. Formerly owned by Hunt-Wesson and manufactured in New Orleans, LA, Blue Plate Mayonnaise is now produced in Knoxville, TN.
Professional athletes have used mayonnaise as a home remedy for aching joints and an ache blocker. When applied direct to the aching joint it acts as a natural lubricator for overly tense muscle areas.
## Europe
In northern Europe, mayonnaise is often served with French fries, especially in the The Netherlands, Belgium and Germany, as well as increasingly in the United Kingdom, France and Spain. It is also served with cold chicken or hard-boiled eggs in The Netherlands, France, Poland, Ukraine and the UK.
Guidelines issued in September 1991 by Europe's Federation of the Condiment Sauce Industries recommend that oil and liquid egg yolk levels in mayonnaise should be at least 70% and 5% respectively, although this is not legislated. Most available brands easily exceed this target. [1]
## Japan
Japanese mayonnaise is typically made with apple cider vinegar or rice vinegar and a small amount of MSG, which gives it a different flavor profile from mayonnaise made from distilled vinegar. It is most often sold in soft plastic squeeze bottles. Its texture is thinner than most Western commercial mayonnaises. A variety containing karashi (Japanese mustard) is also common.
Apart from salads, it is popular with dishes such as okonomiyaki, takoyaki and yakisoba. It is sometimes served with cooked vegetables, or mixed with soy sauce or wasabi and used as dips. In the Tōkai region, it is a frequent condiment on hiyashi chuka (cold noodle salad).
Kewpie (Q.P.) is the most popular brand of Japanese mayonnaise, advertised with a Kewpie doll logo.
People who are known to like mayonnaise are commonly called mayoler (マヨラー) by their friends.
## Russia
Mayonnaise is very popular in Russia where it is made with sunflower seed oil which gives it a very distinctive flavor. A 2004 study showed that Russia is the only market in Europe where more mayonnaise is sold than ketchup by volume. Leading brands are Calve (marketed by Unilever) and Sloboda (marketed by Efko).
Furthermore, in many Russian speaking countries, one can find different commercial flavors of mayonnaise, such as olive, quail-egg, and lemon.
[2]
## Chile
Chile is the world's third major per capita consumer of mayonnaise and first in Latin America. [3] Since mayonnaise became widely accessible in the 1980s Chileans have used it on locos, hot dogs, French fries, and on boiled potatoes.
## As a base for other sauces
Mayonnaise is the base for many other chilled sauces and salad dressings. For example:
- Aïoli is often made as an olive-oil mayonnaise with garlic.
- Rouille is aïoli with added red pepper or paprika.
- Tartar sauce is mayonnaise spiced with pickled cucumbers and onion. Capers, olives, and crushed hardboiled eggs are sometimes included. A simpler recipe calls for sweet pickle relish and more lemon juice.
- Some types of Russian dressing (also known as Marie Rose sauce in Europe) combine mayonnaise with tomato sauce or ketchup and yoghurt or heavy cream. In North America, however, most homemade varieties and all commercial brands of Russian dressing use little or no mayonnaise as a base. They are very dark red and sweet dressings made with vegetable oil, tomato paste, vinegar, sugar, and a variety of herbs and spices (often including mustard).
- Thousand Island dressing is a salmon-pink dressing that combines tomato sauce and/or tomato ketchup or ketchup-based chili sauce, minced sweet pickles or sweet pickle relish, assorted herbs and spices (usually including mustard), and sometimes including chopped hard-boiled egg—all thoroughly blended into a mayonnaise base.
- Fry sauce is a mixture of mayonnaise, ketchup or another red sauce (e.g., Tabasco sauce, Buffalo wing sauce, or one of many smokey barbecue sauces popular in the Northwest states), spices, and sometimes a strong tasting salty liquid (such as worchestershire or soy sauce) is added to balance out the sweeter red sauces. Commonly eaten on french fries in Utah, Idaho, eastern Washington and rural Oregon.
- Mayonesa is a lime-flavored mayonnaise, usually found in Mexican or Spanish grocers in North America.
- Sauce rémoulade, in classic French cuisine is mayonnaise to which has been added mustard, gherkins, capers, parsley, chervil, tarragon, and possibly anchovy essence.[7] An industrially made variety is popular in Denmark with french fries and fried fish. It is quite different from most of the remoulade sauces that are frequently found in Louisiana and generally do not have a mayonnaise base.
- Ranch dressing is made of buttermilk or sour cream, mayonnaise, and minced green onion, along with other seasonings.
# Notes
- ↑ "Mayonnaise is an emulsion of oil droplets suspended in a base composed of egg yolk, lemon juice or vinegar, water, and often mustard, which provide both flavor and stabilizing particles and carbohydrates." On Food and Cooking, Harold McGee, Scribner, New York, 2004.
- ↑ David, E. (1960). "French Provincial Cooking" (1999 edition) p.120
- ↑ A more usual definition of moyeu, from Mallarme.net: "Partie centrale de la roue où s’emboîtent les rais, et par où passe l’essieu. "Mais de ce que les moyeux des roues de votre carrosse auront pris feu, s’ensuit-il que votre carrosse n’ait pas été fait expressément pour vous porter d’un lieu à un autre?" Voltaire, Dictionnaire Philosophique, "Causes finales." Translation: "Central part of the wheel, where the spokes are housed, through which the axle passes." A fourteenthth-century surgeon, Guy de Chauliac, did use moyeu to mean yolk of the egg: "Oeufs sont tempérez : toutes fois l'aulbin tire à froideur, et le moyeu [le jaune] à la chaleur, avec sédation." ("Eggs are tempered, for albumen tends to "cooling" and the yolk tends to "heating", in the Four humours theory. The word moyeu would have been pronounced quite close to "mayo".
- ↑ The page reference has not been identified; the passage appeared either in Lacam's Mémorial historique et géographie de la pâtisserie (privately printed, Paris 1908), in his Nouveau pâtissier glacier français et étranger (1865) or his Glacier classique et artistique en France et en Italie, (1893).
- ↑ Egg-Free Vegan Mayonnaise Recipe
- ↑ Happy Birthday, Dear Mayo - We Hold You Dear : NPR
- ↑ See, for example, Larousse Gastronomique, 2003, ISBN 0 600 60863 8, page 1054.
# External links
Template:Cookbook
- Creative Cooking School website: offers six possible sources of sauce mayonnaise, including Pierre Lacam's suggestion.
- Science Channel's The Making Series: #2 Making of Mayonnaise (video in Japanese)
- NPR's Report on the 250th Birthday of Mayonnaise and its history | https://www.wikidoc.org/index.php/Mayonnaise | |
80a558d80c9405aeef78654ebf65fe4b86951865 | wikidoc | Mebeverine | Mebeverine
Mebeverine is a drug whose major therapeutic role is in the treatment of irritable bowel syndrome (IBS) and the associated abdominal cramping. It works by relaxing the muscles in and around the gut. It is a musculotropic antispasmodic drug without anticholinergic side-effects. The drug is also indicated for treatment of gastrointestinal spasm secondary to organic disorder.
# Indications
Spastic functional disturbances of the colon:
- Irritable bowel syndrome in its primary form
- Irritable bowel syndrome associated with organic lesions of the gastrointestinal tract such as; diverticulosis and diverticulitis, regional enteritis, disease of the gall bladder and gall ducts, gastric and duodenal ulcers, dysentery, and aspecific or specific inflammation of the digestive tract.
- Mebeverine should be taken 20 minutes before meals.
# Mechanism of action
Mebeverine is an antimuscarinic. It belongs to a group of compounds called musculotropic antispasmodics. These compounds act directly on the gut muscles at the cellular level to relax them. This relieves painful muscle spasms of the gut, without affecting its normal motility. Mebeverine is used to relieve symptoms of irritable bowel syndrome and related intestinal disorders that are the result of spasms in the intestinal muscles. These include colicky abdominal pain and cramps, diarrhoea alternating with constipation and flatulence (wind).
Mebeverine is also an inhibitor of calcium-depot replenishment. Therefore, it has dual mode of action which normalizes the small bowel motility.
# Adverse effects
Side effects may include:
- Indigestion or heartburn
- Constipation
- Dizziness
- Insomnia (difficulty sleeping)
- anorexia (loss of appetite)
- Headache
- Tiredness
- Slow heart beat
- Rash and/or itchy skin
Since 1978, 21 cases of severe adverse reactions to mebeverine were reported in the Netherlands.
Most reactions consisted of urticaria or maculopapular rash, sometimes accompanied by fever, polyarthritis, thrombopenia or angioedema.
Very rarely, people taking this medicine may develop allergic reactions.
# Pregnancy and breastfeeding
Mebeverine passes into breast milk, but the amount is considered too small to be harmful to a nursing infant.
# Driving and using machines
Mebeverine is unlikely to affect the ability to operate machinery or to drive, yet not completely out of the question.
# History
It was first registered in 1965.
# Availability
Mebervine is a generic drug and is available internationally under many brand names. | Mebeverine
Mebeverine is a drug whose major therapeutic role is in the treatment of irritable bowel syndrome (IBS) and the associated abdominal cramping. It works by relaxing the muscles in and around the gut. It is a musculotropic antispasmodic drug without anticholinergic side-effects. The drug is also indicated for treatment of gastrointestinal spasm secondary to organic disorder.
# Indications
Spastic functional disturbances of the colon:
- Irritable bowel syndrome in its primary form
- Irritable bowel syndrome associated with organic lesions of the gastrointestinal tract such as; diverticulosis and diverticulitis, regional enteritis, disease of the gall bladder and gall ducts, gastric and duodenal ulcers, dysentery, and aspecific or specific inflammation of the digestive tract.
- Mebeverine should be taken 20 minutes before meals.
# Mechanism of action
Mebeverine is an antimuscarinic. It belongs to a group of compounds called musculotropic antispasmodics. These compounds act directly on the gut muscles at the cellular level to relax them. This relieves painful muscle spasms of the gut, without affecting its normal motility. Mebeverine is used to relieve symptoms of irritable bowel syndrome and related intestinal disorders that are the result of spasms in the intestinal muscles. These include colicky abdominal pain and cramps, diarrhoea alternating with constipation and flatulence (wind).
Mebeverine is also an inhibitor of calcium-depot replenishment. Therefore, it has dual mode of action which normalizes the small bowel motility.
# Adverse effects
Side effects may include:[1]
- Indigestion or heartburn
- Constipation
- Dizziness
- Insomnia (difficulty sleeping)
- anorexia (loss of appetite)
- Headache
- Tiredness
- Slow heart beat
- Rash and/or itchy skin
Since 1978, 21 cases of severe adverse reactions to mebeverine were reported in the Netherlands.[2]
Most reactions consisted of urticaria or maculopapular rash, sometimes accompanied by fever, polyarthritis, thrombopenia or angioedema.
Very rarely, people taking this medicine may develop allergic reactions.[3]
# Pregnancy and breastfeeding
Mebeverine passes into breast milk, but the amount is considered too small to be harmful to a nursing infant.[1]
# Driving and using machines
Mebeverine is unlikely to affect the ability to operate machinery or to drive, yet not completely out of the question. [4] [5]
# History
It was first registered in 1965.[6]
# Availability
Mebervine is a generic drug and is available internationally under many brand names.[7] | https://www.wikidoc.org/index.php/Mebeverine | |
6031897658ef3603ef50f80b51033e16917d778e | wikidoc | Mebutamate | Mebutamate
# Overview
Mebutamate (Capla, Dormate) is an anxiolytic and sedative drug with antihypertensive effects of the carbamate class. It has effects comparable to those of barbiturates such as secobarbital, but is only around 1/3 the potency of secobarbital as a sedative. Side effects include dizziness and headaches.
Mebutamate is one of many GABAergic drugs which act via allosteric agonism of the GABAA receptor at the β-subreceptor similair to barbiturates. In contrast, benzodiazepines act at the α-subreceptor. As such, carbamates and barbiturates, possess analgesic properties which the benzodiazepine class of drugs do not.
Other carbamates with the same mechanism of action and pharmacological properties include meprobamate, carisoprodol, felbamate, and tybamate). | Mebutamate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Mebutamate (Capla, Dormate) is an anxiolytic and sedative drug with antihypertensive effects of the carbamate class. It has effects comparable to those of barbiturates such as secobarbital, but is only around 1/3 the potency of secobarbital as a sedative. Side effects include dizziness and headaches.
Mebutamate is one of many GABAergic drugs which act via allosteric agonism of the GABAA receptor at the β-subreceptor similair to barbiturates. In contrast, benzodiazepines act at the α-subreceptor. As such, carbamates and barbiturates, possess analgesic properties which the benzodiazepine class of drugs do not.
Other carbamates with the same mechanism of action and pharmacological properties include meprobamate, carisoprodol, felbamate, and tybamate). | https://www.wikidoc.org/index.php/Mebutamate | |
f2a55d6d061236d061c31d011945722a28c51b79 | wikidoc | Mecasermin | Mecasermin
# 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
Mecasermin is an endocrine-metabolic agent that is FDA approved for the treatment of growth failure in children with severe primary IGF-1 deficiency or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH. Common adverse reactions include hypoglycemia, local and systemic hypersensitivity, tonsillar hypertrophy.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Preprandial glucose monitoring is recommended at treatment initiation and until a well-tolerated dose is established. If frequent symptoms of hypoglycemia or severe hypoglycemia occur, preprandial glucose monitoring should continue. The dosage of INCRELEX® should be individualized for each patient. The recommended starting dose of INCRELEX® is 0.04 to 0.08 mg/kg (40 to 80 micrograms/kg) twice daily by subcutaneous injection. If well-tolerated for at least one week, the dose may be increased by 0.04 mg/kg per dose, to the maximum dose of 0.12 mg/kg given twice daily. Doses greater than 0.12 mg/kg given twice daily have not been evaluated in children with Primary IGFD and, due to potential hypoglycemic effects, should not be used. If hypoglycemia occurs with recommended doses despite adequate food intake, the dose should be reduced. INCRELEX® should be administered shortly before or after (± 20 minutes) a meal or snack. If the patient is unable to eat shortly before or after a dose for any reason, that dose of INCRELEX® should be withheld. Subsequent doses of INCRELEX® should never be increased to make up for one or more omitted dose.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mecasermin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mecasermin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Preprandial glucose monitoring is recommended at treatment initiation and until a well-tolerated dose is established. If frequent symptoms of hypoglycemia or severe hypoglycemia occur, preprandial glucose monitoring should continue. The dosage of INCRELEX® should be individualized for each patient. The recommended starting dose of INCRELEX® is 0.04 to 0.08 mg/kg (40 to 80 micrograms/kg) twice daily by subcutaneous injection. If well-tolerated for at least one week, the dose may be increased by 0.04 mg/kg per dose, to the maximum dose of 0.12 mg/kg given twice daily. Doses greater than 0.12 mg/kg given twice daily have not been evaluated in children with Primary IGFD and, due to potential hypoglycemic effects, should not be used. If hypoglycemia occurs with recommended doses despite adequate food intake, the dose should be reduced. INCRELEX® should be administered shortly before or after (± 20 minutes) a meal or snack. If the patient is unable to eat shortly before or after a dose for any reason, that dose of INCRELEX® should be withheld. Subsequent doses of INCRELEX® should never be increased to make up for one or more omitted dose.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mecasermin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mecasermin in pediatric patients.
# Contraindications
- Active or Suspected Neoplasia
- INCRELEX® is contraindicated in the presence of active or suspected malignancy, and therapy should be discontinued if evidence of malignancy develops.
- Known Hypersensitivity
- INCRELEX® should not be used by patients who are allergic to mecasermin (rhIGF-1) or any of the inactive ingredients in INCRELEX®, or who have experienced a severe hypersensitivity to INCRELEX®.
- Intravenous Administration
- Intravenous administration of INCRELEX® is contraindicated.
- Closed Epiphyses
- INCRELEX® should not be used for growth promotion in patients with closed epiphyses.
# Warnings
### Precautions
- Hypoglycemia
- Because INCRELEX® has insulin-like hypoglycemic effects it should be administered shortly before or after (± 20 minutes) a meal or snack. Glucose monitoring and INCRELEX® dose titration are recommended until a well tolerated dose is established and subsequently as medically indicated. Special attention should be paid to small children because their oral intake may not be consistent. Patients should avoid engaging in any high-risk activities (e.g., driving, etc.) within 2 to 3 hours after dosing, particularly during the initiation of INCRELEX® treatment until tolerability and a stable dose have been established. INCRELEX® should not be administered when the meal or snack is omitted. The dose of INCRELEX® should never be increased to make up for one or more omitted doses.
- Hypersensitivity and Allergic Reactions, including Anaphylaxis
- Allergic reactions to INCRELEX® have been reported post-marketing. They range from localized (injection site) reactions to systemic reactions, including anaphylaxis requiring hospitalization. Parents and patients should be informed that such reactions are possible and that if a systemic allergic reaction occurs, treatment should be interrupted and prompt medical attention should be sought.
- Intracranial Hypertension
- Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or vomiting have occurred in patients treated with INCRELEX®. IH-associated signs and symptoms resolved after interruption of dosing. Funduscopic examination is recommended at the initiation and periodically during the course of INCRELEX® therapy.
- Lymphoid Tissue Hypertrophy
- Lymphoid tissue (e.g., tonsillar and adenoidal) hypertrophy associated with complications, such as snoring, sleep apnea, and chronic middle-ear effusions have been reported with the use of INCRELEX®. Patients should have periodic examinations to rule out such potential complications and receive appropriate treatment if necessary.
- Slipped Capital Femoral Epiphysis
- Slipped capital femoral epiphysis can occur in patients who experience rapid growth. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during INCRELEX® therapy should be carefully evaluated.
- Progression of Preexisting Scoliosis
- Progression of scoliosis may occur in patients who experience rapid growth. Because INCRELEX® increases growth rate, patients with a history of scoliosis who are treated with INCRELEX® should be monitored for progression of scoliosis.
- Benzyl Alcohol
- Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The "gasping syndrome," (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.
# 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.
- In clinical studies of 71 subjects with Primary IGFD treated for a mean duration of 3.9 years and representing 274 subject-years, no subjects withdrew from any clinical study because of adverse reactions. Adverse reactions to INCRELEX® treatment that occurred in 5% or more of these study participants are listed below by organ class.
Hypoglycemia
Lipohypertrophy, bruising
Otitis media, serous otitis media
Snoring, tonsillar hypertrophy
Headache, dizziness, convulsions
Vomiting
Hypoacusis, fluid in middle ear, ear pain, abnormal tympanometry
Cardiac murmur
Arthralgia, pain in extremity
Thymus hypertrophy
Ear tube insertion
- Hypoglycemia was reported by 30 subjects (42%) at least once during their course of therapy. Most cases of hypoglycemia were mild or moderate in severity. Five subjects had severe hypoglycemia (requiring assistance and treatment) on one or more occasion and 4 subjects experienced hypoglycemic seizures/loss of consciousness on one or more occasion. Of the 30 subjects reporting hypoglycemia, 14 (47%) had a history of hypoglycemia prior to treatment. The frequency of hypoglycemia was highest in the first month of treatment, and episodes were more frequent in younger children. Symptomatic hypoglycemia was generally avoided when a meal or snack was consumed either shortly (i.e., 20 minutes) before or after the administration of INCRELEX®.
- Tonsillar hypertrophy was noted in 11 (15%) subjects in the first 1 to 2 years of therapy with lesser tonsillar growth in subsequent years. Tonsillectomy or tonsillectomy/adenoidectomy was performed in 7 subjects; 3 of these had obstructive sleep apnea, which resolved after the procedure in all three cases.
- Intracranial hypertension occurred in three subjects. In two subjects the events resolved without interruption of INCRELEX® treatment. INCRELEX® treatment was discontinued in the third subject and resumed later at a lower dose without recurrence.
- Mild elevations in the serum AST and LDH were found in a significant proportion of patients before and during treatment. Rise in levels of these serum enzymes did not lead to treatment discontinuation. ALT elevations were occasionally noted during treatment.
- Renal and splenic lengths (measured by ultrasound) increased rapidly on INCRELEX® treatment during the first years of therapy. This lengthening slowed down subsequently; though in some patients, renal and/or splenic length reached or surpassed the 95th percentile. Renal function (as defined by serum creatinine and calculated creatinine clearance) was normal in all patients, irrespective of renal growth.
- Elevations in cholesterol and triglycerides to above the upper limit of normal were observed before and during treatment.
- Echocardiographic evidence of cardiomegaly/valvulopathy was observed in a few individuals without associated clinical symptoms. The relation of these cardiac changes to drug treatment cannot be assessed due to underlying disease and the lack of a control group.
- Thickening of the soft tissues of the face was observed in several patients and should be monitored during INCRELEX® treatment.
- As with all therapeutic proteins, there is potential for immunogenicity. Anti-IGF-1 antibodies were present at one or more of the periodic assessments in 14 of 23 children with Primary IGFD treated for 2 years. However, no clinical consequences of these antibodies were observed (e.g., attenuation of growth). The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to INCRELEX® with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
- The following adverse reactions have been identified during post approval use of INCRELEX®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Anaphylaxis, generalized urticaria, angioedema, dyspnea
In the post-marketing setting, the frequency of cases indicative of anaphylaxis was estimated to be 0.3%. Symptoms included hives, angioedema, and dyspnea, and some patients required hospitalization. Upon re-administration, symptoms did not re-occur in all patients.
Pruritus, urticaria.
Alopecia, hair texture abnormal.
Injection site reactions (e.g. erythema, pain, haematoma, haemorrhage, induration, rash, swelling).
Osteonecrosis/avascular necrosis (occasionally associated with slipped capital femoral epiphysis)
# Drug Interactions
There is limited information regarding Mecasermin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Studies to assess embryo-fetal toxicity evaluated the effects of INCRELEX® during organogenesis in Sprague Dawley rats given 1, 4, and 16 mg/kg/day and in New Zealand White rabbits given 0.125, 0.5, and 2 mg/kg/day, administered intravenously. There were no observed embryo-fetal developmental abnormalities in rats given up to 16 mg/kg/day (20 times the maximum recommended human dose based on body surface area comparison). In the rabbit study, the NOAEL for fetal toxicity was 0.5 mg/kg (2 times the MRHD based on BSA) due to an increase in fetal death at 2 mg/kg. INCRELEX® displayed no teratogenicity or maternal toxicity in rabbits given up to 2 mg/kg (8 times the MRHD based on BSA).
The effects of INCRELEX® on an unborn child have not been studied. Therefore, there is insufficient medical information to determine whether there are significant risks to a fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mecasermin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Mecasermin during labor and delivery.
### Nursing Mothers
- Excretion of INCRELEX® in human milk has not been studied. Caution should be exercised when INCRELEX® is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 2 years of age have not been established.
### Geriatic Use
- The safety and effectiveness of INCRELEX® in patients aged 65 and over have not been established.
### Gender
There is no FDA guidance on the use of Mecasermin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Mecasermin with respect to specific racial populations.
### Renal Impairment
- No studies have been conducted in Primary IGFD children or adult subjects with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Mecasermin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Mecasermin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Mecasermin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Mecasermin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Mecasermin in the drug label.
# Overdosage
## Acute Overdose
- Treatment of acute overdose should be directed at reversing hypoglycemia. Oral glucose or food should be consumed. If the overdose results in loss of consciousness, intravenous glucose or parenteral glucagon may be required to reverse the hypoglycemic effects.
- A small number of overdose cases have been reported in the post-marketing experience. In one case of acute overdose, a 3-year old patient experienced hypoglycemia after receiving one 4 mg dose of INCRELEX® (a 10-fold increase beyond the prescribed dose). The event resolved following treatment with IV glucose.
- Long term overdosage with INCRELEX® may result in signs and symptoms of acromegaly.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Mecasermin in the drug label.
# Pharmacology
## Mechanism of Action
- Insulin-like growth factor-1 (IGF-1) is a key hormonal mediator on statural growth. Under normal circumstances, growth hormone (GH) binds to its receptor in the liver, and other tissues, and stimulates the synthesis/secretion of IGF-1. In target tissues, the Type 1 IGF-1 receptor, which is homologous to the insulin receptor, is activated by IGF-1, leading to intracellular signaling which stimulates multiple processes resulting in statural growth. The metabolic actions of IGF-1 are in part directed at stimulating the uptake of glucose, fatty acids, and amino acids so that metabolism supports growing tissues.
## Structure
- INCRELEX® (mecasermin injection) contains human insulin-like growth factor-1 (rhIGF-1) produced by recombinant DNA technology. IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfide bridges and a molecular weight of 7649 daltons. The amino acid sequence of the product is identical to that of endogenous human IGF-1. The rhIGF-1 protein is synthesized in bacteria (E. coli) that have been modified by the addition of the gene for human IGF-1.
- INCRELEX® is a sterile, aqueous, clear and colorless solution intended for subcutaneous injection. Each multi-dose vial of INCRELEX® contains 10 mg per mL mecasermin, 9 mg per mL benzyl alcohol, 5.84 mg per mL sodium chloride, 2 mg per mL polysorbate 20, and 0.05M acetate at a pH of approximately 5.4.
## Pharmacodynamics
- The following actions have been demonstrated for endogenous human IGF-1:
- Tissue Growth – 1) Skeletal growth occurs at the cartilage growth plates of the epiphyses of bones where stem cells divide to produce new cartilage cells or chondrocytes. The growth of chondrocytes is under the control of IGF-1 and GH. The chondrocytes become calcified so that new bone is formed allowing the length of the bones to increase. This results in skeletal growth until the cartilage growth plates fuse at the end of puberty. 2) Cell growth: IGF-1 receptors are present on most types of cells and tissues. IGF-1 has mitogenic activities that lead to an increased number of cells in the body. 3) Organ growth: Treatment of IGF-1 deficient rats with rhIGF-1 results in whole body and organ growth.
- Carbohydrate Metabolism –IGF-1 suppresses hepatic glucose production and stimulates peripheral glucose utilization and therefore has a hypoglycemic potential. IGF-1 has inhibitory effects on insulin secretion.
## Pharmacokinetics
- Absorption – The absolute bioavailability of rhIGF-1 after subcutaneous administration in healthy subjects is estimated to be close to 100%. However, the absolute bioavailability of INCRELEX® given subcutaneously to subjects with primary insulin-like growth factor-1 deficiency (Primary IGFD) has not been determined.
- Distribution – In blood, IGF-1 is bound to six IGF binding proteins, with > 80% bound as a complex with IGFBP-3 and an acid-labile subunit. IGFBP-3 is greatly reduced in subjects with severe Primary IGFD, resulting in increased clearance of IGF-1 in these subjects relative to healthy subjects. The total IGF-1 volume of distribution after subcutaneous administration in subjects with severe Primary IGFD is estimated to be 0.257 (± 0.073) L/kg at an INCRELEX® dose of 0.045 mg/kg, and is estimated to increase as the dose of INCRELEX® increases.
- Elimination – IGF-1 is metabolized by both liver and kidney. The mean terminal t1/2 after single subcutaneous administration of 0.12 mg/kg INCRELEX® in pediatric subjects with severe Primary IGFD is estimated to be 5.8 hours. Clearance of INCRELEX® is inversely proportional to IGF binding protein-3 (IGFBP-3) levels. CL/F is estimated to be 0.04 L/hr/kg at 0.5 micrograms/mL of IGFBP-3, and 0.01 L/hr/kg at 3 micrograms/mL IGFBP-3; the latter is the median IGFBP-3 in subjects with normal IGF-1 serum levels.
- Gender – In children with Primary IGFD there were no apparent differences between males and females in the pharmacokinetics of INCRELEX®.
- Race –The effect of race on pharmacokinetics of INCRELEX® has not been studied.
- Renal impairment– No studies have been conducted in Primary IGFD children with renal impairment.
- Hepatic impairment– No studies have been conducted to determine the effect of hepatic impairment on the pharmacokinetics of rhIGF-1 in Primary IGFD children with hepatic impairment.
## Nonclinical Toxicology
- Carcinogenesis: INCRELEX® was tumorigenic in rats in a study using doses of 0, 0.25, 1, 4, and 10 mg/kg/day by subcutaneous injection for up to 2 years. The incidence of adrenal medullary hyperplasia and pheochromocytoma increased in male rats given ≥1 mg/kg/day (≥ 1 times the clinical exposure with the maximum recommended human dose based on AUC) and in female rats at all dose levels (≥ 30% of the clinical exposure with the MRHD based on AUC). The incidence of keratoacanthoma in the skin increased in male rats given 4 and 10 mg/kg/day (≥ 4 times the MRHD). The incidence of mammary gland carcinoma in male rats increased in animals treated with 10 mg/kg/day (7 times the MRHD based on AUC). Only doses that exceeded the maximum tolerated dose (MTD) (based on excess mortality secondary to IGF-1 induced hypoglycemia) caused skin and mammary tumors.
- Mutagenesis: INCRELEX® was not clastogenic in the in vitro chromosome aberration assay and the in vivo mouse micronucleus assay.
- Impairment of fertility: INCRELEX® had no effects on fertility in rats using intravenous doses 0.25, 1, and 4 mg/day (up to 4 times the clinical exposure with the MRHD based on AUC.)
# Clinical Studies
- Five clinical studies (four open-label and one double-blind, placebo-controlled), with subcutaneous doses of INCRELEX® generally ranging from 0.06 to 0.12 mg/kg (60 to 120 micrograms/kg) administered twice daily, were conducted in 71 pediatric subjects with severe Primary IGFD. Patients were enrolled in the trials on the basis of extreme short stature, slow growth rates, low IGF-1 serum concentrations, and normal growth hormone secretion. Data from these 5 clinical studies were pooled for a global efficacy and safety analysis. Baseline characteristics for the patients evaluated in the primary and secondary efficacy analyses were (mean, SD): chronological age (years): 6.7 ± 3.8; height (cm): 84.8 ± 15.3 cm; height standard deviation score (SDS): -6.7 ± 1.8; height velocity (cm/yr): 2.8 ± 1.8; height velocity SDS: -3.3 ± 1.7; IGF-1 (ng/mL): 21.6 ± 20.6; IGF-1 SDS: -4.3 ± 1.6; and bone age (years): 4.2 ± 2.8. Sixty-one subjects had at least one year of treatment. Fifty-three (87%) had Laron Syndrome; 7 (11%) had GH gene deletion, and 1 (2%) had neutralizing antibodies to GH. Thirty-seven (61%) of the subjects were male; forty-eight (79%) were Caucasian. Fifty-six (92%) of the subjects were pre-pubertal at baseline.
- Annual results for height velocity, height velocity SDS, and height SDS are shown in Table 1. Pre-treatment height velocity data were available for 58 subjects. The height velocities at a given year of treatment were compared by paired t-tests to the pre-treatment height velocities of the same subjects completing that treatment year.
- Forty-nine subjects were included in an analysis of the effects of INCRELEX® on bone age advancement. The mean ± SD change in chronological age was 4.9 ± 3.4 years and the mean ± SD change in bone age was 5.3 ± 3.4 years.
# How Supplied
- NDC-15054-1040-5 INCRELEX® is supplied as a 10 mg per mL sterile solution in multiple dose glass vials (40 mg per vial).
- Before Opening – Vials of INCRELEX® are stable when refrigerated . Avoid freezing the vials of INCRELEX®. Protect from direct light. Expiration dates are stated on the labels.
- After Opening – Vials of INCRELEX® are stable for 30 days after initial vial entry when stored at 2° to 8°C (35° to 46°F). Avoid freezing the vials of INCRELEX®. Protect from direct light.
- Vial contents should be clear without particulate matter. If the solution is cloudy or contains particulate matter, the contents must not be injected. INCRELEX® should not be used after its expiration date. Keep refrigerated and use within 30 days of initial vial entry. Remaining unused material should be discarded.
## Storage
There is limited information regarding Mecasermin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients and/or their parents should be instructed in the proper administration of INCRELEX®. INCRELEX® should be given shortly before or after (20 minutes on either side of) a meal or snack. INCRELEX® should not be administered when the meal or snack is omitted. The dose of INCRELEX® should never be increased to make up for one or more omitted doses. INCRELEX® therapy should be initiated at a low dose and the dose should be increased only if no hypoglycemia episodes have occurred after at least 7 days of dosing. If severe hypoglycemia or persistent hypoglycemia occurs on treatment despite adequate food intake, INCRELEX® dose reduction should be considered. Providers should educate patients and caregivers on how to recognize the signs and symptoms of hypoglycemia.
- Providers should educate patients and caregivers on the identification of signs and symptoms of serious allergic reactions to INCRELEX® and the need to seek prompt medical contact should such a reaction occur. They should be informed that if an allergic reaction occurs, INCRELEX treatment should be discontinued.
- Patients and/or parents should be thoroughly instructed in the importance of proper needle disposal. A puncture-resistant container should be used for the disposal of used needles and/or syringes (consistent with applicable state requirements). Needles and syringes must not be reused.
# Precautions with Alcohol
- Alcohol-Mecasermin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- INCRELEX®
# Look-Alike Drug Names
There is limited information regarding Mecasermin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Mecasermin
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
Mecasermin is an endocrine-metabolic agent that is FDA approved for the treatment of growth failure in children with severe primary IGF-1 deficiency or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH. Common adverse reactions include hypoglycemia, local and systemic hypersensitivity, tonsillar hypertrophy.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Preprandial glucose monitoring is recommended at treatment initiation and until a well-tolerated dose is established. If frequent symptoms of hypoglycemia or severe hypoglycemia occur, preprandial glucose monitoring should continue. The dosage of INCRELEX® should be individualized for each patient. The recommended starting dose of INCRELEX® is 0.04 to 0.08 mg/kg (40 to 80 micrograms/kg) twice daily by subcutaneous injection. If well-tolerated for at least one week, the dose may be increased by 0.04 mg/kg per dose, to the maximum dose of 0.12 mg/kg given twice daily. Doses greater than 0.12 mg/kg given twice daily have not been evaluated in children with Primary IGFD and, due to potential hypoglycemic effects, should not be used. If hypoglycemia occurs with recommended doses despite adequate food intake, the dose should be reduced. INCRELEX® should be administered shortly before or after (± 20 minutes) a meal or snack. If the patient is unable to eat shortly before or after a dose for any reason, that dose of INCRELEX® should be withheld. Subsequent doses of INCRELEX® should never be increased to make up for one or more omitted dose.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mecasermin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mecasermin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Preprandial glucose monitoring is recommended at treatment initiation and until a well-tolerated dose is established. If frequent symptoms of hypoglycemia or severe hypoglycemia occur, preprandial glucose monitoring should continue. The dosage of INCRELEX® should be individualized for each patient. The recommended starting dose of INCRELEX® is 0.04 to 0.08 mg/kg (40 to 80 micrograms/kg) twice daily by subcutaneous injection. If well-tolerated for at least one week, the dose may be increased by 0.04 mg/kg per dose, to the maximum dose of 0.12 mg/kg given twice daily. Doses greater than 0.12 mg/kg given twice daily have not been evaluated in children with Primary IGFD and, due to potential hypoglycemic effects, should not be used. If hypoglycemia occurs with recommended doses despite adequate food intake, the dose should be reduced. INCRELEX® should be administered shortly before or after (± 20 minutes) a meal or snack. If the patient is unable to eat shortly before or after a dose for any reason, that dose of INCRELEX® should be withheld. Subsequent doses of INCRELEX® should never be increased to make up for one or more omitted dose.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mecasermin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mecasermin in pediatric patients.
# Contraindications
- Active or Suspected Neoplasia
- INCRELEX® is contraindicated in the presence of active or suspected malignancy, and therapy should be discontinued if evidence of malignancy develops.
- Known Hypersensitivity
- INCRELEX® should not be used by patients who are allergic to mecasermin (rhIGF-1) or any of the inactive ingredients in INCRELEX®, or who have experienced a severe hypersensitivity to INCRELEX®.
- Intravenous Administration
- Intravenous administration of INCRELEX® is contraindicated.
- Closed Epiphyses
- INCRELEX® should not be used for growth promotion in patients with closed epiphyses.
# Warnings
### Precautions
- Hypoglycemia
- Because INCRELEX® has insulin-like hypoglycemic effects it should be administered shortly before or after (± 20 minutes) a meal or snack. Glucose monitoring and INCRELEX® dose titration are recommended until a well tolerated dose is established and subsequently as medically indicated. Special attention should be paid to small children because their oral intake may not be consistent. Patients should avoid engaging in any high-risk activities (e.g., driving, etc.) within 2 to 3 hours after dosing, particularly during the initiation of INCRELEX® treatment until tolerability and a stable dose have been established. INCRELEX® should not be administered when the meal or snack is omitted. The dose of INCRELEX® should never be increased to make up for one or more omitted doses.
- Hypersensitivity and Allergic Reactions, including Anaphylaxis
- Allergic reactions to INCRELEX® have been reported post-marketing. They range from localized (injection site) reactions to systemic reactions, including anaphylaxis requiring hospitalization. Parents and patients should be informed that such reactions are possible and that if a systemic allergic reaction occurs, treatment should be interrupted and prompt medical attention should be sought.
- Intracranial Hypertension
- Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or vomiting have occurred in patients treated with INCRELEX®. IH-associated signs and symptoms resolved after interruption of dosing. Funduscopic examination is recommended at the initiation and periodically during the course of INCRELEX® therapy.
- Lymphoid Tissue Hypertrophy
- Lymphoid tissue (e.g., tonsillar and adenoidal) hypertrophy associated with complications, such as snoring, sleep apnea, and chronic middle-ear effusions have been reported with the use of INCRELEX®. Patients should have periodic examinations to rule out such potential complications and receive appropriate treatment if necessary.
- Slipped Capital Femoral Epiphysis
- Slipped capital femoral epiphysis can occur in patients who experience rapid growth. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during INCRELEX® therapy should be carefully evaluated.
- Progression of Preexisting Scoliosis
- Progression of scoliosis may occur in patients who experience rapid growth. Because INCRELEX® increases growth rate, patients with a history of scoliosis who are treated with INCRELEX® should be monitored for progression of scoliosis.
- Benzyl Alcohol
- Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The "gasping syndrome," (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.
# 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.
- In clinical studies of 71 subjects with Primary IGFD treated for a mean duration of 3.9 years and representing 274 subject-years, no subjects withdrew from any clinical study because of adverse reactions. Adverse reactions to INCRELEX® treatment that occurred in 5% or more of these study participants are listed below by organ class.
Hypoglycemia
Lipohypertrophy, bruising
Otitis media, serous otitis media
Snoring, tonsillar hypertrophy
Headache, dizziness, convulsions
Vomiting
Hypoacusis, fluid in middle ear, ear pain, abnormal tympanometry
Cardiac murmur
Arthralgia, pain in extremity
Thymus hypertrophy
Ear tube insertion
- Hypoglycemia was reported by 30 subjects (42%) at least once during their course of therapy. Most cases of hypoglycemia were mild or moderate in severity. Five subjects had severe hypoglycemia (requiring assistance and treatment) on one or more occasion and 4 subjects experienced hypoglycemic seizures/loss of consciousness on one or more occasion. Of the 30 subjects reporting hypoglycemia, 14 (47%) had a history of hypoglycemia prior to treatment. The frequency of hypoglycemia was highest in the first month of treatment, and episodes were more frequent in younger children. Symptomatic hypoglycemia was generally avoided when a meal or snack was consumed either shortly (i.e., 20 minutes) before or after the administration of INCRELEX®.
- Tonsillar hypertrophy was noted in 11 (15%) subjects in the first 1 to 2 years of therapy with lesser tonsillar growth in subsequent years. Tonsillectomy or tonsillectomy/adenoidectomy was performed in 7 subjects; 3 of these had obstructive sleep apnea, which resolved after the procedure in all three cases.
- Intracranial hypertension occurred in three subjects. In two subjects the events resolved without interruption of INCRELEX® treatment. INCRELEX® treatment was discontinued in the third subject and resumed later at a lower dose without recurrence.
- Mild elevations in the serum AST and LDH were found in a significant proportion of patients before and during treatment. Rise in levels of these serum enzymes did not lead to treatment discontinuation. ALT elevations were occasionally noted during treatment.
- Renal and splenic lengths (measured by ultrasound) increased rapidly on INCRELEX® treatment during the first years of therapy. This lengthening slowed down subsequently; though in some patients, renal and/or splenic length reached or surpassed the 95th percentile. Renal function (as defined by serum creatinine and calculated creatinine clearance) was normal in all patients, irrespective of renal growth.
- Elevations in cholesterol and triglycerides to above the upper limit of normal were observed before and during treatment.
- Echocardiographic evidence of cardiomegaly/valvulopathy was observed in a few individuals without associated clinical symptoms. The relation of these cardiac changes to drug treatment cannot be assessed due to underlying disease and the lack of a control group.
- Thickening of the soft tissues of the face was observed in several patients and should be monitored during INCRELEX® treatment.
- As with all therapeutic proteins, there is potential for immunogenicity. Anti-IGF-1 antibodies were present at one or more of the periodic assessments in 14 of 23 children with Primary IGFD treated for 2 years. However, no clinical consequences of these antibodies were observed (e.g., attenuation of growth). The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to INCRELEX® with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
- The following adverse reactions have been identified during post approval use of INCRELEX®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Anaphylaxis, generalized urticaria, angioedema, dyspnea
In the post-marketing setting, the frequency of cases indicative of anaphylaxis was estimated to be 0.3%. Symptoms included hives, angioedema, and dyspnea, and some patients required hospitalization. Upon re-administration, symptoms did not re-occur in all patients.
Pruritus, urticaria.
Alopecia, hair texture abnormal.
Injection site reactions (e.g. erythema, pain, haematoma, haemorrhage, induration, rash, swelling).
Osteonecrosis/avascular necrosis (occasionally associated with slipped capital femoral epiphysis)
# Drug Interactions
There is limited information regarding Mecasermin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Studies to assess embryo-fetal toxicity evaluated the effects of INCRELEX® during organogenesis in Sprague Dawley rats given 1, 4, and 16 mg/kg/day and in New Zealand White rabbits given 0.125, 0.5, and 2 mg/kg/day, administered intravenously. There were no observed embryo-fetal developmental abnormalities in rats given up to 16 mg/kg/day (20 times the maximum recommended human dose [MRHD] based on body surface area [BSA] comparison). In the rabbit study, the NOAEL for fetal toxicity was 0.5 mg/kg (2 times the MRHD based on BSA) due to an increase in fetal death at 2 mg/kg. INCRELEX® displayed no teratogenicity or maternal toxicity in rabbits given up to 2 mg/kg (8 times the MRHD based on BSA).
The effects of INCRELEX® on an unborn child have not been studied. Therefore, there is insufficient medical information to determine whether there are significant risks to a fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mecasermin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Mecasermin during labor and delivery.
### Nursing Mothers
- Excretion of INCRELEX® in human milk has not been studied. Caution should be exercised when INCRELEX® is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 2 years of age have not been established.
### Geriatic Use
- The safety and effectiveness of INCRELEX® in patients aged 65 and over have not been established.
### Gender
There is no FDA guidance on the use of Mecasermin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Mecasermin with respect to specific racial populations.
### Renal Impairment
- No studies have been conducted in Primary IGFD children or adult subjects with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Mecasermin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Mecasermin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Mecasermin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Mecasermin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Mecasermin in the drug label.
# Overdosage
## Acute Overdose
- Treatment of acute overdose should be directed at reversing hypoglycemia. Oral glucose or food should be consumed. If the overdose results in loss of consciousness, intravenous glucose or parenteral glucagon may be required to reverse the hypoglycemic effects.
- A small number of overdose cases have been reported in the post-marketing experience. In one case of acute overdose, a 3-year old patient experienced hypoglycemia after receiving one 4 mg dose of INCRELEX® (a 10-fold increase beyond the prescribed dose). The event resolved following treatment with IV glucose.
- Long term overdosage with INCRELEX® may result in signs and symptoms of acromegaly.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Mecasermin in the drug label.
# Pharmacology
## Mechanism of Action
- Insulin-like growth factor-1 (IGF-1) is a key hormonal mediator on statural growth. Under normal circumstances, growth hormone (GH) binds to its receptor in the liver, and other tissues, and stimulates the synthesis/secretion of IGF-1. In target tissues, the Type 1 IGF-1 receptor, which is homologous to the insulin receptor, is activated by IGF-1, leading to intracellular signaling which stimulates multiple processes resulting in statural growth. The metabolic actions of IGF-1 are in part directed at stimulating the uptake of glucose, fatty acids, and amino acids so that metabolism supports growing tissues.
## Structure
- INCRELEX® (mecasermin [rDNA origin] injection) contains human insulin-like growth factor-1 (rhIGF-1) produced by recombinant DNA technology. IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfide bridges and a molecular weight of 7649 daltons. The amino acid sequence of the product is identical to that of endogenous human IGF-1. The rhIGF-1 protein is synthesized in bacteria (E. coli) that have been modified by the addition of the gene for human IGF-1.
- INCRELEX® is a sterile, aqueous, clear and colorless solution intended for subcutaneous injection. Each multi-dose vial of INCRELEX® contains 10 mg per mL mecasermin, 9 mg per mL benzyl alcohol, 5.84 mg per mL sodium chloride, 2 mg per mL polysorbate 20, and 0.05M acetate at a pH of approximately 5.4.
## Pharmacodynamics
- The following actions have been demonstrated for endogenous human IGF-1:
- Tissue Growth – 1) Skeletal growth occurs at the cartilage growth plates of the epiphyses of bones where stem cells divide to produce new cartilage cells or chondrocytes. The growth of chondrocytes is under the control of IGF-1 and GH. The chondrocytes become calcified so that new bone is formed allowing the length of the bones to increase. This results in skeletal growth until the cartilage growth plates fuse at the end of puberty. 2) Cell growth: IGF-1 receptors are present on most types of cells and tissues. IGF-1 has mitogenic activities that lead to an increased number of cells in the body. 3) Organ growth: Treatment of IGF-1 deficient rats with rhIGF-1 results in whole body and organ growth.
- Carbohydrate Metabolism –IGF-1 suppresses hepatic glucose production and stimulates peripheral glucose utilization and therefore has a hypoglycemic potential. IGF-1 has inhibitory effects on insulin secretion.
## Pharmacokinetics
- Absorption – The absolute bioavailability of rhIGF-1 after subcutaneous administration in healthy subjects is estimated to be close to 100%. However, the absolute bioavailability of INCRELEX® given subcutaneously to subjects with primary insulin-like growth factor-1 deficiency (Primary IGFD) has not been determined.
- Distribution – In blood, IGF-1 is bound to six IGF binding proteins, with > 80% bound as a complex with IGFBP-3 and an acid-labile subunit. IGFBP-3 is greatly reduced in subjects with severe Primary IGFD, resulting in increased clearance of IGF-1 in these subjects relative to healthy subjects. The total IGF-1 volume of distribution after subcutaneous administration in subjects with severe Primary IGFD is estimated to be 0.257 (± 0.073) L/kg at an INCRELEX® dose of 0.045 mg/kg, and is estimated to increase as the dose of INCRELEX® increases.
- Elimination – IGF-1 is metabolized by both liver and kidney. The mean terminal t1/2 after single subcutaneous administration of 0.12 mg/kg INCRELEX® in pediatric subjects with severe Primary IGFD is estimated to be 5.8 hours. Clearance of INCRELEX® is inversely proportional to IGF binding protein-3 (IGFBP-3) levels. CL/F is estimated to be 0.04 L/hr/kg at 0.5 micrograms/mL of IGFBP-3, and 0.01 L/hr/kg at 3 micrograms/mL IGFBP-3; the latter is the median IGFBP-3 in subjects with normal IGF-1 serum levels.
- Gender – In children with Primary IGFD there were no apparent differences between males and females in the pharmacokinetics of INCRELEX®.
- Race –The effect of race on pharmacokinetics of INCRELEX® has not been studied.
- Renal impairment– No studies have been conducted in Primary IGFD children with renal impairment.
- Hepatic impairment– No studies have been conducted to determine the effect of hepatic impairment on the pharmacokinetics of rhIGF-1 in Primary IGFD children with hepatic impairment.
## Nonclinical Toxicology
- Carcinogenesis: INCRELEX® was tumorigenic in rats in a study using doses of 0, 0.25, 1, 4, and 10 mg/kg/day by subcutaneous injection for up to 2 years. The incidence of adrenal medullary hyperplasia and pheochromocytoma increased in male rats given ≥1 mg/kg/day (≥ 1 times the clinical exposure with the maximum recommended human dose [MRHD] based on AUC) and in female rats at all dose levels (≥ 30% of the clinical exposure with the MRHD based on AUC). The incidence of keratoacanthoma in the skin increased in male rats given 4 and 10 mg/kg/day (≥ 4 times the MRHD). The incidence of mammary gland carcinoma in male rats increased in animals treated with 10 mg/kg/day (7 times the MRHD based on AUC). Only doses that exceeded the maximum tolerated dose (MTD) (based on excess mortality secondary to IGF-1 induced hypoglycemia) caused skin and mammary tumors.
- Mutagenesis: INCRELEX® was not clastogenic in the in vitro chromosome aberration assay and the in vivo mouse micronucleus assay.
- Impairment of fertility: INCRELEX® had no effects on fertility in rats using intravenous doses 0.25, 1, and 4 mg/day (up to 4 times the clinical exposure with the MRHD based on AUC.)
# Clinical Studies
- Five clinical studies (four open-label and one double-blind, placebo-controlled), with subcutaneous doses of INCRELEX® generally ranging from 0.06 to 0.12 mg/kg (60 to 120 micrograms/kg) administered twice daily, were conducted in 71 pediatric subjects with severe Primary IGFD. Patients were enrolled in the trials on the basis of extreme short stature, slow growth rates, low IGF-1 serum concentrations, and normal growth hormone secretion. Data from these 5 clinical studies were pooled for a global efficacy and safety analysis. Baseline characteristics for the patients evaluated in the primary and secondary efficacy analyses were (mean, SD): chronological age (years): 6.7 ± 3.8; height (cm): 84.8 ± 15.3 cm; height standard deviation score (SDS): -6.7 ± 1.8; height velocity (cm/yr): 2.8 ± 1.8; height velocity SDS: -3.3 ± 1.7; IGF-1 (ng/mL): 21.6 ± 20.6; IGF-1 SDS: -4.3 ± 1.6; and bone age (years): 4.2 ± 2.8. Sixty-one subjects had at least one year of treatment. Fifty-three (87%) had Laron Syndrome; 7 (11%) had GH gene deletion, and 1 (2%) had neutralizing antibodies to GH. Thirty-seven (61%) of the subjects were male; forty-eight (79%) were Caucasian. Fifty-six (92%) of the subjects were pre-pubertal at baseline.
- Annual results for height velocity, height velocity SDS, and height SDS are shown in Table 1. Pre-treatment height velocity data were available for 58 subjects. The height velocities at a given year of treatment were compared by paired t-tests to the pre-treatment height velocities of the same subjects completing that treatment year.
- Forty-nine subjects were included in an analysis of the effects of INCRELEX® on bone age advancement. The mean ± SD change in chronological age was 4.9 ± 3.4 years and the mean ± SD change in bone age was 5.3 ± 3.4 years.
# How Supplied
- NDC-15054-1040-5 INCRELEX® is supplied as a 10 mg per mL sterile solution in multiple dose glass vials (40 mg per vial).
- Before Opening – Vials of INCRELEX® are stable when refrigerated [2° to 8°C (35° to 46°F)]. Avoid freezing the vials of INCRELEX®. Protect from direct light. Expiration dates are stated on the labels.
- After Opening – Vials of INCRELEX® are stable for 30 days after initial vial entry when stored at 2° to 8°C (35° to 46°F). Avoid freezing the vials of INCRELEX®. Protect from direct light.
- Vial contents should be clear without particulate matter. If the solution is cloudy or contains particulate matter, the contents must not be injected. INCRELEX® should not be used after its expiration date. Keep refrigerated and use within 30 days of initial vial entry. Remaining unused material should be discarded.
## Storage
There is limited information regarding Mecasermin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients and/or their parents should be instructed in the proper administration of INCRELEX®. INCRELEX® should be given shortly before or after (20 minutes on either side of) a meal or snack. INCRELEX® should not be administered when the meal or snack is omitted. The dose of INCRELEX® should never be increased to make up for one or more omitted doses. INCRELEX® therapy should be initiated at a low dose and the dose should be increased only if no hypoglycemia episodes have occurred after at least 7 days of dosing. If severe hypoglycemia or persistent hypoglycemia occurs on treatment despite adequate food intake, INCRELEX® dose reduction should be considered. Providers should educate patients and caregivers on how to recognize the signs and symptoms of hypoglycemia.
- Providers should educate patients and caregivers on the identification of signs and symptoms of serious allergic reactions to INCRELEX® and the need to seek prompt medical contact should such a reaction occur. They should be informed that if an allergic reaction occurs, INCRELEX treatment should be discontinued.
- Patients and/or parents should be thoroughly instructed in the importance of proper needle disposal. A puncture-resistant container should be used for the disposal of used needles and/or syringes (consistent with applicable state requirements). Needles and syringes must not be reused.
# Precautions with Alcohol
- Alcohol-Mecasermin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- INCRELEX®[1]
# Look-Alike Drug Names
There is limited information regarding Mecasermin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Mecasermin | |
95547dd630a07e75d1136e8a4268c728246ef733 | wikidoc | Mecillinam | Mecillinam
# Overview
Mecillinam (INN) or amdinocillin (USAN) is an extended-spectrum penicillin antibiotic that binds specifically to penicillin binding protein 2 (PBP2), and is only considered to be active against Gram-negative bacteria. It is used primarily in the treatment of urinary tract infections, and has also been used to treat typhoid and paratyphoid fever. Because mecillinam has very low oral bioavailability, an orally active prodrug was developed: pivmecillinam. Neither drug is available in the United States.
# Medical uses
Mecillinam is used in the treatment of infections due to susceptible gram-negative bacteria, especially urinary tract infections which are most commonly caused by Escherichia coli. Mecillinam is active against most pathogenic Gram-negative bacteria, except Pseudomonas aeruginosa and some species of Proteus. Several studies have also found it to be as effective as other antibiotics for treating Staphylococcus saprophyticus infection, though it is Gram-positive, possibly because mecillinam reaches very high concentrations in urine.
Worldwide resistance to mecillinam in bacteria causing urinary tract infection has remained very low since its introduction; a 2003 study conducted in 16 European countries and Canada found resistance to range from 1.2% (Escherichia coli) to 5.2% (Proteus mirabilis). Another large study conducted in Europe and Brazil obtained similar results — 95.9% of E. coli strains, for instance, were sensitive to mecillinam.
# Adverse effects
The adverse effect profile of mecillinam is similar to that of other penicillins. Its most common side effects are rash and gastrointestinal upset, including nausea and vomiting.
# History
With the codename FL 1060, mecillinam was developed by the Danish pharmaceutical company Leo Pharmaceutical Products (now LEO Pharma). It was first described in the scientific literature in a 1972 paper. | Mecillinam
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Mecillinam (INN) or amdinocillin (USAN) is an extended-spectrum penicillin antibiotic that binds specifically to penicillin binding protein 2 (PBP2),[2] and is only considered to be active against Gram-negative bacteria. It is used primarily in the treatment of urinary tract infections, and has also been used to treat typhoid and paratyphoid fever.[3][4] Because mecillinam has very low oral bioavailability, an orally active prodrug was developed: pivmecillinam. Neither drug is available in the United States.[5]
# Medical uses
Mecillinam is used in the treatment of infections due to susceptible gram-negative bacteria, especially urinary tract infections which are most commonly caused by Escherichia coli.[6] Mecillinam is active against most pathogenic Gram-negative bacteria, except Pseudomonas aeruginosa and some species of Proteus.[5] Several studies have also found it to be as effective as other antibiotics for treating Staphylococcus saprophyticus infection, though it is Gram-positive, possibly because mecillinam reaches very high concentrations in urine.[1]
Worldwide resistance to mecillinam in bacteria causing urinary tract infection has remained very low since its introduction; a 2003 study conducted in 16 European countries and Canada found resistance to range from 1.2% (Escherichia coli) to 5.2% (Proteus mirabilis).[7] Another large study conducted in Europe and Brazil obtained similar results — 95.9% of E. coli strains, for instance, were sensitive to mecillinam.[8]
# Adverse effects
The adverse effect profile of mecillinam is similar to that of other penicillins.[2] Its most common side effects are rash and gastrointestinal upset, including nausea and vomiting.[1]
# History
With the codename FL 1060, mecillinam was developed by the Danish pharmaceutical company Leo Pharmaceutical Products (now LEO Pharma). It was first described in the scientific literature in a 1972 paper.[9][10] | https://www.wikidoc.org/index.php/Mecillinam | |
14210ad159f9a0ef1da1a49d12d1cd3626044ad8 | wikidoc | Mefloquine | Mefloquine
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Mefloquine is a anti-Infective agent , antimalarial that is FDA approved for the treatment of mild to moderate acute malaria caused by mefloquine-susceptible strains of P. falciparum (both chloroquine-susceptible and resistant strains) or by Plasmodium vivax, prophylaxis of P. falciparum and P. vivax malaria infections, including prophylaxis of chloroquine-resistant strains of P. falciparum.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include bradyarrhythmia, abdominal pain, diarrhea, nausea, vomiting, coordination problem, dizziness, dream disorder, headache, insomnia, somnolence, vertigo, anxiety.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Mefloquine Hydrochloride Tablets USP are indicated for the treatment of mild to moderate acute malaria caused by mefloquine-susceptible strains of P. falciparum (both chloroquine-susceptible and resistant strains) or by Plasmodium vivax. There are insufficient clinical data to document the effect of mefloquine in malaria caused by P. ovale or P. malariae.
- Note: Patients with acute P. vivax malaria, treated with mefloquine, are at high risk of relapse because mefloquine does not eliminate exoerythrocytic (hepatic phase) parasites. To avoid relapse, after initial treatment of the acute infection with mefloquine, patients should subsequently be treated with an 8-aminoquinoline derivative (e.g., primaquine).
- Mefloquine Hydrochloride Tablets USP are indicated for the prophylaxis of P. falciparum and P. vivax malaria infections, including prophylaxis of chloroquine-resistant strains of P. falciparum.
### Dosing Information
- Treatment of mild to moderate malaria in adults caused by mefloquine-susceptible strains of P. falciparum or by P. vivax: Dosage: Five tablets (1250 mg) mefloquine hydrochloride to be given as a single oral dose. The drug should not be taken on an empty stomach and should be administered with at least 8 oz (240 mL) of water.
- If a full-treatment course with mefloquine does not lead to improvement within 48 to 72 hours, mefloquine should not be used for retreatment. An alternative therapy should be used. Similarly, if previous prophylaxis with mefloquine failed, mefloquine should not be used for curative treatment (see INDICATIONS AND USAGE).
- Note: Patients with acute P. vivax malaria, treated with mefloquine, are at high risk of relapse because mefloquine does not eliminate exoerythrocytic (hepatic phase) parasites. To avoid relapse after initial treatment of the acute infection with mefloquine, patients should subsequently be treated with an 8-aminoquinoline derivative (e.g., primaquine).
- Dosage: One 250 mg mefloquine hydrochloride tablet once weekly.
- Prophylactic drug administration should begin 1 week before arrival in an endemic area. Subsequent weekly doses should be taken regularly, always on the same day of each week, preferably after the main meal. To reduce the risk of malaria after leaving an endemic area, prophylaxis must be continued for 4 additional weeks to ensure suppressive blood levels of the drug when merozoites emerge from the liver. Tablets should not be taken on an empty stomach and should be administered with at least 8 oz (240 mL) of water.
- In certain cases, e.g., when a traveler is taking other medication, it may be desirable to start prophylaxis 2 to 3 weeks prior to departure, in order to ensure that the combination of drugs is well tolerated (see PRECAUTIONS, DRUG INTERACTIONS).
- When prophylaxis with mefloquine fails, physicians should carefully evaluate which antimalarial to use for therapy.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mefloquine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mefloquine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Treatment of mild to moderate malaria in pediatric patients caused by mefloquine-susceptible strains of P. falciparum: Dosage: 20 to 25 mg/kg body weight. Splitting the total therapeutic dose into 2 doses taken 6 to 8 hours apart may reduce the occurrence or severity of adverse effects. The pediatric dose should not exceed the adult dose.
- Experience with mefloquine in pediatric patients weighing less than 20 kg is limited.
- The drug should not be taken on an empty stomach and should be administered with ample water. The tablets may be crushed and suspended in a small amount of water, milk or other beverage for administration to small children and other persons unable to swallow them whole.
- If a full-treatment course with mefloquine does not lead to improvement within 48 to 72 hours, mefloquine should not be used for retreatment. An alternative therapy should be used. Similarly, if previous prophylaxis with mefloquine has failed, mefloquine should not be used for curative treatment.
- In pediatric patients, the administration of mefloquine for the treatment of malaria has been associated with early vomiting. In some cases, early vomiting has been cited as a possible cause of treatment failure (see PRECAUTIONS). If a significant loss of drug product is observed or suspected because of vomiting, a second full dose of mefloquine should be administered to patients who vomit less than 30 minutes after receiving the drug. If vomiting occurs 30 to 60 minutes after a dose, an additional half-dose should be given. If vomiting recurs, the patient should be monitored closely and alternative malaria treatment considered if improvement is not observed within a reasonable period of time.
- The safety and effectiveness of mefloquine to treat malaria in pediatric patients below the age of 6 months have not been established.
- The recommended prophylactic dose of mefloquine is approximately 5 mg/kg body weight once weekly. One 250 mg mefloquine hydrochloride tablet should be taken once weekly in pediatric patients weighing over 45 kg. In pediatric patients weighing less than 45 kg, the weekly dose decreases in proportion to body weight:
- 30 to 45 kg: 3/4 tablet
- 20 to 30 kg: 1/2 tablet
- Experience with mefloquine in pediatric patients weighing less than 20 kg is limited.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mefloquine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non Guideline-Supported Use of Mefloquine in pediatric patients.
# Contraindications
- Use of mefloquine hydrochloride tablets is contraindicated in patients with a known hypersensitivity to mefloquine or related compounds (e.g., quinine and quinidine) or to any of the excipients contained in the formulation. Mefloquine hydrochloride tablets should not be prescribed for prophylaxis in patients with active depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia or other major psychiatric disorders, or with a history of convulsions.
# Warnings
- In case of life-threatening, serious or overwhelming malaria infections due to P. falciparum, patients should be treated with an intravenous antimalarial drug. Following completion of intravenous treatment, mefloquine may be given to complete the course of therapy.
- Halofantrine should not be administered with mefloquine or within 15 weeks of the last dose of mefloquine due to the risk of a potentially fatal prolongation of the QTc interval.
- Ketoconazole should not be administered with mefloquine or within 15 weeks of the last dose of mefloquine due to the risk of a potentially fatal prolongation of the QTc interval. Ketoconazole increases plasma concentrations and elimination half-life of mefloquine following coadministration.
- Concomitant administration of mefloquine and quinine or quinidine may produce electrocardiographic abnormalities.
- Mefloquine may cause neuropsychiatric adverse reactions in adults and children. Neuropsychiatric symptoms can be difficult to identify in children. Therefore, vigilance is required to monitor for the occurrence of these symptoms, especially in nonverbal children.
- Psychiatric symptoms ranging from anxiety, paranoia, and depression to hallucinations and psychotic behavior can occur with mefloquine use. Symptoms may occur early in the course of mefloquine use. In some cases, these symptoms have been reported to continue for months or years after mefloquine has been stopped. Cases of suicidal ideation and suicide have been reported.
- Mefloquine should not be prescribed for prophylaxis in patients with active depression, generalized anxiety disorder, psychosis, or schizophrenia or other major psychiatric disorders. Mefloquine should be used with caution in patients with a previous history of depression.
- During prophylactic use, the occurrence of psychiatric symptoms such as acute anxiety, depression, restlessness or confusion suggest a risk for more serious psychiatric disturbances or neurologic adverse reactions. In these cases, the drug should be discontinued and an alternative medication should be substituted.
- Neurologic symptoms such as dizziness or vertigo, tinnitus, and loss of balance have been reported. These adverse reactions may occur early in the course of mefloquine use and in some cases have been reported to continue for months or years after mefloquine has been stopped. Dizziness or vertigo, tinnitus, and loss of balance have been reported to be permanent in some cases. During prophylactic use, if neurologic symptoms occur, the drug should be discontinued and an alternative medication should be substituted.
- Caution should be exercised with regard to activities requiring alertness and fine motor coordination, such as driving, piloting aircraft, operating machinery, and deep-sea diving, while symptoms persist.
- Mefloquine may increase the risk of convulsions in patients with epilepsy. The drug should therefore be prescribed only for curative treatment in such patients and only if there are compelling medical reasons for its use.
- Concomitant administration of mefloquine and quinine or chloroquine may increase the risk of convulsions.
### PRECAUTIONS
- Hypersensitivity reactions have been reported with mefloquine use.
- In patients with impaired liver function the elimination of mefloquine may be prolonged, leading to higher plasma levels and a higher risk of adverse reactions.
- This drug has been administered for longer than one year. If the drug is to be administered for a prolonged period, periodic evaluations including liver function tests and evaluations for neuropsychiatric effects should be performed.
- Periodic ophthalmic examinations are recommended. Retinal abnormalities seen in humans with long-term chloroquine use have not been observed with mefloquine use, however, long- term feeding of mefloquine to rats resulted in dose-related ocular lesions (retinal degeneration, retinal edema and lenticular opacity at 12.5 mg/kg/day and higher) (see ANIMAL TOXICOLOGY).
- Parenteral studies in animals show that mefloquine, a myocardial depressant, possesses 20% of the anti-fibrillatory action of quinidine and produces 50% of the increase in the PR interval reported with quinine. The effect of mefloquine on the compromised cardiovascular system has not been evaluated. However, transitory and clinically silent ECG alterations have been reported during the use of mefloquine; alterations included sinus bradycardia, sinus arrhythmia, first degree AV-block, prolongation of the QTc interval and abnormal T waves (see also cardiovascular effects under PRECAUTIONS, DRUG INTERACTIONS and ADVERSE REACTIONS). The benefits of mefloquine therapy should be weighed against the possibility of adverse effects in patients with cardiac disease.
- Geographical drug resistance patterns of P. falciparum occur and the preferred choice of malaria prophylaxis might be different from one area to another. For example, resistance of P. falciparum to mefloquine has been reported, predominantly in areas of multi-drug resistance in South-East Asia. Cross-resistance between mefloquine and halofantrine and cross-resistance between mefloquine and quinine have been observed in some regions.
- Cases of agranulocytosis and aplastic anemia have been reported.
- Periodic evaluation of hepatic function should be performed during prolonged prophylaxis.
# Adverse Reactions
## Clinical Trials Experience
- At the doses used for treatment of acute malaria infections, the symptoms possibly attributable to drug administration cannot be distinguished from those symptoms usually attributable to the disease itself.
- Among subjects who received mefloquine for prophylaxis of malaria, the most frequently observed adverse experience was vomiting (3%). Dizziness, syncope, extrasystoles and other complaints affecting less than 1% were also reported.
- Two serious adverse reactions were cardiopulmonary arrest in one patient shortly after ingesting a single prophylactic dose of mefloquine while concomitantly using propranolol (see PRECAUTIONS, DRUG INTERACTIONS), and encephalopathy of unknown etiology during prophylactic mefloquine administration. The relationship of encephalopathy to drug administration could not be clearly established.
- Among subjects who received mefloquine for treatment, the most frequently observed adverse experiences included: dizziness, myalgia, nausea, fever, headache, vomiting, chills, diarrhea, skin rash, abdominal pain, fatigue, loss of appetite, and tinnitus. Those side effects occurring in less than 1% included bradycardia, hair loss, emotional problems, pruritus, asthenia, transient emotional disturbances and telogen effluvium (loss of resting hair). Seizures have also been reported.
- The most frequently observed laboratory alterations which could be possibly attributable to drug administration were decreased hematocrit, transient elevation of transaminases, leukopenia and thrombocytopenia. These alterations were observed in patients with acute malaria who received treatment doses of the drug and were attributed to the disease itself.
- During prophylactic administration of mefloquine to indigenous populations in malaria-endemic areas, the following alterations in laboratory values were observed: transient elevation of transaminases, leukocytosis or thrombocytopenia.
- Because of the long half-life of mefloquine, adverse reactions to mefloquine may occur or persist up to several weeks after discontinuation of the drug.
## Postmarketing Experience
- Postmarketing surveillance indicates that the same kind of adverse reactions are reported during prophylaxis, as well as acute treatment. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to mefloquine exposure.
- The most frequently reported adverse reactions are nausea, vomiting, loose stools or diarrhea, abdominal pain, dizziness or vertigo, loss of balance, and neuropsychiatric events such as headache, somnolence, and sleep disorders (insomnia, abnormal dreams). These adverse reactions may occur early in the course of mefloquine use. It has been reported that dizziness or vertigo, tinnitus and hearing impairment, and loss of balance may continue for months or years after discontinuation of the drug and may be permanent in some cases.
- More severe neuropsychiatric disorders have been reported such as: sensory and motor neuropathies (including paresthesia, tremor and ataxia), convulsions, agitation or restlessness, anxiety, depression, mood swings, panic attacks, memory impairment, confusion, hallucinations, aggression, psychotic or paranoid reactions and encephalopathy. Cases of suicidal ideation and suicide have been reported.
- Other less frequently reported adverse reactions include:
- Circulatory disturbances (hypotension, hypertension, flushing, syncope), chest pain, tachycardia or palpitation, bradycardia, irregular heart rate, extrasystoles, A-V block, and other transient cardiac conduction alterations.
- Rash, exanthema, erythema, urticaria, pruritus, edema, hair loss, erythema multiforme, and Stevens-Johnson syndrome.
- Muscle weakness, muscle cramps, myalgia, and arthralgia.
- Dyspnea, pneumonitis of possible allergic etiology
- Drug-related hepatic disorders from asymptomatic transient transaminase elevations to hepatic failure.
- Agranulocytosis, aplastic anemia.
- Visual disturbances, asthenia, malaise, fatigue, fever, hyperhidrosis, chills, dyspepsia and loss of appetite.
# Drug Interactions
- Drug-drug interactions with mefloquine have not been explored in detail. There is one report of cardiopulmonary arrest, with full recovery, in a patient who was taking a beta blocker (propranolol) (see PRECAUTIONS, CARDIAC EFFECTS). The effects of mefloquine on the compromised cardiovascular system have not been evaluated. The benefits of mefloquine therapy should be weighed against the possibility of adverse effects in patients with cardiac disease.
- Halofantrine should not be administered with mefloquine or within 15 weeks of the last dose of mefloquine due to the risk of a potential fatal prolongation of the QTc interval.
- Concomitant administration of mefloquine and other related antimalarial compounds (e.g., quinine, quinidine and chloroquine) may produce electrocardiographic abnormalities and increase the risk of convulsions (see WARNINGS). If these drugs are to be used in the initial treatment of severe malaria, mefloquine administration should be delayed at least 12 hours after the last dose. Clinically significant QTc prolongation has not been found with mefloquine alone.
- Coadministration of a single 500 mg oral dose of mefloquine with 400 mg of ketoconazole once daily for 10 days in 8 healthy volunteers resulted in an increase in the mean Cmax and AUC of mefloquine by 64% and 79%, respectively, and an increase in the mean elimination half-life of mefloquine from 322 hours to 448 hours. Ketoconazole should not be administered with mefloquine or within 15 weeks of the last dose of mefloquine due to the risk of a potentially fatal prolongation of the QTc interval (see WARNINGS).
- Coadministration of other drugs known to alter cardiac conduction (e.g., anti-arrhythmic or beta-adrenergic blocking agents, calcium channel blockers, antihistamines or H1-blocking agents, tricyclic antidepressants and phenothiazines) might also contribute to a prolongation of the QTc interval. There are no data that conclusively establish whether the concomitant administration of mefloquine and the above listed agents has an effect on cardiac function.
- In patients taking an anticonvulsant (e.g., valproic acid, carbamazepine, phenobarbital or phenytoin), the concomitant use of mefloquine may reduce seizure control by lowering the plasma levels of the anticonvulsant. Therefore, patients concurrently taking anti-seizure medication and mefloquine should have the blood level of their anti-seizure medication monitored and the dosage adjusted appropriately (see PRECAUTIONS).
- When mefloquine is taken concurrently with oral live typhoid vaccines, attenuation of immunization cannot be excluded. Vaccinations with attenuated live bacteria should therefore be completed at least 3 days before the first dose of mefloquine hydrochloride tablets.
- Coadministration of a single 500 mg oral dose of mefloquine and 600 mg of rifampin once daily for 7 days in 7 healthy Thai volunteers resulted in a decrease in the mean Cmax and AUC of mefloquine by 19% and 68%, respectively, and a decrease in the mean elimination half-life of mefloquine from 305 hours to 113 hours. Rifampin should be used cautiously in patients taking mefloquine.
- Mefloquine does not inhibit or induce the CYP 450 enzyme system. Thus, concomitant administration of mefloquine hydrochloride tablets and substrates of the CYP 450 enzyme system is not expected to result in a drug interaction. However, mefloquine is metabolized by CYP3A4 and inhibitors of CYP3A4 may modify the pharmacokinetics/metabolism of mefloquine, leading to an increase in mefloquine plasma concentrations and potential risk of adverse reactions. Therefore, mefloquine hydrochloride tablets should be used with caution when administered concomitantly with CYP3A4 inhibitors. Similarly, inducers of CYP3A4 may modify the pharmacokinetics/metabolism of mefloquine, leading to a decrease in mefloquine plasma concentrations and potential reduction in efficacy of mefloquine hydrochloride tablets. Therefore, mefloquine hydrochloride tablets should also be used with caution when administered concomitantly with CYP3A4 inducers.
- It has been shown in vitro that mefloquine is a substrate and an inhibitor of P-glycoprotein. Therefore, drug-drug interactions could also occur with drugs that are substrates or are known to modify the expression of this transporter. The clinical relevance of these interactions is not known to date.
- No other drug interactions are known. Nevertheless, the effects of mefloquine on travelers receiving concomitant medications, particularly diabetics or patients using anticoagulants, should be checked before departure.
- In clinical trials, the concomitant administration of sulfadoxine and pyrimethamine did not alter the adverse reaction profile of mefloquine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Data from published studies in pregnant women have shown no increase in the risk of teratogenic effects or adverse pregnancy outcomes following mefloquine treatment or prophylaxis during pregnancy. Reproduction studies in mice, rats and rabbits have shown teratogenic effects at doses similar to the clinical acute treatment dose in humans. Because the studies in humans cannot rule out the possibility of harm, mefloquine should be used during pregnancy only if clearly needed.
- Published data on mefloquine use during pregnancy include randomized controlled trials, intervention trials, prospective and retrospective cohort studies, and case series. These data showed that pregnant women who took mefloquine at various doses for both prevention and treatment of malaria did not have an increased risk of teratogenic effects or adverse pregnancy outcomes compared to the background rate in the general population. These data include more than 700 exposures to mefloquine in the first trimester of pregnancy and over 2,000 exposures in the second and third trimester.
- Mefloquine administered to pregnant mice, rats, and rabbits was teratogenic at doses similar to the clinical acute treatment dose of 21 to 25 mg/kg, based on body surface area comparisons. In all three animal species, CNS effects (e.g., exencephaly, hydrocephaly or partially missing medulla oblongata) and craniofacial malformations were observed. At the same doses, mefloquine was also embryotoxic in mice and rabbits. All of these findings were observed at doses that were maternally toxic.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mefloquine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Mefloquine during labor and delivery.
### Nursing Mothers
- Mefloquine is excreted in human milk in small amounts, the activity of which is unknown. Based on a study in a few subjects, low concentrations (3% to 4%) of mefloquine were excreted in human milk following a dose equivalent to 250 mg of the free base. Caution should be exercised when administered to a nursing woman.
### Pediatric Use
- Use of mefloquine to treat acute, uncomplicated P. falciparum malaria in pediatric patients is supported by evidence from adequate and well-controlled studies of mefloquine in adults with additional data from published open-label and comparative trials using mefloquine to treat malaria caused by P. falciparum in patients younger than 16 years of age. The safety and effectiveness of mefloquine for the treatment of malaria in pediatric patients below the age of 6 months have not been established.
- In several studies, the administration of mefloquine for the treatment of malaria was associated with early vomiting in pediatric patients. Early vomiting was cited in some reports as a possible cause of treatment failure. If a second dose is not tolerated, the patient should be monitored closely and alternative malaria treatment considered if improvement is not observed within a reasonable period of time.
### Geriatic Use
- Clinical studies of mefloquine did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Since electrocardiographic abnormalities have been observed in individuals treated with mefloquine and underlying cardiac disease is more prevalent in elderly than in younger patients, the benefits of mefloquine therapy should be weighed against the possibility of adverse cardiac effects in elderly patients.
### Gender
There is no FDA guidance on the use of Mefloquine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Mefloquine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Mefloquine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Mefloquine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Mefloquine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Mefloquine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- In patients taking an anticonvulsant (e.g., valproic acid, carbamazepine, phenobarbital or phenytoin), the concomitant use of mefloquine may reduce seizure control by lowering the plasma levels of the anticonvulsant. Therefore, patients concurrently taking anti-seizure medication and mefloquine should have the blood level of their anti-seizure medication monitored and the dosage adjusted appropriately.
- In several studies, the administration of mefloquine for the treatment of malaria was associated with early vomiting in pediatric patients. Early vomiting was cited in some reports as a possible cause of treatment failure. If a second dose is not tolerated, the patient should be monitored closely and alternative malaria treatment considered if improvement is not observed within a reasonable period of time.
- In cases of overdosage with mefloquine, the symptoms mentioned under ADVERSE REACTIONS may be more pronounced.
- Patients should be managed by symptomatic and supportive care following mefloquine overdose. There are no specific antidotes. Monitor cardiac function (if possible by ECG) and neuropsychiatric status. Provide symptomatic and intensive supportive treatment as required.
# IV Compatibility
There is limited information regarding IV Compatibility of Mefloquine in the drug label.
# Overdosage
- In cases of overdosage with mefloquine, the symptoms mentioned under ADVERSE REACTIONS may be more pronounced.
- Patients should be managed by symptomatic and supportive care following mefloquine overdose. There are no specific antidotes. Monitor cardiac function (if possible by ECG) and neuropsychiatric status. Provide symptomatic and intensive supportive treatment as required.
# Pharmacology
## Mechanism of Action
- Mefloquine is an antimalarial agent which acts as a blood schizonticide. Its exact mechanism of action is not known.
## Structure
- Mefloquine Hydrochloride Tablets USP are an antimalarial agent available as 250 mg tablets of mefloquine hydrochloride (equivalent to 228 mg of the free base) for oral administration.
- Mefloquine Hydrochloride USP is a 4-quinolinemethanol derivative with the specific chemical name of (R*, S*)-(±)-α-2-piperidinyl-2,8-bis (trifluoromethyl)-4-quinolinemethanol hydrochloride. It is a 2-aryl substituted chemical structural analog of quinine. The drug is a white to almost white crystalline compound, slightly soluble in water. The structural formula is as follows:
## Pharmacodynamics
### Microbiology
- Mefloquine is active against the erythrocytic stages of Plasmodium species (see INDICATIONS AND USAGE). However, the drug has no effect against the exoerythrocytic (hepatic) stages of the parasite. Mefloquine is effective against malaria parasites resistant to chloroquine.
- Strains of P. falciparum with decreased susceptibility to mefloquine can be selected in vitro or in vivo. Resistance of P. falciparum to mefloquine has been reported in areas of multi-drug resistance in South East Asia. Increased incidences of resistance have also been reported in other parts of the world.
- Cross-resistance between mefloquine and halofantrine and cross-resistance between mefloquine and quinine have been observed in some regions.
## Pharmacokinetics
- The absolute oral bioavailability of mefloquine has not been determined since an intravenous formulation is not available. The bioavailability of the tablet formation compared with an oral solution was over 85%. The presence of food significantly enhances the rate and extent of absorption, leading to about a 40% increase in bioavailability. In healthy volunteers, plasma concentrations peak 6 to 24 hours (median, about 17 hours) after a single dose of mefloquine. In a similar group of volunteers, maximum plasma concentrations in mcg/L are roughly equivalent to the dose in milligrams (for example, a single 1000 mg dose produces a maximum concentration of about 1000 mcg/L). In healthy volunteers, a dose of 250 mg once weekly produces maximum steady-state plasma concentrations of 1000 to 2000 mcg/L, which are reached after 7 to 10 weeks.
- In healthy adults, the apparent volume of distribution is approximately 20 L/kg, indicating extensive tissue distribution. Mefloquine may accumulate in parasitized erythrocytes. Experiments conducted in vitro with human blood using concentrations between 50 and 1000 mg/mL showed a relatively constant erythrocyte-to-plasma concentration ratio of about 2 to 1. The equilibrium reached in less than 30 minutes was found to be reversible. Protein binding is about 98%.
- Mefloquine crosses the placenta. Excretion into breast milk appears to be minimal.
- Mefloquine is extensively metabolized in the liver by the cytochrome P450 system. In vitro and in vivo studies strongly suggested that CYP3A4 is the major isoform involved.
- Two metabolites of mefloquine have been identified in humans. The main metabolite, 2,8-bis-trifluoromethyl-4-quinoline carboxylic acid, is inactive in Plasmodium falciparum. In a study in healthy volunteers, the carboxylic acid metabolite appeared in plasma 2 to 4 hours after a single oral dose. Maximum plasma concentrations of the metabolite, which were about 50% higher than those of mefloquine, were reached after 2 weeks. Thereafter, plasma levels of the main metabolite and mefloquine declined at a similar rate. The area under the plasma concentration-time curve (AUC) of the main metabolite was 3 to 5 times larger than that of the parent drug. The other metabolite, an alcohol, was present in minute quantities only.
- In several studies in healthy adults, the mean elimination half-life of mefloquine varied between 2 and 4 weeks, with an average of about 3 weeks. Total clearance, which is essentially hepatic, is in the order of 30 mL/min. There is evidence that mefloquine is excreted mainly in the bile and feces. In volunteers, urinary excretion of unchanged mefloquine and its main metabolite under steady-state condition accounted for about 9% and 4% of the dose, respectively. Concentrations of other metabolites could not be measured in the urine.
- Children and the Elderly:
- No relevant age-related changes have been observed in the pharmacokinetics of mefloquine. Therefore, the dosage for children has been extrapolated from the recommended adult dose.
- No pharmacokinetic studies have been performed in patients with renal insufficiency since only a small proportion of the drug is eliminated renally. Mefloquine and its main metabolite are not appreciably removed by hemodialysis. No special chemoprophylactic dosage adjustments are indicated for dialysis patients to achieve concentrations in plasma similar to those in healthy persons.
- Although clearance of mefloquine may increase in late pregnancy, in general, pregnancy has no clinically relevant effect on the pharmacokinetics of mefloquine.
- The pharmacokinetics of mefloquine may be altered in acute malaria.
- Pharmacokinetic differences have been observed between various ethnic populations. In practice, however, these are of minor importance compared with host immune status and sensitivity of the parasite.
- During long-term prophylaxis (>2 years), the trough concentrations and the elimination half-life of mefloquine were similar to those obtained in the same population after 6 months of drug use, which is when they reached steady-state.
- In vitro and in vivo studies showed no hemolysis associated with glucose-6-phosphate dehydrogenase deficiency .
## Nonclinical Toxicology
- Ocular lesions were observed in rats fed mefloquine daily for 2 years. All surviving rats given 30 mg/kg/day had ocular lesions in both eyes characterized by retinal degeneration, opacity of the lens, and retinal edema. Similar but less severe lesions were observed in 80% of female and 22% of male rats fed 12.5 mg/kg/day for 2 years. At doses of 5 mg/kg/day, only corneal lesions were observed. They occurred in 9% of rats studied.
- Male Wistar rats orally administered-mefloquine daily for 22 days at the equivalent human therapeutic plasma concentration showed CNS penetration of mefloquine, with a 30-50 fold greater brain/plasma drug ratio up to 10 days after the final dose administered.
# Clinical Studies
There is limited information regarding Clinical Studies of Mefloquine in the drug label.
# How Supplied
Mefloquine Hydrochloride Tablets USP, 250 mg are available as white, oval-shaped, flat-faced, beveled-edge, scored tablets, debossed with b171 on the scored side and plain on the other side, packaged in unit-dose cartons of 25 tablets.
KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.
## Storage
Store at 20° to 25°C (68° to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
Mefloquine HCl Tablets USP 250mg 25s Carton Text
NDC 0555-0171-78
MEFLOQUINE HCl
Tablets USP
250 mg
Each tablet contains 250 mg mefloquine hydrochloride USP.
PHARMACIST: Dispense the enclosed Medication Guide to each patient.
Rx only
25 UNIT-DOSE TABLETS (5 x 5)
TEVA
# Patient Counseling Information
- Medication Guide: As required by law, a mefloquine hydrochloride tablets Medication Guide is supplied to patients when mefloquine is dispensed. An information wallet card is also supplied to patients when mefloquine is dispensed. Patients should be instructed to read the Medication Guide when mefloquine is received and to carry the information wallet card with them when they are taking mefloquine. The complete texts of the Medication Guide and information wallet card are reprinted at the end of this document.
- Patients should be advised:
- that malaria can be a life-threatening infection
that mefloquine hydrochloride tablets are being prescribed to help prevent or treat this serious infection;
- that some patients are unable to take this medication because of side effects, including dizziness or vertigo and loss of balance, and it may be necessary to change medications. In some patients it has been reported that these symptoms may continue for months or years after discontinuation of the drug and can be permanent in some cases;
- that insomnia may occur
- that when used as prophylaxis, the first dose of mefloquine hydrochloride tablets should be taken one week prior to arrival in an endemic area;
- that if the patients experience psychiatric adverse reactions such as acute anxiety, depression, restlessness or confusion, or suicidal ideation, the drug should be discontinued and an alternative medication should be substituted;
- that no chemoprophylactic regimen is 100% effective, and protective clothing, insect repellents, and bed nets are important components of malaria prophylaxis;
- to seek medical attention for any febrile illness that occurs after return from a malaria area and to inform their physician that they may have been exposed to malaria.
### MEDICATION GUIDE
- Mefloquine Hydrochloride Tablets USP
- Your doctor or pharmacist will give you an Information Wallet Card along with this
- Medication Guide. It has important information about mefloquine and should be carried with
- you at all times while you take mefloquine.
- What is the most important information I should know about mefloquine?
- 1. Heart Problems.
- Do not take halofantrine (used to treat malaria) or ketoconazole (used for fungal infections) with mefloquine or within 15 weeks of your last dose of mefloquine. You may get serious heart problems (problems with the electrical system of your heart called QT prolongation) that can lead to death. Do not take quinine (Qualaquin) or quinidine (used to treat malaria or irregular heart beat) with mefloquine. You may get serious heart problems.
- 2. Mental problems. Symptoms of serious mental problems may include:
- severe anxiety
- paranoia (feelings of mistrust towards others)
- hallucinations (seeing or hearing things that are not there)
- depression
- feeling restless
- unusual behavior
- feeling confused
- Some people who take mefloquine think about suicide (putting an end to their life). Some people who were taking mefloquine committed suicide. It is not known if mefloquine was responsible for those suicides.
- If you have any of these serious mental problems, or you develop other serious side effects or mental problems, you should contact your doctor right away as it may be necessary to stop taking mefloquine and use a different medicine to prevent malaria.
- 3. Problems with your body’s nervous system. Symptoms of serious nervous system problems may include:
- dizziness
- a feeling that you or things around you are moving or spinning (vertigo)
- loss of balance
- ringing sound in your ears (tinnitus)
- convulsions (seizures) in people who already have seizures (epilepsy)
- convulsions (seizures) in people who take quinine or chloroquine (used to treat malaria) :- with mefloquine. Do not take quinine (Qualaquin) or chloroquine (Aralen) with mefloquine.
- unable to sleep (insomnia)
- Dizziness, vertigo, tinnitus, and loss of balance can go on for months or years after
- mefloquine is stopped or may become permanent in some people.
- Important:
- You need to take malaria prevention medicine before you travel to a malaria area, while
- you are in a malaria area, and after you return from a malaria area.
- If you are told by a doctor to stop taking mefloquine because of the side effects or for other reasons, you will need to take different malaria medicine.
If you do not have access to a doctor or to another medicine and have to stop taking mefloquine, leave the malaria area and contact a doctor as soon as possible because leaving the malaria area may not protect you from getting malaria. You will still need to take malaria prevention medicine for another 4 weeks after you leave the malaria area.
- Mefloquine is a prescription medicine used to prevent and treat malaria. Malaria can be a life-threatening infection. Mefloquine does not work for all types of malaria.
- It is not known if mefloquine is safe and effective in children under 6 months old for the
treatment of malaria. It is not known how well mefloquine works to prevent malaria in children
weighing less than 44 pounds (20 kilograms).
- Do not take mefloquine if you have:
- depression or had depression recently
- had recent mental problems, including anxiety disorder, schizophrenia, or psychosis (losing touch with reality)
- seizures or had seizures (epilepsy or convulsions)
- an allergy to quinine, quinidine, mefloquine or any ingredients in mefloquine. See the end of this Medication Guide for a complete list of ingredients in mefloquine.
- Talk to your doctor before you take mefloquine if you have any of the medical conditions listed above.
- Before taking mefloquine, tell your doctor about all your medical conditions, including if you have:
- heart disease
- liver problems
- seizures or epilepsy
- diabetes
- blood clotting problems or take blood thinner medicines (anticoagulants)
- mental problems
- are pregnant or plan to become pregnant. It is not known if mefloquine will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
- You should use birth control while you take mefloquine and for 3 months after you stop mefloquine. If you have an unplanned pregnancy, talk to your doctor right away.
- are breastfeeding or plan to breastfeed. Mefloquine can pass into your breast milk and may harm your baby. Ask your doctor if you will need to stop breastfeeding or use a different medicine.
- Contact your doctor right away if you have a fever after leaving a malaria area.
- Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Mefloquine and other medicines may affect each other causing side effects.
- Take mefloquine exactly as your doctor tells you to take it. Your doctor will tell you how many mefloquine tablets to take and when to take them.
- You will start taking mefloquine to prevent malaria between 1 to 3 weeks before you travel to a malaria area.
- Take mefloquine just after eating your largest meal of the day and with at least 1 cup (8 ounces) of water.
- Do not take mefloquine on an empty stomach.
- If you vomit after taking mefloquine, contact your doctor to see if you should take another dose.
- Continue taking mefloquine for 4 weeks after returning from a malaria area.
- Mefloquine tablets may be crushed and mixed with a small amount of water, milk or other beverage for children or other people unable to swallow mefloquine whole. Your doctor will tell you the correct dose for your child based on your child’s weight.
- If you take mefloquine for a year or longer, your doctor should check your:
- eyes (especially if you have trouble seeing while you take mefloquine)
- liver function (to see if there has been damage to your liver)
- Use protective clothing, insect repellents, and bed nets to protect you from being bitten by mosquitoes. Medicine alone does not always stop you from catching malaria from mosquito bites.
- Avoid activities such as driving a car or using heavy machinery or other activities needing alertness and careful movements (fine motor coordination) until you know how mefloquine affects you. You may feel dizzy or lose your balance. This could happen for months or years after you stop taking mefloquine and can be permanent in some cases. See “What are the possible side effects of mefloquine?”
- See “What is the most important information I should know about mefloquine?”
- Mefloquine may cause serious side effects, including:
- liver problems
- Call your healthcare provider right away if you have unexplained symptoms such as nausea or
vomiting, stomach pain, fever, weakness, itching, unusual tiredness, loss of appetite, light colored bowel movements, dark colored urine, yellowing of your skin or the white of your eyes.
- The most common side effects of mefloquine include:
- nausea
- vomiting
- diarrhea
- babdominal pain
- headache
- The most common side effects in people who take mefloquine for treatment include:
- muscle pain
- fever
- chills
- skin rash
- fatigue
- loss of appetite
- irregular heart beat
- Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of mefloquine. For more information, ask your doctor or pharmacist.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- Store mefloquine between 20ºC to 25ºC (68ºF to 77ºF)
- Safely throw away medicine that is out of date or no longer needed.
- Keep mefloquine and all medicines out of the reach of children.
- Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use mefloquine for a condition for which it was not prescribed. Do not give mefloquine to other people, even if they have the same symptoms that you have. It may harm them.
- This Medication Guide summarizes the most important information about mefloquine. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about mefloquine that is written for health professionals.
- Active ingredients: mefloquine hydrochloride
- Inactive ingredients: colloidal silicon dioxide, corn starch, crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, poloxamer and talc.
- This Medication Guide has been approved by the U.S. Food and Drug Administration.
TEVA PHARMACEUTICALS USA
Sellersville, PA 18960
Rev. B 6/2013
TEVA PHARMACEUTICALS USA
Sellersville, PA 18960
Rev. B 6/2013
# Precautions with Alcohol
- Alcohol-Mefloquine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Lariam®
# Look-Alike Drug Names
There is limited information regarding Mefloquine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Mefloquine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
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# Black Box Warning
# Overview
Mefloquine is a anti-Infective agent , antimalarial that is FDA approved for the treatment of mild to moderate acute malaria caused by mefloquine-susceptible strains of P. falciparum (both chloroquine-susceptible and resistant strains) or by Plasmodium vivax, prophylaxis of P. falciparum and P. vivax malaria infections, including prophylaxis of chloroquine-resistant strains of P. falciparum.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include bradyarrhythmia, abdominal pain, diarrhea, nausea, vomiting, coordination problem, dizziness, dream disorder, headache, insomnia, somnolence, vertigo, anxiety.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Mefloquine Hydrochloride Tablets USP are indicated for the treatment of mild to moderate acute malaria caused by mefloquine-susceptible strains of P. falciparum (both chloroquine-susceptible and resistant strains) or by Plasmodium vivax. There are insufficient clinical data to document the effect of mefloquine in malaria caused by P. ovale or P. malariae.
- Note: Patients with acute P. vivax malaria, treated with mefloquine, are at high risk of relapse because mefloquine does not eliminate exoerythrocytic (hepatic phase) parasites. To avoid relapse, after initial treatment of the acute infection with mefloquine, patients should subsequently be treated with an 8-aminoquinoline derivative (e.g., primaquine).
- Mefloquine Hydrochloride Tablets USP are indicated for the prophylaxis of P. falciparum and P. vivax malaria infections, including prophylaxis of chloroquine-resistant strains of P. falciparum.
### Dosing Information
- Treatment of mild to moderate malaria in adults caused by mefloquine-susceptible strains of P. falciparum or by P. vivax: Dosage: Five tablets (1250 mg) mefloquine hydrochloride to be given as a single oral dose. The drug should not be taken on an empty stomach and should be administered with at least 8 oz (240 mL) of water.
- If a full-treatment course with mefloquine does not lead to improvement within 48 to 72 hours, mefloquine should not be used for retreatment. An alternative therapy should be used. Similarly, if previous prophylaxis with mefloquine failed, mefloquine should not be used for curative treatment (see INDICATIONS AND USAGE).
- Note: Patients with acute P. vivax malaria, treated with mefloquine, are at high risk of relapse because mefloquine does not eliminate exoerythrocytic (hepatic phase) parasites. To avoid relapse after initial treatment of the acute infection with mefloquine, patients should subsequently be treated with an 8-aminoquinoline derivative (e.g., primaquine).
- Dosage: One 250 mg mefloquine hydrochloride tablet once weekly.
- Prophylactic drug administration should begin 1 week before arrival in an endemic area. Subsequent weekly doses should be taken regularly, always on the same day of each week, preferably after the main meal. To reduce the risk of malaria after leaving an endemic area, prophylaxis must be continued for 4 additional weeks to ensure suppressive blood levels of the drug when merozoites emerge from the liver. Tablets should not be taken on an empty stomach and should be administered with at least 8 oz (240 mL) of water.
- In certain cases, e.g., when a traveler is taking other medication, it may be desirable to start prophylaxis 2 to 3 weeks prior to departure, in order to ensure that the combination of drugs is well tolerated (see PRECAUTIONS, DRUG INTERACTIONS).
- When prophylaxis with mefloquine fails, physicians should carefully evaluate which antimalarial to use for therapy.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mefloquine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mefloquine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Treatment of mild to moderate malaria in pediatric patients caused by mefloquine-susceptible strains of P. falciparum: Dosage: 20 to 25 mg/kg body weight. Splitting the total therapeutic dose into 2 doses taken 6 to 8 hours apart may reduce the occurrence or severity of adverse effects. The pediatric dose should not exceed the adult dose.
- Experience with mefloquine in pediatric patients weighing less than 20 kg is limited.
- The drug should not be taken on an empty stomach and should be administered with ample water. The tablets may be crushed and suspended in a small amount of water, milk or other beverage for administration to small children and other persons unable to swallow them whole.
- If a full-treatment course with mefloquine does not lead to improvement within 48 to 72 hours, mefloquine should not be used for retreatment. An alternative therapy should be used. Similarly, if previous prophylaxis with mefloquine has failed, mefloquine should not be used for curative treatment.
- In pediatric patients, the administration of mefloquine for the treatment of malaria has been associated with early vomiting. In some cases, early vomiting has been cited as a possible cause of treatment failure (see PRECAUTIONS). If a significant loss of drug product is observed or suspected because of vomiting, a second full dose of mefloquine should be administered to patients who vomit less than 30 minutes after receiving the drug. If vomiting occurs 30 to 60 minutes after a dose, an additional half-dose should be given. If vomiting recurs, the patient should be monitored closely and alternative malaria treatment considered if improvement is not observed within a reasonable period of time.
- The safety and effectiveness of mefloquine to treat malaria in pediatric patients below the age of 6 months have not been established.
- The recommended prophylactic dose of mefloquine is approximately 5 mg/kg body weight once weekly. One 250 mg mefloquine hydrochloride tablet should be taken once weekly in pediatric patients weighing over 45 kg. In pediatric patients weighing less than 45 kg, the weekly dose decreases in proportion to body weight:
- 30 to 45 kg: 3/4 tablet
- 20 to 30 kg: 1/2 tablet
- Experience with mefloquine in pediatric patients weighing less than 20 kg is limited.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mefloquine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non Guideline-Supported Use of Mefloquine in pediatric patients.
# Contraindications
- Use of mefloquine hydrochloride tablets is contraindicated in patients with a known hypersensitivity to mefloquine or related compounds (e.g., quinine and quinidine) or to any of the excipients contained in the formulation. Mefloquine hydrochloride tablets should not be prescribed for prophylaxis in patients with active depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia or other major psychiatric disorders, or with a history of convulsions.
# Warnings
- In case of life-threatening, serious or overwhelming malaria infections due to P. falciparum, patients should be treated with an intravenous antimalarial drug. Following completion of intravenous treatment, mefloquine may be given to complete the course of therapy.
- Halofantrine should not be administered with mefloquine or within 15 weeks of the last dose of mefloquine due to the risk of a potentially fatal prolongation of the QTc interval.
- Ketoconazole should not be administered with mefloquine or within 15 weeks of the last dose of mefloquine due to the risk of a potentially fatal prolongation of the QTc interval. Ketoconazole increases plasma concentrations and elimination half-life of mefloquine following coadministration.
- Concomitant administration of mefloquine and quinine or quinidine may produce electrocardiographic abnormalities.
- Mefloquine may cause neuropsychiatric adverse reactions in adults and children. Neuropsychiatric symptoms can be difficult to identify in children. Therefore, vigilance is required to monitor for the occurrence of these symptoms, especially in nonverbal children.
- Psychiatric symptoms ranging from anxiety, paranoia, and depression to hallucinations and psychotic behavior can occur with mefloquine use. Symptoms may occur early in the course of mefloquine use. In some cases, these symptoms have been reported to continue for months or years after mefloquine has been stopped. Cases of suicidal ideation and suicide have been reported.
- Mefloquine should not be prescribed for prophylaxis in patients with active depression, generalized anxiety disorder, psychosis, or schizophrenia or other major psychiatric disorders. Mefloquine should be used with caution in patients with a previous history of depression.
- During prophylactic use, the occurrence of psychiatric symptoms such as acute anxiety, depression, restlessness or confusion suggest a risk for more serious psychiatric disturbances or neurologic adverse reactions. In these cases, the drug should be discontinued and an alternative medication should be substituted.
- Neurologic symptoms such as dizziness or vertigo, tinnitus, and loss of balance have been reported. These adverse reactions may occur early in the course of mefloquine use and in some cases have been reported to continue for months or years after mefloquine has been stopped. Dizziness or vertigo, tinnitus, and loss of balance have been reported to be permanent in some cases. During prophylactic use, if neurologic symptoms occur, the drug should be discontinued and an alternative medication should be substituted.
- Caution should be exercised with regard to activities requiring alertness and fine motor coordination, such as driving, piloting aircraft, operating machinery, and deep-sea diving, while symptoms persist.
- Mefloquine may increase the risk of convulsions in patients with epilepsy. The drug should therefore be prescribed only for curative treatment in such patients and only if there are compelling medical reasons for its use.
- Concomitant administration of mefloquine and quinine or chloroquine may increase the risk of convulsions.
### PRECAUTIONS
- Hypersensitivity reactions have been reported with mefloquine use.
- In patients with impaired liver function the elimination of mefloquine may be prolonged, leading to higher plasma levels and a higher risk of adverse reactions.
- This drug has been administered for longer than one year. If the drug is to be administered for a prolonged period, periodic evaluations including liver function tests and evaluations for neuropsychiatric effects should be performed.
- Periodic ophthalmic examinations are recommended. Retinal abnormalities seen in humans with long-term chloroquine use have not been observed with mefloquine use, however, long- term feeding of mefloquine to rats resulted in dose-related ocular lesions (retinal degeneration, retinal edema and lenticular opacity at 12.5 mg/kg/day and higher) (see ANIMAL TOXICOLOGY).
- Parenteral studies in animals show that mefloquine, a myocardial depressant, possesses 20% of the anti-fibrillatory action of quinidine and produces 50% of the increase in the PR interval reported with quinine. The effect of mefloquine on the compromised cardiovascular system has not been evaluated. However, transitory and clinically silent ECG alterations have been reported during the use of mefloquine; alterations included sinus bradycardia, sinus arrhythmia, first degree AV-block, prolongation of the QTc interval and abnormal T waves (see also cardiovascular effects under PRECAUTIONS, DRUG INTERACTIONS and ADVERSE REACTIONS). The benefits of mefloquine therapy should be weighed against the possibility of adverse effects in patients with cardiac disease.
- Geographical drug resistance patterns of P. falciparum occur and the preferred choice of malaria prophylaxis might be different from one area to another. For example, resistance of P. falciparum to mefloquine has been reported, predominantly in areas of multi-drug resistance in South-East Asia. Cross-resistance between mefloquine and halofantrine and cross-resistance between mefloquine and quinine have been observed in some regions.
- Cases of agranulocytosis and aplastic anemia have been reported.
- Periodic evaluation of hepatic function should be performed during prolonged prophylaxis.
# Adverse Reactions
## Clinical Trials Experience
- At the doses used for treatment of acute malaria infections, the symptoms possibly attributable to drug administration cannot be distinguished from those symptoms usually attributable to the disease itself.
- Among subjects who received mefloquine for prophylaxis of malaria, the most frequently observed adverse experience was vomiting (3%). Dizziness, syncope, extrasystoles and other complaints affecting less than 1% were also reported.
- Two serious adverse reactions were cardiopulmonary arrest in one patient shortly after ingesting a single prophylactic dose of mefloquine while concomitantly using propranolol (see PRECAUTIONS, DRUG INTERACTIONS), and encephalopathy of unknown etiology during prophylactic mefloquine administration. The relationship of encephalopathy to drug administration could not be clearly established.
- Among subjects who received mefloquine for treatment, the most frequently observed adverse experiences included: dizziness, myalgia, nausea, fever, headache, vomiting, chills, diarrhea, skin rash, abdominal pain, fatigue, loss of appetite, and tinnitus. Those side effects occurring in less than 1% included bradycardia, hair loss, emotional problems, pruritus, asthenia, transient emotional disturbances and telogen effluvium (loss of resting hair). Seizures have also been reported.
- The most frequently observed laboratory alterations which could be possibly attributable to drug administration were decreased hematocrit, transient elevation of transaminases, leukopenia and thrombocytopenia. These alterations were observed in patients with acute malaria who received treatment doses of the drug and were attributed to the disease itself.
- During prophylactic administration of mefloquine to indigenous populations in malaria-endemic areas, the following alterations in laboratory values were observed: transient elevation of transaminases, leukocytosis or thrombocytopenia.
- Because of the long half-life of mefloquine, adverse reactions to mefloquine may occur or persist up to several weeks after discontinuation of the drug.
## Postmarketing Experience
- Postmarketing surveillance indicates that the same kind of adverse reactions are reported during prophylaxis, as well as acute treatment. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to mefloquine exposure.
- The most frequently reported adverse reactions are nausea, vomiting, loose stools or diarrhea, abdominal pain, dizziness or vertigo, loss of balance, and neuropsychiatric events such as headache, somnolence, and sleep disorders (insomnia, abnormal dreams). These adverse reactions may occur early in the course of mefloquine use. It has been reported that dizziness or vertigo, tinnitus and hearing impairment, and loss of balance may continue for months or years after discontinuation of the drug and may be permanent in some cases.
- More severe neuropsychiatric disorders have been reported such as: sensory and motor neuropathies (including paresthesia, tremor and ataxia), convulsions, agitation or restlessness, anxiety, depression, mood swings, panic attacks, memory impairment, confusion, hallucinations, aggression, psychotic or paranoid reactions and encephalopathy. Cases of suicidal ideation and suicide have been reported.
- Other less frequently reported adverse reactions include:
- Circulatory disturbances (hypotension, hypertension, flushing, syncope), chest pain, tachycardia or palpitation, bradycardia, irregular heart rate, extrasystoles, A-V block, and other transient cardiac conduction alterations.
- Rash, exanthema, erythema, urticaria, pruritus, edema, hair loss, erythema multiforme, and Stevens-Johnson syndrome.
- Muscle weakness, muscle cramps, myalgia, and arthralgia.
- Dyspnea, pneumonitis of possible allergic etiology
- Drug-related hepatic disorders from asymptomatic transient transaminase elevations to hepatic failure.
- Agranulocytosis, aplastic anemia.
- Visual disturbances, asthenia, malaise, fatigue, fever, hyperhidrosis, chills, dyspepsia and loss of appetite.
# Drug Interactions
- Drug-drug interactions with mefloquine have not been explored in detail. There is one report of cardiopulmonary arrest, with full recovery, in a patient who was taking a beta blocker (propranolol) (see PRECAUTIONS, CARDIAC EFFECTS). The effects of mefloquine on the compromised cardiovascular system have not been evaluated. The benefits of mefloquine therapy should be weighed against the possibility of adverse effects in patients with cardiac disease.
- Halofantrine should not be administered with mefloquine or within 15 weeks of the last dose of mefloquine due to the risk of a potential fatal prolongation of the QTc interval.
- Concomitant administration of mefloquine and other related antimalarial compounds (e.g., quinine, quinidine and chloroquine) may produce electrocardiographic abnormalities and increase the risk of convulsions (see WARNINGS). If these drugs are to be used in the initial treatment of severe malaria, mefloquine administration should be delayed at least 12 hours after the last dose. Clinically significant QTc prolongation has not been found with mefloquine alone.
- Coadministration of a single 500 mg oral dose of mefloquine with 400 mg of ketoconazole once daily for 10 days in 8 healthy volunteers resulted in an increase in the mean Cmax and AUC of mefloquine by 64% and 79%, respectively, and an increase in the mean elimination half-life of mefloquine from 322 hours to 448 hours. Ketoconazole should not be administered with mefloquine or within 15 weeks of the last dose of mefloquine due to the risk of a potentially fatal prolongation of the QTc interval (see WARNINGS).
- Coadministration of other drugs known to alter cardiac conduction (e.g., anti-arrhythmic or beta-adrenergic blocking agents, calcium channel blockers, antihistamines or H1-blocking agents, tricyclic antidepressants and phenothiazines) might also contribute to a prolongation of the QTc interval. There are no data that conclusively establish whether the concomitant administration of mefloquine and the above listed agents has an effect on cardiac function.
- In patients taking an anticonvulsant (e.g., valproic acid, carbamazepine, phenobarbital or phenytoin), the concomitant use of mefloquine may reduce seizure control by lowering the plasma levels of the anticonvulsant. Therefore, patients concurrently taking anti-seizure medication and mefloquine should have the blood level of their anti-seizure medication monitored and the dosage adjusted appropriately (see PRECAUTIONS).
- When mefloquine is taken concurrently with oral live typhoid vaccines, attenuation of immunization cannot be excluded. Vaccinations with attenuated live bacteria should therefore be completed at least 3 days before the first dose of mefloquine hydrochloride tablets.
- Coadministration of a single 500 mg oral dose of mefloquine and 600 mg of rifampin once daily for 7 days in 7 healthy Thai volunteers resulted in a decrease in the mean Cmax and AUC of mefloquine by 19% and 68%, respectively, and a decrease in the mean elimination half-life of mefloquine from 305 hours to 113 hours. Rifampin should be used cautiously in patients taking mefloquine.
- Mefloquine does not inhibit or induce the CYP 450 enzyme system. Thus, concomitant administration of mefloquine hydrochloride tablets and substrates of the CYP 450 enzyme system is not expected to result in a drug interaction. However, mefloquine is metabolized by CYP3A4 and inhibitors of CYP3A4 may modify the pharmacokinetics/metabolism of mefloquine, leading to an increase in mefloquine plasma concentrations and potential risk of adverse reactions. Therefore, mefloquine hydrochloride tablets should be used with caution when administered concomitantly with CYP3A4 inhibitors. Similarly, inducers of CYP3A4 may modify the pharmacokinetics/metabolism of mefloquine, leading to a decrease in mefloquine plasma concentrations and potential reduction in efficacy of mefloquine hydrochloride tablets. Therefore, mefloquine hydrochloride tablets should also be used with caution when administered concomitantly with CYP3A4 inducers.
- It has been shown in vitro that mefloquine is a substrate and an inhibitor of P-glycoprotein. Therefore, drug-drug interactions could also occur with drugs that are substrates or are known to modify the expression of this transporter. The clinical relevance of these interactions is not known to date.
- No other drug interactions are known. Nevertheless, the effects of mefloquine on travelers receiving concomitant medications, particularly diabetics or patients using anticoagulants, should be checked before departure.
- In clinical trials, the concomitant administration of sulfadoxine and pyrimethamine did not alter the adverse reaction profile of mefloquine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Data from published studies in pregnant women have shown no increase in the risk of teratogenic effects or adverse pregnancy outcomes following mefloquine treatment or prophylaxis during pregnancy. Reproduction studies in mice, rats and rabbits have shown teratogenic effects at doses similar to the clinical acute treatment dose in humans. Because the studies in humans cannot rule out the possibility of harm, mefloquine should be used during pregnancy only if clearly needed.
- Published data on mefloquine use during pregnancy include randomized controlled trials, intervention trials, prospective and retrospective cohort studies, and case series. These data showed that pregnant women who took mefloquine at various doses for both prevention and treatment of malaria did not have an increased risk of teratogenic effects or adverse pregnancy outcomes compared to the background rate in the general population. These data include more than 700 exposures to mefloquine in the first trimester of pregnancy and over 2,000 exposures in the second and third trimester.
- Mefloquine administered to pregnant mice, rats, and rabbits was teratogenic at doses similar to the clinical acute treatment dose of 21 to 25 mg/kg, based on body surface area comparisons. In all three animal species, CNS effects (e.g., exencephaly, hydrocephaly or partially missing medulla oblongata) and craniofacial malformations were observed. At the same doses, mefloquine was also embryotoxic in mice and rabbits. All of these findings were observed at doses that were maternally toxic.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mefloquine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Mefloquine during labor and delivery.
### Nursing Mothers
- Mefloquine is excreted in human milk in small amounts, the activity of which is unknown. Based on a study in a few subjects, low concentrations (3% to 4%) of mefloquine were excreted in human milk following a dose equivalent to 250 mg of the free base. Caution should be exercised when administered to a nursing woman.
### Pediatric Use
- Use of mefloquine to treat acute, uncomplicated P. falciparum malaria in pediatric patients is supported by evidence from adequate and well-controlled studies of mefloquine in adults with additional data from published open-label and comparative trials using mefloquine to treat malaria caused by P. falciparum in patients younger than 16 years of age. The safety and effectiveness of mefloquine for the treatment of malaria in pediatric patients below the age of 6 months have not been established.
- In several studies, the administration of mefloquine for the treatment of malaria was associated with early vomiting in pediatric patients. Early vomiting was cited in some reports as a possible cause of treatment failure. If a second dose is not tolerated, the patient should be monitored closely and alternative malaria treatment considered if improvement is not observed within a reasonable period of time.
### Geriatic Use
- Clinical studies of mefloquine did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Since electrocardiographic abnormalities have been observed in individuals treated with mefloquine and underlying cardiac disease is more prevalent in elderly than in younger patients, the benefits of mefloquine therapy should be weighed against the possibility of adverse cardiac effects in elderly patients.
### Gender
There is no FDA guidance on the use of Mefloquine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Mefloquine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Mefloquine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Mefloquine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Mefloquine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Mefloquine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- In patients taking an anticonvulsant (e.g., valproic acid, carbamazepine, phenobarbital or phenytoin), the concomitant use of mefloquine may reduce seizure control by lowering the plasma levels of the anticonvulsant. Therefore, patients concurrently taking anti-seizure medication and mefloquine should have the blood level of their anti-seizure medication monitored and the dosage adjusted appropriately.
- In several studies, the administration of mefloquine for the treatment of malaria was associated with early vomiting in pediatric patients. Early vomiting was cited in some reports as a possible cause of treatment failure. If a second dose is not tolerated, the patient should be monitored closely and alternative malaria treatment considered if improvement is not observed within a reasonable period of time.
- In cases of overdosage with mefloquine, the symptoms mentioned under ADVERSE REACTIONS may be more pronounced.
- Patients should be managed by symptomatic and supportive care following mefloquine overdose. There are no specific antidotes. Monitor cardiac function (if possible by ECG) and neuropsychiatric status. Provide symptomatic and intensive supportive treatment as required.
# IV Compatibility
There is limited information regarding IV Compatibility of Mefloquine in the drug label.
# Overdosage
- In cases of overdosage with mefloquine, the symptoms mentioned under ADVERSE REACTIONS may be more pronounced.
- Patients should be managed by symptomatic and supportive care following mefloquine overdose. There are no specific antidotes. Monitor cardiac function (if possible by ECG) and neuropsychiatric status. Provide symptomatic and intensive supportive treatment as required.
# Pharmacology
## Mechanism of Action
- Mefloquine is an antimalarial agent which acts as a blood schizonticide. Its exact mechanism of action is not known.
## Structure
- Mefloquine Hydrochloride Tablets USP are an antimalarial agent available as 250 mg tablets of mefloquine hydrochloride (equivalent to 228 mg of the free base) for oral administration.
- Mefloquine Hydrochloride USP is a 4-quinolinemethanol derivative with the specific chemical name of (R*, S*)-(±)-α-2-piperidinyl-2,8-bis (trifluoromethyl)-4-quinolinemethanol hydrochloride. It is a 2-aryl substituted chemical structural analog of quinine. The drug is a white to almost white crystalline compound, slightly soluble in water. The structural formula is as follows:
## Pharmacodynamics
### Microbiology
- Mefloquine is active against the erythrocytic stages of Plasmodium species (see INDICATIONS AND USAGE). However, the drug has no effect against the exoerythrocytic (hepatic) stages of the parasite. Mefloquine is effective against malaria parasites resistant to chloroquine.
- Strains of P. falciparum with decreased susceptibility to mefloquine can be selected in vitro or in vivo. Resistance of P. falciparum to mefloquine has been reported in areas of multi-drug resistance in South East Asia. Increased incidences of resistance have also been reported in other parts of the world.
- Cross-resistance between mefloquine and halofantrine and cross-resistance between mefloquine and quinine have been observed in some regions.
## Pharmacokinetics
- The absolute oral bioavailability of mefloquine has not been determined since an intravenous formulation is not available. The bioavailability of the tablet formation compared with an oral solution was over 85%. The presence of food significantly enhances the rate and extent of absorption, leading to about a 40% increase in bioavailability. In healthy volunteers, plasma concentrations peak 6 to 24 hours (median, about 17 hours) after a single dose of mefloquine. In a similar group of volunteers, maximum plasma concentrations in mcg/L are roughly equivalent to the dose in milligrams (for example, a single 1000 mg dose produces a maximum concentration of about 1000 mcg/L). In healthy volunteers, a dose of 250 mg once weekly produces maximum steady-state plasma concentrations of 1000 to 2000 mcg/L, which are reached after 7 to 10 weeks.
- In healthy adults, the apparent volume of distribution is approximately 20 L/kg, indicating extensive tissue distribution. Mefloquine may accumulate in parasitized erythrocytes. Experiments conducted in vitro with human blood using concentrations between 50 and 1000 mg/mL showed a relatively constant erythrocyte-to-plasma concentration ratio of about 2 to 1. The equilibrium reached in less than 30 minutes was found to be reversible. Protein binding is about 98%.
- Mefloquine crosses the placenta. Excretion into breast milk appears to be minimal.
- Mefloquine is extensively metabolized in the liver by the cytochrome P450 system. In vitro and in vivo studies strongly suggested that CYP3A4 is the major isoform involved.
- Two metabolites of mefloquine have been identified in humans. The main metabolite, 2,8-bis-trifluoromethyl-4-quinoline carboxylic acid, is inactive in Plasmodium falciparum. In a study in healthy volunteers, the carboxylic acid metabolite appeared in plasma 2 to 4 hours after a single oral dose. Maximum plasma concentrations of the metabolite, which were about 50% higher than those of mefloquine, were reached after 2 weeks. Thereafter, plasma levels of the main metabolite and mefloquine declined at a similar rate. The area under the plasma concentration-time curve (AUC) of the main metabolite was 3 to 5 times larger than that of the parent drug. The other metabolite, an alcohol, was present in minute quantities only.
- In several studies in healthy adults, the mean elimination half-life of mefloquine varied between 2 and 4 weeks, with an average of about 3 weeks. Total clearance, which is essentially hepatic, is in the order of 30 mL/min. There is evidence that mefloquine is excreted mainly in the bile and feces. In volunteers, urinary excretion of unchanged mefloquine and its main metabolite under steady-state condition accounted for about 9% and 4% of the dose, respectively. Concentrations of other metabolites could not be measured in the urine.
- Children and the Elderly:
- No relevant age-related changes have been observed in the pharmacokinetics of mefloquine. Therefore, the dosage for children has been extrapolated from the recommended adult dose.
- No pharmacokinetic studies have been performed in patients with renal insufficiency since only a small proportion of the drug is eliminated renally. Mefloquine and its main metabolite are not appreciably removed by hemodialysis. No special chemoprophylactic dosage adjustments are indicated for dialysis patients to achieve concentrations in plasma similar to those in healthy persons.
- Although clearance of mefloquine may increase in late pregnancy, in general, pregnancy has no clinically relevant effect on the pharmacokinetics of mefloquine.
- The pharmacokinetics of mefloquine may be altered in acute malaria.
- Pharmacokinetic differences have been observed between various ethnic populations. In practice, however, these are of minor importance compared with host immune status and sensitivity of the parasite.
- During long-term prophylaxis (>2 years), the trough concentrations and the elimination half-life of mefloquine were similar to those obtained in the same population after 6 months of drug use, which is when they reached steady-state.
- In vitro and in vivo studies showed no hemolysis associated with glucose-6-phosphate dehydrogenase deficiency .
## Nonclinical Toxicology
- Ocular lesions were observed in rats fed mefloquine daily for 2 years. All surviving rats given 30 mg/kg/day had ocular lesions in both eyes characterized by retinal degeneration, opacity of the lens, and retinal edema. Similar but less severe lesions were observed in 80% of female and 22% of male rats fed 12.5 mg/kg/day for 2 years. At doses of 5 mg/kg/day, only corneal lesions were observed. They occurred in 9% of rats studied.
- Male Wistar rats orally administered-mefloquine daily for 22 days at the equivalent human therapeutic plasma concentration showed CNS penetration of mefloquine, with a 30-50 fold greater brain/plasma drug ratio up to 10 days after the final dose administered.
# Clinical Studies
There is limited information regarding Clinical Studies of Mefloquine in the drug label.
# How Supplied
Mefloquine Hydrochloride Tablets USP, 250 mg are available as white, oval-shaped, flat-faced, beveled-edge, scored tablets, debossed with b171 on the scored side and plain on the other side, packaged in unit-dose cartons of 25 tablets.
KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.
## Storage
Store at 20° to 25°C (68° to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
Mefloquine HCl Tablets USP 250mg 25s Carton Text
NDC 0555-0171-78
MEFLOQUINE HCl
Tablets USP
250 mg
Each tablet contains 250 mg mefloquine hydrochloride USP.
PHARMACIST: Dispense the enclosed Medication Guide to each patient.
Rx only
25 UNIT-DOSE TABLETS (5 x 5)
TEVA
# Patient Counseling Information
- Medication Guide: As required by law, a mefloquine hydrochloride tablets Medication Guide is supplied to patients when mefloquine is dispensed. An information wallet card is also supplied to patients when mefloquine is dispensed. Patients should be instructed to read the Medication Guide when mefloquine is received and to carry the information wallet card with them when they are taking mefloquine. The complete texts of the Medication Guide and information wallet card are reprinted at the end of this document.
- Patients should be advised:
- that malaria can be a life-threatening infection
that mefloquine hydrochloride tablets are being prescribed to help prevent or treat this serious infection;
- that some patients are unable to take this medication because of side effects, including dizziness or vertigo and loss of balance, and it may be necessary to change medications. In some patients it has been reported that these symptoms may continue for months or years after discontinuation of the drug and can be permanent in some cases;
- that insomnia may occur
- that when used as prophylaxis, the first dose of mefloquine hydrochloride tablets should be taken one week prior to arrival in an endemic area;
- that if the patients experience psychiatric adverse reactions such as acute anxiety, depression, restlessness or confusion, or suicidal ideation, the drug should be discontinued and an alternative medication should be substituted;
- that no chemoprophylactic regimen is 100% effective, and protective clothing, insect repellents, and bed nets are important components of malaria prophylaxis;
- to seek medical attention for any febrile illness that occurs after return from a malaria area and to inform their physician that they may have been exposed to malaria.
### MEDICATION GUIDE
- Mefloquine Hydrochloride Tablets USP
- Your doctor or pharmacist will give you an Information Wallet Card along with this
- Medication Guide. It has important information about mefloquine and should be carried with
- you at all times while you take mefloquine.
- What is the most important information I should know about mefloquine?
- 1. Heart Problems.
- Do not take halofantrine (used to treat malaria) or ketoconazole (used for fungal infections) with mefloquine or within 15 weeks of your last dose of mefloquine. You may get serious heart problems (problems with the electrical system of your heart called QT prolongation) that can lead to death. Do not take quinine (Qualaquin) or quinidine (used to treat malaria or irregular heart beat) with mefloquine. You may get serious heart problems.
- 2. Mental problems. Symptoms of serious mental problems may include:
- severe anxiety
- paranoia (feelings of mistrust towards others)
- hallucinations (seeing or hearing things that are not there)
- depression
- feeling restless
- unusual behavior
- feeling confused
- Some people who take mefloquine think about suicide (putting an end to their life). Some people who were taking mefloquine committed suicide. It is not known if mefloquine was responsible for those suicides.
- If you have any of these serious mental problems, or you develop other serious side effects or mental problems, you should contact your doctor right away as it may be necessary to stop taking mefloquine and use a different medicine to prevent malaria.
- 3. Problems with your body’s nervous system. Symptoms of serious nervous system problems may include:
- dizziness
- a feeling that you or things around you are moving or spinning (vertigo)
- loss of balance
- ringing sound in your ears (tinnitus)
- convulsions (seizures) in people who already have seizures (epilepsy)
- convulsions (seizures) in people who take quinine or chloroquine (used to treat malaria) :* with mefloquine. Do not take quinine (Qualaquin) or chloroquine (Aralen) with mefloquine.
- unable to sleep (insomnia)
- Dizziness, vertigo, tinnitus, and loss of balance can go on for months or years after
- mefloquine is stopped or may become permanent in some people.
- Important:
- You need to take malaria prevention medicine before you travel to a malaria area, while
- you are in a malaria area, and after you return from a malaria area.
- If you are told by a doctor to stop taking mefloquine because of the side effects or for other reasons, you will need to take different malaria medicine.
If you do not have access to a doctor or to another medicine and have to stop taking mefloquine, leave the malaria area and contact a doctor as soon as possible because leaving the malaria area may not protect you from getting malaria. You will still need to take malaria prevention medicine for another 4 weeks after you leave the malaria area.
- Mefloquine is a prescription medicine used to prevent and treat malaria. Malaria can be a life-threatening infection. Mefloquine does not work for all types of malaria.
- It is not known if mefloquine is safe and effective in children under 6 months old for the
treatment of malaria. It is not known how well mefloquine works to prevent malaria in children
weighing less than 44 pounds (20 kilograms).
- Do not take mefloquine if you have:
- depression or had depression recently
- had recent mental problems, including anxiety disorder, schizophrenia, or psychosis (losing touch with reality)
- seizures or had seizures (epilepsy or convulsions)
- an allergy to quinine, quinidine, mefloquine or any ingredients in mefloquine. See the end of this Medication Guide for a complete list of ingredients in mefloquine.
- Talk to your doctor before you take mefloquine if you have any of the medical conditions listed above.
- Before taking mefloquine, tell your doctor about all your medical conditions, including if you have:
- heart disease
- liver problems
- seizures or epilepsy
- diabetes
- blood clotting problems or take blood thinner medicines (anticoagulants)
- mental problems
- are pregnant or plan to become pregnant. It is not known if mefloquine will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
- You should use birth control while you take mefloquine and for 3 months after you stop mefloquine. If you have an unplanned pregnancy, talk to your doctor right away.
- are breastfeeding or plan to breastfeed. Mefloquine can pass into your breast milk and may harm your baby. Ask your doctor if you will need to stop breastfeeding or use a different medicine.
- Contact your doctor right away if you have a fever after leaving a malaria area.
- Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Mefloquine and other medicines may affect each other causing side effects.
- Take mefloquine exactly as your doctor tells you to take it. Your doctor will tell you how many mefloquine tablets to take and when to take them.
- You will start taking mefloquine to prevent malaria between 1 to 3 weeks before you travel to a malaria area.
- Take mefloquine just after eating your largest meal of the day and with at least 1 cup (8 ounces) of water.
- Do not take mefloquine on an empty stomach.
- If you vomit after taking mefloquine, contact your doctor to see if you should take another dose.
- Continue taking mefloquine for 4 weeks after returning from a malaria area.
- Mefloquine tablets may be crushed and mixed with a small amount of water, milk or other beverage for children or other people unable to swallow mefloquine whole. Your doctor will tell you the correct dose for your child based on your child’s weight.
- If you take mefloquine for a year or longer, your doctor should check your:
- eyes (especially if you have trouble seeing while you take mefloquine)
- liver function (to see if there has been damage to your liver)
- Use protective clothing, insect repellents, and bed nets to protect you from being bitten by mosquitoes. Medicine alone does not always stop you from catching malaria from mosquito bites.
- Avoid activities such as driving a car or using heavy machinery or other activities needing alertness and careful movements (fine motor coordination) until you know how mefloquine affects you. You may feel dizzy or lose your balance. This could happen for months or years after you stop taking mefloquine and can be permanent in some cases. See “What are the possible side effects of mefloquine?”
- See “What is the most important information I should know about mefloquine?”
- Mefloquine may cause serious side effects, including:
- liver problems
- Call your healthcare provider right away if you have unexplained symptoms such as nausea or
vomiting, stomach pain, fever, weakness, itching, unusual tiredness, loss of appetite, light colored bowel movements, dark colored urine, yellowing of your skin or the white of your eyes.
- The most common side effects of mefloquine include:
- nausea
- vomiting
- diarrhea
- babdominal pain
- headache
- The most common side effects in people who take mefloquine for treatment include:
- muscle pain
- fever
- chills
- skin rash
- fatigue
- loss of appetite
- irregular heart beat
- Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of mefloquine. For more information, ask your doctor or pharmacist.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- Store mefloquine between 20ºC to 25ºC (68ºF to 77ºF)
- Safely throw away medicine that is out of date or no longer needed.
- Keep mefloquine and all medicines out of the reach of children.
- Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use mefloquine for a condition for which it was not prescribed. Do not give mefloquine to other people, even if they have the same symptoms that you have. It may harm them.
- This Medication Guide summarizes the most important information about mefloquine. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about mefloquine that is written for health professionals.
- Active ingredients: mefloquine hydrochloride
- Inactive ingredients: colloidal silicon dioxide, corn starch, crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, poloxamer and talc.
- This Medication Guide has been approved by the U.S. Food and Drug Administration.
TEVA PHARMACEUTICALS USA
Sellersville, PA 18960
Rev. B 6/2013
TEVA PHARMACEUTICALS USA
Sellersville, PA 18960
Rev. B 6/2013
# Precautions with Alcohol
- Alcohol-Mefloquine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Lariam®
# Look-Alike Drug Names
There is limited information regarding Mefloquine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Mefloquine | |
8297c978a8207f81f8fbe8639eba1fcb5ed1d8d5 | wikidoc | Megaureter | Megaureter
# Overview
Megaureter is a medical anomaly whereby the ureter is abnormally dilated. Congenital megaureter is an uncommon condition which is more common in males, may be bilateral, and is often associated with other congenital anomalies. The cause is thought to be aperistalsis of the distal ureter, leading to dilatation.
A functional obstruction at the lower end of the ureter leads to progressive dilatation and a tendency to infection. The ureteric orifice appears normal and a ureteric catheter passes easily.
Definitive surgical treatment involves refashioning the lower end of the affected ureter so that a tunnelled reimplantation into the bladder can be done to prevent reflux. | Megaureter
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Megaureter is a medical anomaly whereby the ureter is abnormally dilated. Congenital megaureter is an uncommon condition which is more common in males, may be bilateral, and is often associated with other congenital anomalies. The cause is thought to be aperistalsis of the distal ureter, leading to dilatation.
A functional obstruction at the lower end of the ureter leads to progressive dilatation and a tendency to infection. The ureteric orifice appears normal and a ureteric catheter passes easily.
Definitive surgical treatment involves refashioning the lower end of the affected ureter so that a tunnelled reimplantation into the bladder can be done to prevent reflux. | https://www.wikidoc.org/index.php/Megaureter | |
d85c6b933a7e8ac8242ba04b3523d48c15ef9c66 | wikidoc | Melanocyte | Melanocyte
# Overview
Melanocytes are cells located in the bottom layer (the stratum basale) of the skin's epidermis and in the middle layer of the eye (the uvea).
# Melanogenesis
Through a process called melanogenesis, these cells produce melanin, which is a pigment found in the skin, eyes, and hair. This melanogenesis leads to a long lasting tan which is in contrast to the tan that originates from oxidation of already existing melanin.
There are both basal and activated levels of melanogenesis; lighter-skinned people generally have low basal levels of melanogenesis. Exposure to UV-B radiation causes an increased melanogenesis due to the DNA photodamage that is generated by UV-B.
Since the action spectrum of sunburn and melanogenesis are virtually identical, it is assumed that they are induced by the same mechanism. The agreement of the action spectrum with the absorption spectrum of DNA points towards the formation of cyclobutane pyrimidine dimers (direct DNA damage). The acronym for cyclobutane pyrimidine dimers is CPD's.
# Human differences
There are typically between 1000 and 2000 melanocytes per square millimeter of skin. Melanocytes comprise from 5% to 10% of the cells in the basal layer of epidermis. Although their size can vary, melanocytes are typically 7 micrometres in length.
The difference in skin color between fair people and dark people is due not to the number (quantity) of melanocytes in their skin, but to the melanocytes' level of activity.
Albinos lack an enzyme called tyrosinase. Tyrosinase is required for melanocytes to produce melanin from the amino acid tyrosine.
# Embryology
Embryologically, melanocytes are derived from the neural crest, which is a completely different source than that of the surrounding skin cells (keratinocytes).
All melanocytes have the capacity to migrate widely in the embryo. Therefore, a cancer of a melanocyte (which is called a melanoma) will spread (metastasize) very easily. For this reason, melanomas are often fatal. When melanomas are surgically removed, much of the surrounding tissue must be taken as well.
# Stimulation
Numerous stimuli are able to alter melanogenesis, or the production of melanin by cultured melanocytes, although the method by which it works is not fully understood. Vitamin D metabolites, retinoids, melanocyte-stimulating hormone (ie: Melanotan), forskolin, cholera toxin, isobutylmethylxanthine, diacylglycerol analogues, and UV irradiation all trigger melanogenesis and in turn, pigmentation. The production of melanin is also initiated by ACTH (an adrenocorticotropic hormone).
Once made, melanin is moved along arm-like structures called dendrites in a special container called a melanosome which is shipped to the keratinocytes. Melanosomes are vesicles or packages of the chemical inside a plasma membrane. The melanin is in organelles called "melanosomes", that are organized as a cap protecting the nucleus of the keratinocyte.
When ultraviolet rays penetrate the skin and damage DNA; thymidine dinucleotide (pTpT) fragments from damaged DNA will trigger melanogenesis and cause the melanocyte to produce melanosomes, which are then transferred by dendrite to the top layer of keratinocytes. | Melanocyte
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Melanocytes are cells located in the bottom layer (the stratum basale) of the skin's epidermis and in the middle layer of the eye (the uvea).
# Melanogenesis
Through a process called melanogenesis, these cells produce melanin, which is a pigment found in the skin, eyes, and hair. This melanogenesis leads to a long lasting tan which is in contrast to the tan that originates from oxidation of already existing melanin.[1]
There are both basal and activated levels of melanogenesis; lighter-skinned people generally have low basal levels of melanogenesis. Exposure to UV-B radiation causes an increased melanogenesis due to the DNA photodamage that is generated by UV-B.[2]
Since the action spectrum of sunburn and melanogenesis are virtually identical, it is assumed that they are induced by the same mechanism.[3] The agreement of the action spectrum with the absorption spectrum of DNA points towards the formation of cyclobutane pyrimidine dimers (direct DNA damage). The acronym for cyclobutane pyrimidine dimers is CPD's.
# Human differences
There are typically between 1000 and 2000 melanocytes per square millimeter of skin. Melanocytes comprise from 5% to 10% of the cells in the basal layer of epidermis. Although their size can vary, melanocytes are typically 7 micrometres in length.
The difference in skin color between fair people and dark people is due not to the number (quantity) of melanocytes in their skin, but to the melanocytes' level of activity.
Albinos lack an enzyme called tyrosinase. Tyrosinase is required for melanocytes to produce melanin from the amino acid tyrosine.
# Embryology
Embryologically, melanocytes are derived from the neural crest, which is a completely different source than that of the surrounding skin cells (keratinocytes).
All melanocytes have the capacity to migrate widely in the embryo. Therefore, a cancer of a melanocyte (which is called a melanoma) will spread (metastasize) very easily. For this reason, melanomas are often fatal. When melanomas are surgically removed, much of the surrounding tissue must be taken as well.
# Stimulation
Numerous stimuli are able to alter melanogenesis, or the production of melanin by cultured melanocytes, although the method by which it works is not fully understood. Vitamin D metabolites, retinoids, melanocyte-stimulating hormone (ie: Melanotan), forskolin, cholera toxin, isobutylmethylxanthine, diacylglycerol analogues, and UV irradiation all trigger melanogenesis and in turn, pigmentation.[4] The production of melanin is also initiated by ACTH (an adrenocorticotropic hormone).
Once made, melanin is moved along arm-like structures called dendrites in a special container called a melanosome which is shipped to the keratinocytes. Melanosomes are vesicles or packages of the chemical inside a plasma membrane. The melanin is in organelles called "melanosomes", that are organized as a cap protecting the nucleus of the keratinocyte.
When ultraviolet rays penetrate the skin and damage DNA; thymidine dinucleotide (pTpT) fragments from damaged DNA will trigger melanogenesis [5] and cause the melanocyte to produce melanosomes, which are then transferred by dendrite to the top layer of keratinocytes. | https://www.wikidoc.org/index.php/Melanocyte | |
2551fa91a3a2cfca63dd95467e6cbd81ff77d854 | wikidoc | Melanopsin | Melanopsin
Melanopsin is a type of photopigment belonging to a larger family of light-sensitive retinal proteins called opsins and encoded by the gene Opn4. In the mammalian retina, there are two additional categories of opsins, both involved in the formation of visual images: rhodopsin and photopsin (types I, II, and III) in the rod and cone photoreceptor cells, respectively.
In humans, melanopsin is found in intrinsically photosensitive retinal ganglion cells (ipRGCs). It is also found in the iris of mice and primates. Melanopsin is also found in rats, amphioxus, and other chordates. ipRGCs are photoreceptor cells which are particularly sensitive to the absorption of short-wavelength (blue) visible light and communicate information directly to the area of the brain called the suprachiasmatic nucleus (SCN), also known as the central "body clock", in mammals. Melanopsin plays an important non-image-forming role in the setting of circadian rhythms as well as other functions. Mutations in the Opn4 gene can lead to clinical disorders, such as Seasonal Affective Disorder (SAD). According to one study, melanopsin has been found in eighteen sites in the human brain (outside the retinohypothalamic tract), intracellularly, in a granular pattern, in the cerebral cortex, the cerebellar cortex and several phylogenetically old regions, primarily in neuronal soma, not in nuclei. Melanopsin is also expressed in human cones. However, only 0.11% to 0.55% of human cones express melanopsin and are exclusively found in the peripheral regions of the retina. The human peripheral retina senses light at high intensities that is best explained by four different photopigment classes.
# Discovery
Melanopsin was first discovered by Ignacio Provencio as a novel opsin in the melanophores, or light-sensitive skin cells, of the African clawed frog in 1998. A year later, researchers found that mice without any rods or cones, the cells involved in image-forming vision, still entrained to a light-dark cycle. This observation led to the conclusion that neither rods nor cones, located in the outer retina, are necessary for circadian entrainment and that a third class of photoreceptor exists in the mammalian eye. Provencio and colleagues then found in 2000 that melanopsin is also present in mouse retina, specifically in ganglion cells, and that it mediates non-visual photoreceptive tasks. Melanopsin was found to be encoded by Opn4 with orthologs in a variety of organisms.
These retinal ganglion cells were found to be innately photosensitive, since they responded to light even while isolated, and were thus named intrinsically photosensitive Retinal Ganglion Cells (ipRGCs). They constitute a third class of photoreceptor cells in the mammalian retina, besides the already known rods and cones, and were shown to be the principal conduit for light input to circadian photoentrainment. In fact, it was later demonstrated by Satchidananda Panda and colleagues that melanopsin pigment may be involved in entrainment of a circadian oscillator to light cycles in mammals since melanopsin was necessary for blind mice to respond to light.
# Species distribution
Mammals have orthologous melanopsin genes named Opn4m, which are derived from one branch of the Opn4 family, and are approximately 50-55% conserved. However, non-mammalian vertebrates, including chickens and zebrafish, have another version of the melanopsin gene, Opn4x, which appears to have a distinct lineage that diverged from Opn4m about 360 million years ago. Mammals lost the gene Opn4x relatively early in their evolution, leading to a general reduction in photosensory capability. It is thought that this event can be explained by the fact that this occurred during the time in which nocturnal mammals were evolving.
# Structure
The human melanopsin gene, opn4, is expressed in ipRGCs, which comprises only 1-2% of RGCs in the inner mammalian retina, as studied by Samer Hattar and colleagues. The gene spans approximately 11.8 kb and is mapped to the long arm of chromosome 10. The gene includes nine introns and ten exons compared to the four to seven exons typically found in other human opsins. In non-mammalian vertebrates, melanopsin is found in a wider subset of retinal cells, as well as in photosensitive structures outside the retina, such as the iris muscle of the eye, deep brain regions, the pineal gland, and the skin. Paralogs of Opn4 include OPN1LW, OPN1MW, RHO and OPN3 and were discovered by the Genome Project.
Melanopsin, like all other animal opsins (e.g. rhodopsin), is a member of the G-protein coupled receptor (GPCR) family. The melanopsin protein has seven alpha helices integrated in the plasma membrane, an N-terminal domain and a C-terminal domain. It resembles invertebrate opsins far more than vertebrate photopigments, especially in its amino acid sequence and downstream signaling cascade. Like invertebrate opsins, it appears to be a photopigment with intrinsic photoisomerase activity and signals through a G-protein of the Gq family.
# Function
Melanopsin-containing ganglion cells, like rods and cones, exhibit both light and dark adaptation; they adjust their sensitivity according to the recent history of light exposure. However, while rods and cones are responsible for the reception of images, patterns, motion, and color, melanopsin-containing ipRGCs contribute to various reflexive responses of the brain and body to the presence of light.
Evidence for melanopsin's physiological light detection has been tested in mice. A mouse cell line that is not normally photosensitive, Neuro-2a, is rendered light-sensitive by the addition of human melanopsin. The photoresponse is selectively sensitive to short-wavelength light (peak absorption ~479 nm), and has an intrinsic photoisomerase regeneration function that is chromatically shifted to longer wavelengths.
Melanopsin photoreceptors are sensitive to a range of wavelengths and reach peak light absorption at blue light wavelengths around 480 nanometers. Other wavelengths of light activate the melanopsin signaling system with decreasing efficiency as they move away from the optimum 480 nm. For example, shorter wavelengths around 445 nm (closer to violet in the visible spectrum) are half as effective for melanopsin photoreceptor stimulation as light at 480 nm.
Melanopsin in the iris of some, primarily nocturnal, mammals closes the iris when it is exposed to light. This local pupil light reflex (PLR) is absent from primates, even though their irises express melanopsin.
## Mechanism
When light enters the eye, ipRGCs discharge nerve impulses. These neuronal electrical signals travel through neuronal axons to specific brain targets, such as the center of pupillary control called the olivary pretectal nucleus (OPN) of the midbrain. Consequently, stimulation of melanopsin contributes to the regulation of behavioral responses to light, such as pupil size and melatonin release from the pineal gland. The ipRGCs in the mammalian retina form the retinohypothalamic tract that projects to the suprachiasmatic nucleus (SCN), a region of the brain in the hypothalamus which is considered the master pacemaker of circadian rhythms. The retinohypothalamic tract also receives input from rods and cones. Thus, information from all three opsins in the mammalian retina integrate before transmission to the SCN.
Melanopsin-containing ganglion cells are thought to influence these targets by releasing the neurotransmitters glutamate and pituitary adenylate cyclase activating polypeptide (PACAP) from their axon terminals. Melanopsin-containing ganglion cells also receive input from rods and cones that can add to the input to these pathways.
## Effects on circadian rhythm
Melanopsin serves an important role in the photoentrainment of circadian rhythms in mammals. An organism that is photoentrained has aligned its activity to an approximately 24-hour cycle, the solar cycle on Earth. In mammals, melanopsin expressing axons target the suprachiasmatic nucleus (SCN) through the retinohypothalamic tract (RHT).
In mammals, the eye is the main photosensitive organ for the transmission of light signals to the brain. However, blind humans are still able to entrain to the environmental light-dark cycle, despite having no conscious perception of the light. One study exposed subjects to bright light for a prolonged duration of time and measured their melatonin concentrations. Melatonin was not only suppressed in visually unimpaired humans, but also in blind participants, suggesting that the photic pathway used by the circadian system is functionally intact despite blindness. Therefore, physicians no longer practice enucleation of blind patients, or removal of the eyes at birth, since the eyes play a critical role in the photoentrainment of the circadian pacemaker.
In mutant breeds of mice that lacked only rods, only cones, or both rods and cones, all breeds of mice still entrained to changing light stimuli in the environment, but with a limited response, suggesting that rods and cones are not necessary for circadian photoentrainment and that the mammalian eye must have another photopigment required for the regulation of the circadian clock.
Melanopsin-knockout mice display reduced photoentrainment. In comparison to wild-type mice that expressed melanopsin normally, deficits in light-induced phase shifts in locomotion activity were noted in melanopsin-null mice (Opn4 -/-). These melanopsin-deficient mice did not completely lose their circadian rhythms, as they were still able to entrain to changing environmental stimuli, albeit more slowly than normal. This indicated that, although melanopsin is sufficient for entrainment, it must work in conjunction with other photopigments for normal photoentrainment activity. Triple-mutant mice that were rod-less, cone-less, and melanopsin-less display a complete loss in the circadian rhythms, so all three photopigments in these photoreceptors, rhodopsin, photopsin and melanopsin, are necessary for photoentrainment. Therefore, there is a functional redundancy between the three photopigments in the photoentrainment pathway of mammals. Deletion of only one photopigment does not eliminate the organism’s ability to entrain to environmental light-dark cycles, but it does reduce the intensity of the response.
# Regulation
Melanopsin undergoes phosphorylation on its intracellular carboxy tail as a way to deactivate its function. Compared to other opsins, melanopsin has an unusually long carboxy tail that contains 37 serine and threonine amino acid sites that could undergo phosphorylation. However, a cluster of seven amino acids are sufficient to deactivate zebrafish melanopsin. These sites are dephosphorylated when melanopsin is exposed to light and are unique from those that regulate rhodopsin. They are important for proper response to calcium ions in ipRGCs; lack of functional phosphorylation sites, particularly at serine-381 and serine-398, reduce the cell’s response to light-induced calcium ion influx when voltage-gated calcium ion channels open.
In terms of the gene Opn4, Dopamine (DA) is a factor in the regulation of melanopsin mRNA in ipRGCs.
# Clinical significance
The discovery of the role of melanopsin in non-image forming vision has led to a growth in optogenetics. This field has shown promise in clinical applications, including the treatment of human eye diseases such as retinitis pigmentosa and diabetes. A missense mutation in Opn4, P10L, has been implicated in 5% of patients with Seasonal Affective Disorder (SAD). This is a condition in which people experience depressive thoughts in the winter due to decreased available light. Additionally, a melanopsin based receptor has been linked to migraine pain.
## Restoration of vision
There has been recent research on the role of melanopsin in optogenetic therapy for patients with the degenerative eye disease retinitis pigmentosa (RP). Reintroducing functional melanopsin into the eyes of mice with retinal degeneration restores the pupillary light reflex (PLR). These same mice could also distinguish light stimuli from dark stimuli and showed increased sensitivity to room light. The higher sensitivity demonstrated by these mice shows promise for vision restoration that may be applicable to humans and human eye diseases.
## Control of sleep/wake patterns
Melanopsin may aid in controlling sleep cycles and wakefulness. Tsunematsu and colleagues created transgenic mice that expressed melanopsin in hypothalamic orexin neurons. With a short 4-second pulse of blue light (guided by optical fibers), the transgenic mice could successfully transition from slow-wave sleep (SWS), which is commonly known as "deep sleep," to long-lasting wakefulness. After switching off the blue light, the hypothalamic orexin neurons showed activity for several tens of seconds. It has been shown that rods and cones play no role in the onset of sleep by light, distinguishing them from ipRGCs and melanopsin. This provides strong evidence that there is a link between ipRGCs in humans and alertness, particularly with high frequency light (e.g. blue light). Therefore, melanopsin can be used as a therapeutic target for controlling the sleep-wake cycle.
## Regulation of blood glucose levels
In a paper published by Ye and colleagues in 2011, melanopsin was utilized to create an optogenetic synthetic transcription device that was tested in a therapeutic setting to produce glucagon-like peptide 1 (GLP-1), a protein that helps control blood glucose levels in mammals with Type II Diabetes. The researchers subcutaneously implanted mice with microencapsulated transgenic HEK 293 cells that were cotransfected with two vectors including the melanopsin gene and the gene of interest under an NFAT (nuclear factor of activated T cells) promoter, respectively. It is through this engineered pathway that they successfully controlled the expression of GLP-1 in doubly recessive diabetic mice and reduced hyperglycemia, or high blood glucose levels, in these mice. This shows promise for the use of melanopsin as an optogenetic tool for the treatment of Type II diabetes. | Melanopsin
Melanopsin is a type of photopigment belonging to a larger family of light-sensitive retinal proteins called opsins and encoded by the gene Opn4.[1] In the mammalian retina, there are two additional categories of opsins, both involved in the formation of visual images: rhodopsin and photopsin (types I, II, and III) in the rod and cone photoreceptor cells, respectively.
In humans, melanopsin is found in intrinsically photosensitive retinal ganglion cells (ipRGCs).[2] It is also found in the iris of mice and primates.[3] Melanopsin is also found in rats, amphioxus, and other chordates.[4] ipRGCs are photoreceptor cells which are particularly sensitive to the absorption of short-wavelength (blue) visible light and communicate information directly to the area of the brain called the suprachiasmatic nucleus (SCN), also known as the central "body clock", in mammals.[5] Melanopsin plays an important non-image-forming role in the setting of circadian rhythms as well as other functions. Mutations in the Opn4 gene can lead to clinical disorders, such as Seasonal Affective Disorder (SAD).[6] According to one study, melanopsin has been found in eighteen sites in the human brain (outside the retinohypothalamic tract), intracellularly, in a granular pattern, in the cerebral cortex, the cerebellar cortex and several phylogenetically old regions, primarily in neuronal soma, not in nuclei.[7] Melanopsin is also expressed in human cones. However, only 0.11% to 0.55% of human cones express melanopsin and are exclusively found in the peripheral regions of the retina.[8] The human peripheral retina senses light at high intensities that is best explained by four different photopigment classes.[9]
# Discovery
Melanopsin was first discovered by Ignacio Provencio as a novel opsin in the melanophores, or light-sensitive skin cells, of the African clawed frog in 1998.[10] A year later, researchers found that mice without any rods or cones, the cells involved in image-forming vision, still entrained to a light-dark cycle.[11] This observation led to the conclusion that neither rods nor cones, located in the outer retina, are necessary for circadian entrainment and that a third class of photoreceptor exists in the mammalian eye.[1] Provencio and colleagues then found in 2000 that melanopsin is also present in mouse retina, specifically in ganglion cells, and that it mediates non-visual photoreceptive tasks.[12] Melanopsin was found to be encoded by Opn4 with orthologs in a variety of organisms.[1]
These retinal ganglion cells were found to be innately photosensitive, since they responded to light even while isolated, and were thus named intrinsically photosensitive Retinal Ganglion Cells (ipRGCs).[13] They constitute a third class of photoreceptor cells in the mammalian retina, besides the already known rods and cones, and were shown to be the principal conduit for light input to circadian photoentrainment.[12] In fact, it was later demonstrated by Satchidananda Panda and colleagues that melanopsin pigment may be involved in entrainment of a circadian oscillator to light cycles in mammals since melanopsin was necessary for blind mice to respond to light.[14]
# Species distribution
Mammals have orthologous melanopsin genes named Opn4m, which are derived from one branch of the Opn4 family, and are approximately 50-55% conserved.[15] However, non-mammalian vertebrates, including chickens and zebrafish, have another version of the melanopsin gene, Opn4x, which appears to have a distinct lineage that diverged from Opn4m about 360 million years ago.[16] Mammals lost the gene Opn4x relatively early in their evolution, leading to a general reduction in photosensory capability. It is thought that this event can be explained by the fact that this occurred during the time in which nocturnal mammals were evolving.[15]
# Structure
The human melanopsin gene, opn4, is expressed in ipRGCs, which comprises only 1-2% of RGCs in the inner mammalian retina, as studied by Samer Hattar and colleagues.[5] The gene spans approximately 11.8 kb and is mapped to the long arm of chromosome 10. The gene includes nine introns and ten exons compared to the four to seven exons typically found in other human opsins.[12] In non-mammalian vertebrates, melanopsin is found in a wider subset of retinal cells, as well as in photosensitive structures outside the retina, such as the iris muscle of the eye, deep brain regions, the pineal gland, and the skin.[15] Paralogs of Opn4 include OPN1LW, OPN1MW, RHO and OPN3 and were discovered by the Genome Project.[17]
Melanopsin, like all other animal opsins (e.g. rhodopsin), is a member of the G-protein coupled receptor (GPCR) family. The melanopsin protein has seven alpha helices integrated in the plasma membrane, an N-terminal domain and a C-terminal domain.[18] It resembles invertebrate opsins far more than vertebrate photopigments, especially in its amino acid sequence and downstream signaling cascade.[13] Like invertebrate opsins, it appears to be a photopigment with intrinsic photoisomerase activity[19] and signals through a G-protein of the Gq family.
# Function
Melanopsin-containing ganglion cells,[20] like rods and cones, exhibit both light and dark adaptation; they adjust their sensitivity according to the recent history of light exposure.[21] However, while rods and cones are responsible for the reception of images, patterns, motion, and color, melanopsin-containing ipRGCs contribute to various reflexive responses of the brain and body to the presence of light.[13]
Evidence for melanopsin's physiological light detection has been tested in mice. A mouse cell line that is not normally photosensitive, Neuro-2a, is rendered light-sensitive by the addition of human melanopsin. The photoresponse is selectively sensitive to short-wavelength light (peak absorption ~479 nm),[22][23] and has an intrinsic photoisomerase regeneration function that is chromatically shifted to longer wavelengths.[24]
Melanopsin photoreceptors are sensitive to a range of wavelengths and reach peak light absorption at blue light wavelengths around 480 nanometers.[25] Other wavelengths of light activate the melanopsin signaling system with decreasing efficiency as they move away from the optimum 480 nm. For example, shorter wavelengths around 445 nm (closer to violet in the visible spectrum) are half as effective for melanopsin photoreceptor stimulation as light at 480 nm.[25]
Melanopsin in the iris of some, primarily nocturnal, mammals closes the iris when it is exposed to light. This local pupil light reflex (PLR) is absent from primates, even though their irises express melanopsin.[3]
## Mechanism
When light enters the eye, ipRGCs discharge nerve impulses. These neuronal electrical signals travel through neuronal axons to specific brain targets, such as the center of pupillary control called the olivary pretectal nucleus (OPN) of the midbrain. Consequently, stimulation of melanopsin contributes to the regulation of behavioral responses to light, such as pupil size and melatonin release from the pineal gland.[26] The ipRGCs in the mammalian retina form the retinohypothalamic tract that projects to the suprachiasmatic nucleus (SCN), a region of the brain in the hypothalamus which is considered the master pacemaker of circadian rhythms.[5] The retinohypothalamic tract also receives input from rods and cones. Thus, information from all three opsins in the mammalian retina integrate before transmission to the SCN.[27]
Melanopsin-containing ganglion cells are thought to influence these targets by releasing the neurotransmitters glutamate and pituitary adenylate cyclase activating polypeptide (PACAP) from their axon terminals.[28] Melanopsin-containing ganglion cells also receive input from rods and cones that can add to the input to these pathways.
## Effects on circadian rhythm
Melanopsin serves an important role in the photoentrainment of circadian rhythms in mammals. An organism that is photoentrained has aligned its activity to an approximately 24-hour cycle, the solar cycle on Earth.[29] In mammals, melanopsin expressing axons target the suprachiasmatic nucleus (SCN) through the retinohypothalamic tract (RHT).[5]
In mammals, the eye is the main photosensitive organ for the transmission of light signals to the brain. However, blind humans are still able to entrain to the environmental light-dark cycle, despite having no conscious perception of the light. One study exposed subjects to bright light for a prolonged duration of time and measured their melatonin concentrations. Melatonin was not only suppressed in visually unimpaired humans, but also in blind participants, suggesting that the photic pathway used by the circadian system is functionally intact despite blindness.[30] Therefore, physicians no longer practice enucleation of blind patients, or removal of the eyes at birth, since the eyes play a critical role in the photoentrainment of the circadian pacemaker.
In mutant breeds of mice that lacked only rods, only cones, or both rods and cones, all breeds of mice still entrained to changing light stimuli in the environment, but with a limited response, suggesting that rods and cones are not necessary for circadian photoentrainment and that the mammalian eye must have another photopigment required for the regulation of the circadian clock.[31]
Melanopsin-knockout mice display reduced photoentrainment. In comparison to wild-type mice that expressed melanopsin normally, deficits in light-induced phase shifts in locomotion activity were noted in melanopsin-null mice (Opn4 -/-).[14] These melanopsin-deficient mice did not completely lose their circadian rhythms, as they were still able to entrain to changing environmental stimuli, albeit more slowly than normal.[32] This indicated that, although melanopsin is sufficient for entrainment, it must work in conjunction with other photopigments for normal photoentrainment activity. Triple-mutant mice that were rod-less, cone-less, and melanopsin-less display a complete loss in the circadian rhythms, so all three photopigments in these photoreceptors, rhodopsin, photopsin and melanopsin, are necessary for photoentrainment.[33] Therefore, there is a functional redundancy between the three photopigments in the photoentrainment pathway of mammals. Deletion of only one photopigment does not eliminate the organism’s ability to entrain to environmental light-dark cycles, but it does reduce the intensity of the response.
# Regulation
Melanopsin undergoes phosphorylation on its intracellular carboxy tail as a way to deactivate its function. Compared to other opsins, melanopsin has an unusually long carboxy tail that contains 37 serine and threonine amino acid sites that could undergo phosphorylation.[34] However, a cluster of seven amino acids are sufficient to deactivate zebrafish melanopsin. These sites are dephosphorylated when melanopsin is exposed to light and are unique from those that regulate rhodopsin.[35] They are important for proper response to calcium ions in ipRGCs; lack of functional phosphorylation sites, particularly at serine-381 and serine-398, reduce the cell’s response to light-induced calcium ion influx when voltage-gated calcium ion channels open.[36]
In terms of the gene Opn4, Dopamine (DA) is a factor in the regulation of melanopsin mRNA in ipRGCs.[37]
# Clinical significance
The discovery of the role of melanopsin in non-image forming vision has led to a growth in optogenetics. This field has shown promise in clinical applications, including the treatment of human eye diseases such as retinitis pigmentosa and diabetes.[38] A missense mutation in Opn4, P10L, has been implicated in 5% of patients with Seasonal Affective Disorder (SAD).[6] This is a condition in which people experience depressive thoughts in the winter due to decreased available light. Additionally, a melanopsin based receptor has been linked to migraine pain.[39]
## Restoration of vision
There has been recent research on the role of melanopsin in optogenetic therapy for patients with the degenerative eye disease retinitis pigmentosa (RP).[40] Reintroducing functional melanopsin into the eyes of mice with retinal degeneration restores the pupillary light reflex (PLR). These same mice could also distinguish light stimuli from dark stimuli and showed increased sensitivity to room light. The higher sensitivity demonstrated by these mice shows promise for vision restoration that may be applicable to humans and human eye diseases.[38][41]
## Control of sleep/wake patterns
Melanopsin may aid in controlling sleep cycles and wakefulness. Tsunematsu and colleagues created transgenic mice that expressed melanopsin in hypothalamic orexin neurons. With a short 4-second pulse of blue light (guided by optical fibers), the transgenic mice could successfully transition from slow-wave sleep (SWS), which is commonly known as "deep sleep," to long-lasting wakefulness. After switching off the blue light, the hypothalamic orexin neurons showed activity for several tens of seconds.[38][42] It has been shown that rods and cones play no role in the onset of sleep by light, distinguishing them from ipRGCs and melanopsin. This provides strong evidence that there is a link between ipRGCs in humans and alertness, particularly with high frequency light (e.g. blue light). Therefore, melanopsin can be used as a therapeutic target for controlling the sleep-wake cycle.[43]
## Regulation of blood glucose levels
In a paper published by Ye and colleagues in 2011, melanopsin was utilized to create an optogenetic synthetic transcription device that was tested in a therapeutic setting to produce glucagon-like peptide 1 (GLP-1), a protein that helps control blood glucose levels in mammals with Type II Diabetes. The researchers subcutaneously implanted mice with microencapsulated transgenic HEK 293 cells that were cotransfected with two vectors including the melanopsin gene and the gene of interest under an NFAT (nuclear factor of activated T cells) promoter, respectively. It is through this engineered pathway that they successfully controlled the expression of GLP-1 in doubly recessive diabetic mice and reduced hyperglycemia, or high blood glucose levels, in these mice. This shows promise for the use of melanopsin as an optogenetic tool for the treatment of Type II diabetes.[38][44] | https://www.wikidoc.org/index.php/Melanopsin | |
1ce71047e6f96937133e7491c0e9fc5860b1f671 | wikidoc | Menyanthes | Menyanthes
Menyanthes is a monotypic genus of flowering plant in the family Menyanthaceae. The name Menyanthes comes from the Greek words menyein, meaning "disclosing", and anthos, meaning "flower", in reference to the sequential opening of flowers on the inflorescence.
Menyanthes trifoliata is characterized by a horizontal rhizome with alternate, trifoliate leaves. The inflorescence is an erect raceme of white flowers.
Menyanthes trifoliata occurs in bogs and marshes in Asia, Europe, and North America. The North American form is often referred to as M. trifoliata var. minor Michx. It is known in English by the common names bog-bean and buckbean, and in German as Bitterklee or Fieberklee.
- Flowerhead
Flowerhead
- 19th century illustration
19th century illustration
bg:Горчивче
cs:Vachta trojlistá
da:Almindelig Bukkeblad
de:Fieberklee
et:Ubaleht
hsb:Třiłopješkaty kózlik
lt:Trilapis puplaiškis
nl:Waterdrieblad
no:Bukkeblad
fi:Raate
sv:Vattenklöver
uk:Бобівник трилистий | Menyanthes
Menyanthes is a monotypic genus of flowering plant in the family Menyanthaceae. The name Menyanthes comes from the Greek words menyein, meaning "disclosing", and anthos, meaning "flower", in reference to the sequential opening of flowers on the inflorescence.
Menyanthes trifoliata is characterized by a horizontal rhizome with alternate, trifoliate leaves. The inflorescence is an erect raceme of white flowers.
Menyanthes trifoliata occurs in bogs and marshes in Asia, Europe, and North America. The North American form is often referred to as M. trifoliata var. minor Michx. It is known in English by the common names bog-bean and buckbean, and in German as Bitterklee or Fieberklee.
- Flowerhead
Flowerhead
- 19th century illustration
19th century illustration
Template:Wikisource1911Enc
bg:Горчивче
cs:Vachta trojlistá
da:Almindelig Bukkeblad
de:Fieberklee
et:Ubaleht
hsb:Třiłopješkaty kózlik
lt:Trilapis puplaiškis
nl:Waterdrieblad
no:Bukkeblad
fi:Raate
sv:Vattenklöver
uk:Бобівник трилистий
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Menyanthes | |
e1772687bcd03c7ea0027b55588e3d30e3ba50c9 | wikidoc | Thiomersal | Thiomersal
# Overview
Thiomersal (INN) (C9H9HgNaO2S), commonly known in the United States as thimerosal, is an organomercury compound (approximately 49% mercury by weight) used as an antiseptic and antifungal agent.
It was developed and registered under the trade name Merthiolate in 1928 by the pharmaceutical corporation Eli Lilly and Company and has been used as a preservative in vaccines, immunoglobulin preparations, skin test antigens, antivenins, ophthalmic and nasal products, and tattoo inks.
In the U.S., the European Union, and a few other affluent countries, the compound is being phased out from vaccines routinely given to children. Packaging the vaccines in single-dose vials eliminates the need for bacteriostatics such as thiomersal.
# Use
Thiomersal's main use is as an antiseptic and antifungal agent. In multidose injectable drug delivery systems, it prevents serious adverse effects such as the Staphylococcus infection that, in one 1928 incident, killed 12 of 21 children inoculated with a diphtheria vaccine that lacked a preservative. Unlike other vaccine preservatives used at the time, thiomersal does not reduce the potency of the vaccines that it protects. Thiomersal is not needed in more-expensive single-dose injectables.
In the U.S., the European Union, and a few other affluent countries, thiomersal is no longer used as a preservative in routine childhood vaccination schedules. In the U.S., the only exceptions among vaccines routinely recommended for children are some formulations of the inactivated influenza vaccine for children older than two years. Several vaccines that are not routinely recommended for young children do contain thiomersal, including DT (diphtheria and tetanus), Td (tetanus and diphtheria), and TT (tetanus toxoid); other vaccines may contain a trace of thiomersal from steps in manufacture. Also, four rarely used treatments for pit viper, coral snake, and black widow venom still contain thiomersal. Outside North America and Europe, many vaccines contain thiomersal; the World Health Organization has concluded that there is no evidence of toxicity from thiomersal in vaccines and no reason on safety grounds to change to more-expensive single-dose administration.
# Toxicology
Thiomersal is very toxic by inhalation, ingestion, and in contact with skin (EC hazard symbol T+), with a danger of cumulative effects. It is also very toxic to aquatic organisms and may cause long-term adverse effects in aquatic environments (EC hazard symbol N).
In the body, it is metabolized or degraded to ethylmercury (C2H5Hg+) and thiosalicylate.
Few studies of the toxicity of thiomersal in humans have been performed. Animal experiments suggest that thiomersal rapidly dissociates to release ethylmercury after injection; that the disposition patterns of mercury are similar to those after exposure to equivalent doses of ethylmercury chloride; and that the central nervous system and the kidneys are targets, with lack of motor coordination being a common sign. Similar signs and symptoms have been observed in accidental human poisonings. The mechanisms of toxic action are unknown. Fecal excretion accounts for most of the elimination from the body. Ethylmercury clears from blood with a half-time of about 18 days, and from the brain in about 14 days. Inorganic mercury metabolized from ethylmercury has a much longer clearance, at least 120 days; it appears to be much less toxic than the inorganic mercury produced from mercury vapor, for reasons that are not understood.
Risk assessment for effects on the nervous system have been made by extrapolating from dose-response relationships for methylmercury, which is why thiomersal was removed from U.S. childhood vaccines, starting in 1999. However, since then, it has been found that ethylmercury is cleared from the body and the brain significantly faster than methylmercury, so the late-1990s risk assessments turned out to be overly conservative. A 2008 study found that the half-life of blood mercury after vaccination averages 3.7 days for newborns and infants, much shorter than the 44 days for methylmercury.
## Allergies
Thiomersal is used in patch testing for people who have dermatitis, conjunctivitis, and other potentially allergic reactions. A 2007 study in Norway found that 1.9% of adults had a positive patch test reaction to thiomersal; a higher prevalence of contact allergy (up to 6.6%) was observed in German populations. Thiomersal-sensitive individuals can receive intramuscular rather than subcutaneous immunization, so contact allergy is usually clinically irrelevant. Thiomersal allergy has decreased in Denmark, probably because of its exclusion from vaccines there.
## Autism
Many parents, and some scientists and doctors, believe there is a connection between thiomersal and autism. More than 5,000 U.S. families have filed claims alleging autism was caused by vaccines, most implicating thiomersal; the majority of these claims are still being adjudicated, and no awards have been issued. Although there is no convincing evidence that thiomersal is a factor in the onset of autism, parents may first become aware of autistic symptoms in their child around the time of a routine vaccination, and parental concern about vaccines has led to a decreasing uptake of childhood immunizations and an increasing likelihood of measles outbreaks.
# History
Morris S. Kharasch, a chemist at the University of Maryland, filed a patent application for thiomersal in 1927; Eli Lilly was granted the patent for the compound under the trade name Merthiolate in 1928. In vitro tests conducted by Lilly investigators H.M. Powell and W.A. Jamieson found that it was forty to fifty times as effective as phenol against Staphylococcus aureus. It was used to kill bacteria and prevent contamination in antiseptic ointments, creams, jellies, and sprays used by consumers and in hospitals, including nasal sprays, eye drops, contact lens solutions, immunoglobulins, and vaccines. Thiomersal was used as a preservative (bactericide) so that multidose vials of vaccines could be used instead of single-dose vials, which are more expensive. By 1938, Lilly's assistant director of research listed thiomersal as one of the five most important drugs ever developed by the company.
Thiomersal's safety for its intended uses first came under question in the 1970s, when case reports demonstrated potential for neurotoxicity when given in large volumes as a topical antiseptic. At the time, the DPT vaccine was the only childhood vaccine that contained it; a 1976 FDA review concluded that this use of thiomersal was not dangerous. Concerns about mercury arising from Minamata disease and other cases of methylmercury poisoning led U.S. authorities to lower reference doses for methylmercury in the 1990s, about the same time that autism diagnoses began rising sharply. In 1999, a new FDA analysis concluded that infants could receive as much as 187.5 mg of ethylmercury during the first six months; lacking any standard for ethylmercury, it used methylmercury-based standards to recommend that thiomersal be removed from routine childhood vaccines in the U.S., which was done by 2001. Some parents of autistic children adopted thiomersal as an explanation for the increase in reported autism cases and sued vaccine makers; the mercury-autism hypothesis is accepted widely among parents of autistic children, despite scientific studies rejecting it. | Thiomersal
Template:Chembox new
# Overview
Thiomersal (INN) (C9H9HgNaO2S), commonly known in the United States as thimerosal, is an organomercury compound (approximately 49% mercury by weight) used as an antiseptic and antifungal agent.
It was developed and registered under the trade name Merthiolate in 1928 by the pharmaceutical corporation Eli Lilly and Company and has been used as a preservative in vaccines, immunoglobulin preparations, skin test antigens, antivenins, ophthalmic and nasal products, and tattoo inks.
In the U.S., the European Union, and a few other affluent countries, the compound is being phased out from vaccines routinely given to children.[1] Packaging the vaccines in single-dose vials eliminates the need for bacteriostatics such as thiomersal.[2]
# Use
Thiomersal's main use is as an antiseptic and antifungal agent. In multidose injectable drug delivery systems, it prevents serious adverse effects such as the Staphylococcus infection that, in one 1928 incident, killed 12 of 21 children inoculated with a diphtheria vaccine that lacked a preservative.[3] Unlike other vaccine preservatives used at the time, thiomersal does not reduce the potency of the vaccines that it protects.[4] Thiomersal is not needed in more-expensive single-dose injectables.
In the U.S., the European Union, and a few other affluent countries, thiomersal is no longer used as a preservative in routine childhood vaccination schedules.[1] In the U.S., the only exceptions among vaccines routinely recommended for children are some formulations of the inactivated influenza vaccine for children older than two years.[5] Several vaccines that are not routinely recommended for young children do contain thiomersal, including DT (diphtheria and tetanus), Td (tetanus and diphtheria), and TT (tetanus toxoid); other vaccines may contain a trace of thiomersal from steps in manufacture.[3] Also, four rarely used treatments for pit viper, coral snake, and black widow venom still contain thiomersal.[6] Outside North America and Europe, many vaccines contain thiomersal; the World Health Organization has concluded that there is no evidence of toxicity from thiomersal in vaccines and no reason on safety grounds to change to more-expensive single-dose administration.[7]
# Toxicology
Thiomersal is very toxic by inhalation, ingestion, and in contact with skin (EC hazard symbol T+), with a danger of cumulative effects. It is also very toxic to aquatic organisms and may cause long-term adverse effects in aquatic environments (EC hazard symbol N).[8]
In the body, it is metabolized or degraded to ethylmercury (C2H5Hg+) and thiosalicylate.[3]
Few studies of the toxicity of thiomersal in humans have been performed. Animal experiments suggest that thiomersal rapidly dissociates to release ethylmercury after injection; that the disposition patterns of mercury are similar to those after exposure to equivalent doses of ethylmercury chloride; and that the central nervous system and the kidneys are targets, with lack of motor coordination being a common sign. Similar signs and symptoms have been observed in accidental human poisonings. The mechanisms of toxic action are unknown. Fecal excretion accounts for most of the elimination from the body. Ethylmercury clears from blood with a half-time of about 18 days, and from the brain in about 14 days. Inorganic mercury metabolized from ethylmercury has a much longer clearance, at least 120 days; it appears to be much less toxic than the inorganic mercury produced from mercury vapor, for reasons that are not understood.[9]
Risk assessment for effects on the nervous system have been made by extrapolating from dose-response relationships for methylmercury, which is why thiomersal was removed from U.S. childhood vaccines, starting in 1999. However, since then, it has been found that ethylmercury is cleared from the body and the brain significantly faster than methylmercury, so the late-1990s risk assessments turned out to be overly conservative.[9] A 2008 study found that the half-life of blood mercury after vaccination averages 3.7 days for newborns and infants, much shorter than the 44 days for methylmercury.[10]
## Allergies
Thiomersal is used in patch testing for people who have dermatitis, conjunctivitis, and other potentially allergic reactions. A 2007 study in Norway found that 1.9% of adults had a positive patch test reaction to thiomersal;[11] a higher prevalence of contact allergy (up to 6.6%) was observed in German populations.[12] Thiomersal-sensitive individuals can receive intramuscular rather than subcutaneous immunization,[13] so contact allergy is usually clinically irrelevant.[12] Thiomersal allergy has decreased in Denmark, probably because of its exclusion from vaccines there.[14]
## Autism
Many parents, and some scientists and doctors, believe there is a connection between thiomersal and autism.[15] More than 5,000 U.S. families have filed claims alleging autism was caused by vaccines, most implicating thiomersal; the majority of these claims are still being adjudicated, and no awards have been issued.[15] Although there is no convincing evidence that thiomersal is a factor in the onset of autism, parents may first become aware of autistic symptoms in their child around the time of a routine vaccination, and parental concern about vaccines has led to a decreasing uptake of childhood immunizations and an increasing likelihood of measles outbreaks.[16]
# History
Morris S. Kharasch, a chemist at the University of Maryland, filed a patent application for thiomersal in 1927;[17] Eli Lilly was granted the patent for the compound under the trade name Merthiolate in 1928.[4] In vitro tests conducted by Lilly investigators H.M. Powell and W.A. Jamieson found that it was forty to fifty times as effective as phenol against Staphylococcus aureus.[4] It was used to kill bacteria and prevent contamination in antiseptic ointments, creams, jellies, and sprays used by consumers and in hospitals, including nasal sprays, eye drops, contact lens solutions, immunoglobulins, and vaccines. Thiomersal was used as a preservative (bactericide) so that multidose vials of vaccines could be used instead of single-dose vials, which are more expensive. By 1938, Lilly's assistant director of research listed thiomersal as one of the five most important drugs ever developed by the company.[4]
Thiomersal's safety for its intended uses first came under question in the 1970s, when case reports demonstrated potential for neurotoxicity when given in large volumes as a topical antiseptic. At the time, the DPT vaccine was the only childhood vaccine that contained it; a 1976 FDA review concluded that this use of thiomersal was not dangerous.[4] Concerns about mercury arising from Minamata disease and other cases of methylmercury poisoning led U.S. authorities to lower reference doses for methylmercury in the 1990s, about the same time that autism diagnoses began rising sharply. In 1999, a new FDA analysis concluded that infants could receive as much as 187.5 mg of ethylmercury during the first six months; lacking any standard for ethylmercury, it used methylmercury-based standards to recommend that thiomersal be removed from routine childhood vaccines in the U.S., which was done by 2001.[4] Some parents of autistic children adopted thiomersal as an explanation for the increase in reported autism cases and sued vaccine makers; the mercury-autism hypothesis is accepted widely among parents of autistic children, despite scientific studies rejecting it.[4] | https://www.wikidoc.org/index.php/Merthiolate | |
0960a2761548cf9ca23d74f52edc1c4fe4782629 | wikidoc | Mesalazine | Mesalazine
# Overview
Mesalazine (INN, BAN), also known as Mesalamine (USAN) or 5-aminosalicylic acid (5-ASA), is an anti-inflammatory drug used to treat inflammation of the digestive tract (Crohn's disease) and mild to moderate ulcerative colitis. Mesalazine is a bowel-specific aminosalicylate drug that is metabolized in the gut and has its predominant actions there, thereby having fewer systemic side effects.
As a derivative of salicylic acid, 5-ASA is also an antioxidant that traps free radicals, which are potentially damaging by-products of metabolism.
5-ASA is considered the active moiety of sulfasalazine, which is metabolized to it.
# Formulations
It is formulated for oral ingestion as tablets or granules, and for rectal administration as rectal suppository, suspension or enemas. It is sold under a variety of brand names (UK: Asacol, Ipocal, Pentasa & Salofalk. US: Canasa, Rowasa, Pentasa, Asacol and Lialda). The newest of these is Lialda, approved by the FDA in January 2007 for induction of remission in ulcerative colitis. Its main benefit is that it needs to be taken only once a day, which improves convenience and treatment compliance.
Dosing depends on the preparation used, in particular, slow-release tablets may have quite different drug delivery characteristics and are not interchangeable.
Preparations that lower stool pH (such as lactulose, a laxative) will affect the binding of Mesalazine in the bowel and will therefore reduce its efficacy.
# Side effects
Commonly:
- Diarrhea
- Nausea
- Cramping
Uncommonly:
- Headache
- Exacerbation of the colitis
- Hypersensitivity reactions (including rash, urticaria, interstitial nephritis and lupus erythematosus-like syndrome)
- Hair Loss
- Interstitial nephritis
Rarely:
- Acute pancreatitis,
- Hepatitis
- Nephrotic syndrome
- Blood disorders (including agranulocytosis, aplastic anaemia, leukopenia, neutropenia, thrombocytopenia)
Mesalazine avoids the sulphonamide side effects of Sulfasalazine (which contains additional (sulfapyridine), but carries additional rare risks of:
- Allergic lung reactions
- Allergic myocarditis
- Methaemoglobinaemia
# Monitoring
As a result of the small risks of kidney, liver and blood disorders, blood tests should be taken before and after starting treatment. Patients are advised to report any unexplained bleeding, bruising, purpura, sore throat, fever or malaise that occurs during treatment so that a full blood count can be urgently taken. | Mesalazine
# Overview
Mesalazine (INN, BAN), also known as Mesalamine (USAN) or 5-aminosalicylic acid (5-ASA), is an anti-inflammatory drug used to treat inflammation of the digestive tract (Crohn's disease) and mild to moderate ulcerative colitis. Mesalazine is a bowel-specific aminosalicylate drug that is metabolized in the gut and has its predominant actions there, thereby having fewer systemic side effects.
As a derivative of salicylic acid, 5-ASA is also an antioxidant that traps free radicals, which are potentially damaging by-products of metabolism.
5-ASA is considered the active moiety of sulfasalazine, which is metabolized to it.
# Formulations
It is formulated for oral ingestion as tablets or granules, and for rectal administration as rectal suppository, suspension or enemas. It is sold under a variety of brand names (UK: Asacol, Ipocal, Pentasa & Salofalk. US: Canasa, Rowasa, Pentasa, Asacol and Lialda). The newest of these is Lialda, approved by the FDA in January 2007 for induction of remission in ulcerative colitis. Its main benefit is that it needs to be taken only once a day, which improves convenience and treatment compliance.
Dosing depends on the preparation used, in particular, slow-release tablets may have quite different drug delivery characteristics and are not interchangeable.
Preparations that lower stool pH (such as lactulose, a laxative) will affect the binding of Mesalazine in the bowel and will therefore reduce its efficacy.
# Side effects
Commonly:
- Diarrhea
- Nausea
- Cramping
Uncommonly:
- Headache
- Exacerbation of the colitis
- Hypersensitivity reactions (including rash, urticaria, interstitial nephritis and lupus erythematosus-like syndrome)
- Hair Loss
- Interstitial nephritis
Rarely:
- Acute pancreatitis,
- Hepatitis
- Nephrotic syndrome
- Blood disorders (including agranulocytosis, aplastic anaemia, leukopenia, neutropenia, thrombocytopenia)
Mesalazine avoids the sulphonamide side effects of Sulfasalazine (which contains additional (sulfapyridine), but carries additional rare risks of:
- Allergic lung reactions
- Allergic myocarditis
- Methaemoglobinaemia
# Monitoring
As a result of the small risks of kidney, liver and blood disorders, blood tests should be taken before and after starting treatment. Patients are advised to report any unexplained bleeding, bruising, purpura, sore throat, fever or malaise that occurs during treatment so that a full blood count can be urgently taken. | https://www.wikidoc.org/index.php/Mesalazine | |
eda31cf22611b92747f70a5769340010ffacce8f | wikidoc | Mesothelin | Mesothelin
Mesothelin, also known as MSLN, is a protein that in humans is encoded by the MSLN gene.
# Function
Mesothelin is a 40 kDa protein that is expressed in mesothelial cells. The protein was first identified by its reactivity with monoclonal antibody K1. Subsequent cloning studies showed that the mesothelin gene encodes a precursor protein that is processed to yield mesothelin which is attached to the cell membrane by a glycophosphatidylinositol linkage and a 31-kDa shed fragment named megakaryocyte-potentiating factor (MPF). Although it has been proposed that mesothelin may be involved in cell adhesion, its biological function is not known. A knockout mouse line that lacks mesothelin reproduces and develops normally.
Mesothelin is over expressed in several human tumors, including mesothelioma, ovarian cancer, pancreatic adenocarcinoma and cholangiocarcinoma. The interaction between mesothelin and MUC16 (also known as CA125) may facilitate the implantation and peritoneal spread of tumors by cell adhesion. Dr. Mitchell Ho and colleagues at the National Cancer Institute identified the region (residues 296-359) consisting of 64 amino acids at the N-terminus of cell surface mesothelin as the functional binding domain for MUC16.
# Medical applications
Mesothelin is a tumour differentiation antigen that is normally present on the mesothelial cells lining the pleura, peritoneum and pericardium. Since mesothelin is overexpressed in several cancers and is immunogenic, the protein could be exploited as tumor marker or as the antigenic target of a therapeutic cancer vaccine. A 2016 review indicates that some immunotherapeutic strategies have shown encouraging results in early-phase clinical trials.
Elevations of serum mesothelin specific to ovarian and other cancer patients may be measured using ELISA assays. Soluble mesothelin is the extracellular domain of membrane-bound mesothelin shed from tumor cells as demonstrated by mass spectrometry analysis of soluble mesothelin purified from cell culture supernatant. Assays for blood-borne mesothelin and MPF for tumor diagnosis, especially applied to asbestos-related mesothelioma have been developed. Elevated serum mesothelin was found in most patients with mesothelioma (71%) and ovarian cancer (67%). Blood MPF and mesothelin levels were correlated, with modest accuracy for malignant pleural mesothelioma and lung cancer (sensitivity 74% and 59%, specificity 90% and 86%, respectively for MPF and mesothelin assays). Circulating mesothelin is reported in nearly all pancreatic cancers, however the levels in healthy persons often exceed 80 ng/mL (using 40 kD molecular weight as the conversion factor) and to widely overlap the values in the pancreatic cancer patients. It was noted that the cutoff levels for normal could differ as much as 10-fold among publications, depending on the assay used and thus that normal levels must be determined anew when new assays are introduced. Therapeutic antibodies to mesothelin have been developed by phage display and humanization of rabbit monoclonal antibodies. | Mesothelin
Mesothelin, also known as MSLN, is a protein that in humans is encoded by the MSLN gene.[1][2]
# Function
Mesothelin is a 40 kDa protein that is expressed in mesothelial cells.[3] The protein was first identified by its reactivity with monoclonal antibody K1.[4] Subsequent cloning studies showed that the mesothelin gene encodes a precursor protein that is processed to yield mesothelin which is attached to the cell membrane by a glycophosphatidylinositol linkage and a 31-kDa shed fragment named megakaryocyte-potentiating factor (MPF). Although it has been proposed that mesothelin may be involved in cell adhesion, its biological function is not known.[5] A knockout mouse line that lacks mesothelin reproduces and develops normally.[6]
Mesothelin is over expressed in several human tumors, including mesothelioma, ovarian cancer, pancreatic adenocarcinoma[3] and cholangiocarcinoma.[7][8] The interaction between mesothelin and MUC16 (also known as CA125) may facilitate the implantation and peritoneal spread of tumors by cell adhesion. Dr. Mitchell Ho and colleagues at the National Cancer Institute identified the region (residues 296-359) consisting of 64 amino acids at the N-terminus of cell surface mesothelin as the functional binding domain for MUC16.[9]
# Medical applications
Mesothelin is a tumour differentiation antigen that is normally present on the mesothelial cells lining the pleura, peritoneum and pericardium.[10] Since mesothelin is overexpressed in several cancers and is immunogenic, the protein could be exploited as tumor marker or as the antigenic target of a therapeutic cancer vaccine.[5][10] A 2016 review indicates that some immunotherapeutic strategies have shown encouraging results in early-phase clinical trials. [11]
Elevations of serum mesothelin specific to ovarian and other cancer patients may be measured using ELISA assays.[12] Soluble mesothelin is the extracellular domain of membrane-bound mesothelin shed from tumor cells as demonstrated by mass spectrometry analysis of soluble mesothelin purified from cell culture supernatant.[13] Assays for blood-borne mesothelin and MPF for tumor diagnosis, especially applied to asbestos-related mesothelioma have been developed.[14] Elevated serum mesothelin was found in most patients with mesothelioma (71%) and ovarian cancer (67%).[15] Blood MPF and mesothelin levels were correlated, with modest accuracy for malignant pleural mesothelioma and lung cancer (sensitivity 74% and 59%, specificity 90% and 86%, respectively for MPF and mesothelin assays).[16] Circulating mesothelin is reported in nearly all pancreatic cancers,[17] however the levels in healthy persons often exceed 80 ng/mL (using 40 kD molecular weight as the conversion factor) and to widely overlap the values in the pancreatic cancer patients.[18] It was noted that the cutoff levels for normal could differ as much as 10-fold among publications, depending on the assay used[18][16][15] and thus that normal levels must be determined anew when new assays are introduced. Therapeutic antibodies to mesothelin have been developed by phage display[19] [20]and humanization of rabbit monoclonal antibodies[21][22]. | https://www.wikidoc.org/index.php/Mesothelin | |
d327d6818d3e448606073e529e913ffc980dcb82 | wikidoc | Metabolife | Metabolife
Metabolife is an American corporation which manufactures dietary supplements. Metabolife's best-selling product, an ephedra-based supplement called Metabolife 356, once generated over $1 billion in annual sales. However, Metabolife 356 and other ephedra-containing supplements were linked to thousands of serious adverse events, including deaths, culminating in a ban on ephedra-containing dietary supplements as unsafe by the Food and Drug Administration in 2004.
Metabolife founder Michael Ellis was indicted on 8 counts of making false statements to the FDA in an effort to obstruct regulation of ephedra. Metabolife was also investigated by the Internal Revenue Service and the Department of Justice for income tax evasion; ultimately, the company pled guilty to filing fraudulent tax returns and was sentenced to pay a criminal fine of $600,000. Metabolife owner William Bradley also pled guilty to evading millions of dollars in taxes and was sentenced to 6 months in federal prison and 2 years of probation.
In response to falling sales, and facing more than $1 billion in personal injury legal claims related to Metabolife 356, Metabolife filed for Chapter 11 bankruptcy in 2005. The company's furnishings and property, including a large collection of artwork, were liquidated in late 2006 to compensate creditors and settle outstanding personal-injury claims.
# Notes
- ↑ Defending a diet pill, by Daniel Eisenberg. Published in Time on October 18 1999. Accessed April 11 2007.
- ↑ Criminal investigation sought for diet supplement seller. Published in USA Today on August 15 2002. Accessed April 11 2007.
- ↑ Metabolife will plead guilty, end tax probe, by David Washburn. Published in the San Diego Union-Tribune on August 6 2005. Accessed April 11 2007.
- ↑ News Release from the United States Department of Justice, dated December 16 2005. Accessed April 11 2007.
- ↑ Metabolife and Owner William Bradley Plead Guilty to Tax Charges. A press release from the United States Department of Justice, dated October 5 2005. Accessed April 11 2007.
- ↑ Breaking Stories: Case Closed, by Matt Potter. Published on SanDiegoReader.com on October 5 2006. Accessed April 11 2007.
- ↑ Ex-Metabolife Hopes to Settle Ephedra Claims, by Penni Crabtree. Reprinted from the San Diego Union-Tribune on June 2 2006. Accessed April 11 2007.
- ↑ Metabolife Continues Its Search for Buyer, by Mike Allen. Published in the San Diego Business Journal on October 17 2005. Accessed April 11 2007.
- ↑ Metabolife's Artwork Goes on the Block Today, by Diane Bell. Published in the San Diego Union-Tribune on November 30 2006; accessed June 22 2007. | Metabolife
Metabolife is an American corporation which manufactures dietary supplements. Metabolife's best-selling product, an ephedra-based supplement called Metabolife 356, once generated over $1 billion in annual sales.[1] However, Metabolife 356 and other ephedra-containing supplements were linked to thousands of serious adverse events, including deaths, culminating in a ban on ephedra-containing dietary supplements as unsafe by the Food and Drug Administration in 2004.
Metabolife founder Michael Ellis was indicted on 8 counts of making false statements to the FDA in an effort to obstruct regulation of ephedra.[2][3] Metabolife was also investigated by the Internal Revenue Service and the Department of Justice for income tax evasion; ultimately, the company pled guilty to filing fraudulent tax returns and was sentenced to pay a criminal fine of $600,000.[4] Metabolife owner William Bradley also pled guilty to evading millions of dollars in taxes and was sentenced to 6 months in federal prison and 2 years of probation.[5][6]
In response to falling sales, and facing more than $1 billion in personal injury legal claims related to Metabolife 356,[7] Metabolife filed for Chapter 11 bankruptcy in 2005.[8] The company's furnishings and property, including a large collection of artwork, were liquidated in late 2006 to compensate creditors and settle outstanding personal-injury claims.[9]
# Notes
- ↑ Defending a diet pill, by Daniel Eisenberg. Published in Time on October 18 1999. Accessed April 11 2007.
- ↑ Criminal investigation sought for diet supplement seller. Published in USA Today on August 15 2002. Accessed April 11 2007.
- ↑ Metabolife will plead guilty, end tax probe, by David Washburn. Published in the San Diego Union-Tribune on August 6 2005. Accessed April 11 2007.
- ↑ News Release from the United States Department of Justice, dated December 16 2005. Accessed April 11 2007.
- ↑ Metabolife and Owner William Bradley Plead Guilty to Tax Charges. A press release from the United States Department of Justice, dated October 5 2005. Accessed April 11 2007.
- ↑ Breaking Stories: Case Closed, by Matt Potter. Published on SanDiegoReader.com on October 5 2006. Accessed April 11 2007.
- ↑ Ex-Metabolife Hopes to Settle Ephedra Claims, by Penni Crabtree. Reprinted from the San Diego Union-Tribune on June 2 2006. Accessed April 11 2007.
- ↑ Metabolife Continues Its Search for Buyer, by Mike Allen. Published in the San Diego Business Journal on October 17 2005. Accessed April 11 2007.
- ↑ Metabolife's Artwork Goes on the Block Today, by Diane Bell. Published in the San Diego Union-Tribune on November 30 2006; accessed June 22 2007.
# External links
- Metabolife home page
Template:US-company-stub
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Metabolife | |
627489b3a23eb46881cdad93d3d0f6ab59535f9d | wikidoc | Metacarpus | Metacarpus
The metacarpus is the intermediate part of the hand skeleton that is located between the fingers distally and the carpus which forms the connection to the forearm.
# Specific metacarpals
It consists of five cylindrical bones which are numbered from the radial to the ulnar side (ossa metacarpalia I-V).
- First metacarpal bone
- Second metacarpal bone
- Third metacarpal bone
- Fourth metacarpal bone
- Fifth metacarpal bone
# Common characteristics of the metacarpal bones
Each consists of a body and two extremities.
## Body
The body (corpus; shaft) is prismoid in form, and curved, so as to be convex in the longitudinal direction behind, concave in front.
It presents three surfaces: medial, lateral, and dorsal.
- The medial and lateral surfaces are concave, for the attachment of the interosseus muscles, and separated from one another by a prominent anterior ridge.
- The dorsal surface presents in its distal two-thirds a smooth, triangular, flattened area which is covered in by the tendons of the Extensor muscles. This surface is bounded by two lines, which commence in small tubercles situated on either side of the digital extremity, and, passing upward, converge and meet some distance above the center of the bone and form a ridge which runs along the rest of the dorsal surface to the carpal extremity. This ridge separates two sloping surfaces for the attachment of the Interossei dorsales.
To the tubercles on the digital extremities are attached the collateral ligaments of the metacarpophalangeal joints.
## Base
The base or carpal extremity (basis) is of a cuboidal form, and broader behind than in front: it articulates with the carpus, and with the adjoining metacarpal bones; its dorsal and volar surfaces are rough, for the attachment of ligaments.
## Head
The head or digital extremity (capitulum) presents an oblong surface markedly convex from before backward, less so transversely, and flattened from side to side; it articulates with the proximal phalanx.
It is broader, and extends farther upward, on the volar than on the dorsal aspect, and is longer in the antero-posterior than in the transverse diameter.
On either side of the head is a tubercle for the attachment of the collateral ligament of the metacarpophalangeal joint.
The dorsal surface, broad and flat, supports the tendons of the extensor muscles; the volar surface is grooved in the middle line for the passage of the Flexor tendons, and marked on either side by an articular eminence continuous with the terminal articular surface.
# Articulations
Besides their phalangeal articulations, the metacarpal bones articulate as follows:
- the first with the greater multangular;
- the second with the greater multangular, lesser multangular, capitate and third metacarpal;
- the third with the capitate and second and fourth metacarpals;
- the fourth with the capitate, hamate, and third and fifth metacarpals;
- and the fifth with the hamate and fourth metacarpal. | Metacarpus
Template:Infobox Bone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The metacarpus is the intermediate part of the hand skeleton that is located between the fingers distally and the carpus which forms the connection to the forearm.
# Specific metacarpals
It consists of five cylindrical bones which are numbered from the radial to the ulnar side (ossa metacarpalia I-V).
- First metacarpal bone
- Second metacarpal bone
- Third metacarpal bone
- Fourth metacarpal bone
- Fifth metacarpal bone
# Common characteristics of the metacarpal bones
Each consists of a body and two extremities.
## Body
The body (corpus; shaft) is prismoid in form, and curved, so as to be convex in the longitudinal direction behind, concave in front.
It presents three surfaces: medial, lateral, and dorsal.
- The medial and lateral surfaces are concave, for the attachment of the interosseus muscles, and separated from one another by a prominent anterior ridge.
- The dorsal surface presents in its distal two-thirds a smooth, triangular, flattened area which is covered in by the tendons of the Extensor muscles. This surface is bounded by two lines, which commence in small tubercles situated on either side of the digital extremity, and, passing upward, converge and meet some distance above the center of the bone and form a ridge which runs along the rest of the dorsal surface to the carpal extremity. This ridge separates two sloping surfaces for the attachment of the Interossei dorsales.
To the tubercles on the digital extremities are attached the collateral ligaments of the metacarpophalangeal joints.
## Base
The base or carpal extremity (basis) is of a cuboidal form, and broader behind than in front: it articulates with the carpus, and with the adjoining metacarpal bones; its dorsal and volar surfaces are rough, for the attachment of ligaments.
## Head
The head or digital extremity (capitulum) presents an oblong surface markedly convex from before backward, less so transversely, and flattened from side to side; it articulates with the proximal phalanx.
It is broader, and extends farther upward, on the volar than on the dorsal aspect, and is longer in the antero-posterior than in the transverse diameter.
On either side of the head is a tubercle for the attachment of the collateral ligament of the metacarpophalangeal joint.
The dorsal surface, broad and flat, supports the tendons of the extensor muscles; the volar surface is grooved in the middle line for the passage of the Flexor tendons, and marked on either side by an articular eminence continuous with the terminal articular surface.
# Articulations
Besides their phalangeal articulations, the metacarpal bones articulate as follows:
- the first with the greater multangular;
- the second with the greater multangular, lesser multangular, capitate and third metacarpal;
- the third with the capitate and second and fourth metacarpals;
- the fourth with the capitate, hamate, and third and fifth metacarpals;
- and the fifth with the hamate and fourth metacarpal. | https://www.wikidoc.org/index.php/Metacarpal | |
064408557aee5954e4561e91cbd1bfe4824fd00f | wikidoc | Metallurgy | Metallurgy
Metallurgy is a domain of materials science that studies the physical and chemical behavior of metallic elements, their intermetallic compounds, and their compounds, which are called alloys. It is also the technology of metals: the way in which science is applied to their practical use. Metallurgy is commonly used in the craft of metalworking.
# History
The earliest recorded metal employed by humans appears to be gold which can be found free or "native". Small amounts of natural gold have been found in Spanish caves used during the late Paleolithic period, c. 40,000 BC.
Silver, copper, tin and meteoric iron can also be found native, allowing a limited amount of metalworking in early cultures. Egyptian weapons made from meteoric iron in about 3000 B.C. were highly prized as "Daggers from Heaven". However, by learning to get copper and tin by heating rocks and combining copper and tin to make an alloy called bronze, the technology of metallurgy began about 3500 B.C. with the Bronze Age.
The extraction of iron from its ore into a workable metal is much more difficult. It appears to have been invented by the Hittites in about 1200 B.C., beginning the Iron Age. The secret of extracting and working iron was a key factor in the success of the Philistines
Historical developments in ferrous metallurgy can be found in a wide variety of past cultures and civilizations. This includes the ancient and medieval kingdoms and empires of the Middle East and Near East, ancient Egypt and Anatolia (Turkey), Carthage, the Greeks and Romans of ancient Europe, medieval Europe, ancient and medieval China, ancient and medieval India, ancient and medieval Japan, etc. Of interest to note is that many applications, practices, and devices associated or involved in metallurgy were possibly established in ancient China before Europeans mastered these crafts (such as the innovation of the blast furnace, cast iron, steel, hydraulic-powered trip hammers, etc.). However, modern research suggests that Roman technology was far more sophisticated than hitherto supposed, especially in mining methods, metal extraction and forging. They were for example expert in hydraulic mining methods well before the Chinese, or any other civilization of the time.
A 16th century book by Georg Agricola called De re metallica describes the highly developed and complex processes of mining metal ores, metal extraction and metallurgy of the time. Agricola has been described as the "father of metallurgy"
# Extractive metallurgy
Extractive metallurgy is the practice of removing valuable metals from an ore and refining the extracted raw metals into a purer form. In order to convert a metal oxide or sulfide to a purer metal, the ore must be reduced either physically, chemically, or electrolytically.
Extractive metallurgists are interested in three primary streams: feed, concentrate (valuable metal oxide/sulfide), and tailings (waste). After mining, large pieces of the ore feed are broken through crushing and/or grinding in order to obtain particles small enough where each particle is either mostly valuable or mostly waste. Concentrating the particles of a value in a form supporting separation enables the desired metal to be removed from waste products.
Mining may not be necessary if the ore body and physical environment are conducive to leaching. Leaching dissolves minerals in an ore body and results in an enriched solution. The solution is collected and processed to extract valuable metals.
Ore bodies often contain more than one valuable metal. Tailings of a previous process may be used as a feed in another process to extract a secondary product from the original ore. Additionally, a concentrate may contain more than one valuable metal. That concentrate would then be processed to separate the valuable metals into individual constituents.
# Important common alloy systems
Common engineering metals include aluminium, chromium, copper, iron, magnesium, nickel, titanium and zinc. These are most often used as alloys. Much effort has been placed on understanding the iron-carbon alloy system, which includes steels and cast irons. Plain carbon steels are used in low cost, high strength applications where weight and corrosion are not a problem. Cast irons, including ductile iron are also part of the iron-carbon system.
Stainless steel or galvanized steel are used where resistance to corrosion is important. Aluminium alloys and magnesium alloys are used for applications where strength and lightness are required.
Cupro-nickel alloys such as Monel are used in highly corrosive environments and for non-magnetic applications. Nickel-based superalloys like Inconel are used in high temperature applications such as turbochargers, pressure vessels, and heat exchangers. For extremely high temperatures, single crystal alloys are used to minimize creep.
# Production engineering of metals
In production engineering, metallurgy is concerned with the production of metallic components for use in consumer or engineering products. This involves the production of alloys, the shaping, the heat treatment and the surface treatment of the product. The task of the metallurgist is to achieve balance between material properties such as cost, weight, strength, toughness, hardness, corrosion and fatigue resistance, and performance in temperature extremes. To achieve this goal, the operating environment must be carefully considered. In a saltwater environment, ferrous metals and some aluminium alloys corrode quickly. Metals exposed to cold or cryogenic conditions may endure a ductile to brittle transition and lose their toughness, becoming more brittle and prone to cracking. Metals under continual cyclic loading can suffer from metal fatigue. Metals under constant stress at elevated temperatures can creep.
## Metal working processes
Metals are shaped by processes such as casting, forging, flow forming, rolling, extrusion, sintering, metalworking, machining and fabrication. With casting, molten metal is poured into a shaped mould. With forging, a red-hot billet is hammered into shape. With rolling, a billet is passed through successively narrower rollers to create a sheet. With extrusion, a hot and malleable metal is forced under pressure through a die, which shapes it before it cools. With sintering, a powdered metal is compressed into a die at high temperature. With machining, lathes, milling machines, and drills cut the cold metal to shape. With fabrication, sheets of metal are cut with guillotines or gas cutters and bent into shape.
"Cold working" processes, where the product’s shape is altered by rolling, fabrication or other processes while the product is cold, can increase the strength of the product by a process called work hardening. Work hardening creates microscopic defects in the metal, which resist further changes of shape.
Various forms of casting exist in industry and academia. These include sand casting, investment casting (also called the “lost wax process”), die casting and continuous casting.
## Joining
Welding is a technique for joining metal components by melting the base material. A filler material of similar composition may also be melted into the joint.
Brazing is a technique for joining metals at a temperature below their melting point. A filler with a melting point below that of the base metal is used, and is drawn into the joint by capillary action. Brazing results in a mechanical and metallurgical bond between work pieces.
Soldering is a method of joining metals below their melting points using a filler metal.
Soldering results in a mechanical joint and occurs at lower temperatures than brazing.
## Heat treatment
Metals can be heat treated to alter the properties of strength, ductility, toughness, hardness or resistance to corrosion. Common heat treatment processes include annealing, precipitation strengthening, quenching, and tempering. The annealing process softens the metal by allowing recovery of cold work and grain growth. Quenching can be used to harden alloy steels, or in precipitation hardenable alloys, to trap dissolved solute atoms in solution. Tempering will cause the dissolved alloying elements to precipitate, or in the case of quenched steels, improve impact strength and ductile properties.
## Surface treatment
Electroplating is a common surface-treatment technique. It involves bonding a thin layer of another metal such as gold, silver, chromium or zinc to the surface of the product. It is used to reduce corrosion as well as to improve the product's aesthetic appearance.
Thermal spraying techniques are another popular finishing option, and often have better high temperature properties than electroplated coatings.
Case hardening is a process in which an alloying element, most commonly carbon or nitrogen, diffuses into the surface of a monolithic metal. The resulting interstitial solid solution is harder than the base material, which improves wear resistance without sacrificing toughness.
# Electrical and electronic engineering
Metallurgy is also applied to electrical and electronic materials where metals such as aluminium, copper, tin, silver, and gold are used in power lines, wires, printed circuit boards and integrated circuits.
# Metallurgical techniques
Metallurgists study the microscopic and macroscopic properties using metallography, a technique invented by Henry Clifton Sorby. In metallography, an alloy of interest is ground flat and polished to a mirror finish. The sample can then be etched to reveal the microstructure and macrostructure of the metal. A metallurgist can then examine the sample with an optical or electron microscope and learn a great deal about the sample's composition, mechanical properties, and processing history.
Crystallography, often using diffraction of x-rays or electrons, is another valuable tool available to the modern metallurgist. Crystallography allow the identification of unknown materials and reveals the crystal structure of the sample. Quantitative crystallography can be used to calculate the amount of phases present as well as the degree of strain to which a sample has been subjected.
The physical properties of metals can be quantified by mechanical testing. Typical tests include tensile strength, compressive strength, hardness, impact toughness, fatigue and creep life. | Metallurgy
Metallurgy is a domain of materials science that studies the physical and chemical behavior of metallic elements, their intermetallic compounds, and their compounds, which are called alloys. It is also the technology of metals: the way in which science is applied to their practical use. Metallurgy is commonly used in the craft of metalworking.
# History
The earliest recorded metal employed by humans appears to be gold which can be found free or "native". Small amounts of natural gold have been found in Spanish caves used during the late Paleolithic period, c. 40,000 BC.[1]
Silver, copper, tin and meteoric iron can also be found native, allowing a limited amount of metalworking in early cultures. Egyptian weapons made from meteoric iron in about 3000 B.C. were highly prized as "Daggers from Heaven"[2]. However, by learning to get copper and tin by heating rocks and combining copper and tin to make an alloy called bronze, the technology of metallurgy began about 3500 B.C. with the Bronze Age.
The extraction of iron from its ore into a workable metal is much more difficult. It appears to have been invented by the Hittites in about 1200 B.C., beginning the Iron Age. The secret of extracting and working iron was a key factor in the success of the Philistines[3][4]
Historical developments in ferrous metallurgy can be found in a wide variety of past cultures and civilizations. This includes the ancient and medieval kingdoms and empires of the Middle East and Near East, ancient Egypt and Anatolia (Turkey), Carthage, the Greeks and Romans of ancient Europe, medieval Europe, ancient and medieval China, ancient and medieval India, ancient and medieval Japan, etc. Of interest to note is that many applications, practices, and devices associated or involved in metallurgy were possibly established in ancient China before Europeans mastered these crafts (such as the innovation of the blast furnace, cast iron, steel, hydraulic-powered trip hammers, etc.)[5]. However, modern research suggests that Roman technology was far more sophisticated than hitherto supposed, especially in mining methods, metal extraction and forging. They were for example expert in hydraulic mining methods well before the Chinese, or any other civilization of the time[citation needed].
A 16th century book by Georg Agricola called De re metallica describes the highly developed and complex processes of mining metal ores, metal extraction and metallurgy of the time. Agricola has been described as the "father of metallurgy"[6]
# Extractive metallurgy
Extractive metallurgy is the practice of removing valuable metals from an ore and refining the extracted raw metals into a purer form. In order to convert a metal oxide or sulfide to a purer metal, the ore must be reduced either physically, chemically, or electrolytically.
Extractive metallurgists are interested in three primary streams: feed, concentrate (valuable metal oxide/sulfide), and tailings (waste). After mining, large pieces of the ore feed are broken through crushing and/or grinding in order to obtain particles small enough where each particle is either mostly valuable or mostly waste. Concentrating the particles of a value in a form supporting separation enables the desired metal to be removed from waste products.
Mining may not be necessary if the ore body and physical environment are conducive to leaching. Leaching dissolves minerals in an ore body and results in an enriched solution. The solution is collected and processed to extract valuable metals.
Ore bodies often contain more than one valuable metal. Tailings of a previous process may be used as a feed in another process to extract a secondary product from the original ore. Additionally, a concentrate may contain more than one valuable metal. That concentrate would then be processed to separate the valuable metals into individual constituents.
# Important common alloy systems
Common engineering metals include aluminium, chromium, copper, iron, magnesium, nickel, titanium and zinc. These are most often used as alloys. Much effort has been placed on understanding the iron-carbon alloy system, which includes steels and cast irons. Plain carbon steels are used in low cost, high strength applications where weight and corrosion are not a problem. Cast irons, including ductile iron are also part of the iron-carbon system.
Stainless steel or galvanized steel are used where resistance to corrosion is important. Aluminium alloys and magnesium alloys are used for applications where strength and lightness are required.
Cupro-nickel alloys such as Monel are used in highly corrosive environments and for non-magnetic applications. Nickel-based superalloys like Inconel are used in high temperature applications such as turbochargers, pressure vessels, and heat exchangers. For extremely high temperatures, single crystal alloys are used to minimize creep.
# Production engineering of metals
In production engineering, metallurgy is concerned with the production of metallic components for use in consumer or engineering products. This involves the production of alloys, the shaping, the heat treatment and the surface treatment of the product. The task of the metallurgist is to achieve balance between material properties such as cost, weight, strength, toughness, hardness, corrosion and fatigue resistance, and performance in temperature extremes. To achieve this goal, the operating environment must be carefully considered. In a saltwater environment, ferrous metals and some aluminium alloys corrode quickly. Metals exposed to cold or cryogenic conditions may endure a ductile to brittle transition and lose their toughness, becoming more brittle and prone to cracking. Metals under continual cyclic loading can suffer from metal fatigue. Metals under constant stress at elevated temperatures can creep.
## Metal working processes
Metals are shaped by processes such as casting, forging, flow forming, rolling, extrusion, sintering, metalworking, machining and fabrication. With casting, molten metal is poured into a shaped mould. With forging, a red-hot billet is hammered into shape. With rolling, a billet is passed through successively narrower rollers to create a sheet. With extrusion, a hot and malleable metal is forced under pressure through a die, which shapes it before it cools. With sintering, a powdered metal is compressed into a die at high temperature. With machining, lathes, milling machines, and drills cut the cold metal to shape. With fabrication, sheets of metal are cut with guillotines or gas cutters and bent into shape.
"Cold working" processes, where the product’s shape is altered by rolling, fabrication or other processes while the product is cold, can increase the strength of the product by a process called work hardening. Work hardening creates microscopic defects in the metal, which resist further changes of shape.
Various forms of casting exist in industry and academia. These include sand casting, investment casting (also called the “lost wax process”), die casting and continuous casting.
## Joining
Welding is a technique for joining metal components by melting the base material. A filler material of similar composition may also be melted into the joint.
Brazing is a technique for joining metals at a temperature below their melting point. A filler with a melting point below that of the base metal is used, and is drawn into the joint by capillary action. Brazing results in a mechanical and metallurgical bond between work pieces.
Soldering is a method of joining metals below their melting points using a filler metal.
Soldering results in a mechanical joint and occurs at lower temperatures than brazing.
## Heat treatment
Metals can be heat treated to alter the properties of strength, ductility, toughness, hardness or resistance to corrosion. Common heat treatment processes include annealing, precipitation strengthening, quenching, and tempering. The annealing process softens the metal by allowing recovery of cold work and grain growth. Quenching can be used to harden alloy steels, or in precipitation hardenable alloys, to trap dissolved solute atoms in solution. Tempering will cause the dissolved alloying elements to precipitate, or in the case of quenched steels, improve impact strength and ductile properties.
## Surface treatment
Electroplating is a common surface-treatment technique. It involves bonding a thin layer of another metal such as gold, silver, chromium or zinc to the surface of the product. It is used to reduce corrosion as well as to improve the product's aesthetic appearance.
Thermal spraying techniques are another popular finishing option, and often have better high temperature properties than electroplated coatings.
Case hardening is a process in which an alloying element, most commonly carbon or nitrogen, diffuses into the surface of a monolithic metal. The resulting interstitial solid solution is harder than the base material, which improves wear resistance without sacrificing toughness.
# Electrical and electronic engineering
Metallurgy is also applied to electrical and electronic materials where metals such as aluminium, copper, tin, silver, and gold are used in power lines, wires, printed circuit boards and integrated circuits.
# Metallurgical techniques
Metallurgists study the microscopic and macroscopic properties using metallography, a technique invented by Henry Clifton Sorby. In metallography, an alloy of interest is ground flat and polished to a mirror finish. The sample can then be etched to reveal the microstructure and macrostructure of the metal. A metallurgist can then examine the sample with an optical or electron microscope and learn a great deal about the sample's composition, mechanical properties, and processing history.
Crystallography, often using diffraction of x-rays or electrons, is another valuable tool available to the modern metallurgist. Crystallography allow the identification of unknown materials and reveals the crystal structure of the sample. Quantitative crystallography can be used to calculate the amount of phases present as well as the degree of strain to which a sample has been subjected.
The physical properties of metals can be quantified by mechanical testing. Typical tests include tensile strength, compressive strength, hardness, impact toughness, fatigue and creep life. | https://www.wikidoc.org/index.php/Metallurgy | |
d66f39178ca8d6d4bb7a303b988deaea067bbee7 | wikidoc | Metaplasia | Metaplasia
# Overview
Metaplasia (Greek: "change in form") is the reversible replacement of one differentiated cell type with another mature differentiated cell type. The change from one type of cell to another is generally caused by some sort of abnormal stimulus. In simplistic terms, it is as if the original cells are not robust enough to withstand the new environment, and so they change into another type more suited to the new environment. If the stimulus that caused metaplasia is removed or ceases, tissues return to their normal pattern of differentiation. Metaplasia is not synonymous with dysplasia and is not considered carcinogenesis. It is also contrasted with heteroplasia, which is the abnormal growth of cytologic and histologic elements without a stimulus.
# Causes
When cells are faced with physiological or pathological stresses, they respond by adapting in several ways; one of these cellular adaptations is metaplasia. It is a benign (i.e. non-cancerous) change that occurs as a response to chronic physical or chemical irritation, such as cigarette smoke that causes the mucus-secreting ciliated simple columnar respiratory epithelial cells that line the airways to be replaced by simple squamous epithelium, or a stone in the bile duct that causes the replacement of the secretory columnar epithelium with simple squamous epithelium (Squamous metaplasia). Although metaplasia is an adaptation that replaces delicate cells with hardier ones that are more likely to be able to withstand the stresses that the epithelium is faced with, it is also accompanied by a loss of epithelial function, and is considered undesirable; this undesirability is underscored by the propensity for metaplastic regions to eventually turn cancerous if the irritant is not eliminated.
Specialised epithelial cells are already differentiated, and cannot simply transform their morphologies to change from one cell type to another. Metaplasia, then, does not occur as a result of any change in the pre-existing epithelial cells but rather as a result of reprogrammed stem cells present in the organ's connective tissue that are nudged along a different pathway of differentiation by cytokines, growth factors and other substances in the cell's environment.
In a nutshell, metaplasia occurs by stem cells that reprogramme differentiation of cells rather than by transdifferentiation.
## Examples
Barrett's esophagus is an abnormal change in the cells of the lower esophagus, thought to be caused by damage from chronic stomach acid exposure.
Metaplasia of the cervix, which occurs in cervical erosion, can be detected by a cervical smear test. The normal endocervical columnar epithelium is replaced by a squamous epithelium in an area termed the transformation zone. This is a normal physiological event that takes place around puberty. The stimulus is believed to be a change in the vaginal environment, which becomes acidic.
The following table lists some common tissues susceptible to metaplasia, and the stimuli that can cause the change:
# Therapy
The medical significance of metaplasia is that in some sites cells may progress from metaplasia, to develop dysplasia, and then malignant neoplasia (cancer). Thus, at sites where metaplasia is detected, efforts are made to remove the causative irritant, thereby decreasing the risk of progression to malignancy. The metaplastic area must be carefully monitored to ensure that dysplastic change does not begin to occur. A progression to significant dysplasia indicates that the area could need removal to prevent the development of cancer. | Metaplasia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Metaplasia (Greek: "change in form") is the reversible replacement of one differentiated cell type with another mature differentiated cell type. The change from one type of cell to another is generally caused by some sort of abnormal stimulus. In simplistic terms, it is as if the original cells are not robust enough to withstand the new environment, and so they change into another type more suited to the new environment. If the stimulus that caused metaplasia is removed or ceases, tissues return to their normal pattern of differentiation. Metaplasia is not synonymous with dysplasia and is not considered carcinogenesis. It is also contrasted with heteroplasia, which is the abnormal growth of cytologic and histologic elements without a stimulus.
# Causes
When cells are faced with physiological or pathological stresses, they respond by adapting in several ways; one of these cellular adaptations is metaplasia. It is a benign (i.e. non-cancerous) change that occurs as a response to chronic physical or chemical irritation, such as cigarette smoke that causes the mucus-secreting ciliated simple columnar respiratory epithelial cells that line the airways to be replaced by simple squamous epithelium, or a stone in the bile duct that causes the replacement of the secretory columnar epithelium with simple squamous epithelium (Squamous metaplasia). Although metaplasia is an adaptation that replaces delicate cells with hardier ones that are more likely to be able to withstand the stresses that the epithelium is faced with, it is also accompanied by a loss of epithelial function, and is considered undesirable; this undesirability is underscored by the propensity for metaplastic regions to eventually turn cancerous if the irritant is not eliminated.
Specialised epithelial cells are already differentiated, and cannot simply transform their morphologies to change from one cell type to another. Metaplasia, then, does not occur as a result of any change in the pre-existing epithelial cells but rather as a result of reprogrammed stem cells present in the organ's connective tissue that are nudged along a different pathway of differentiation by cytokines, growth factors and other substances in the cell's environment.
In a nutshell, metaplasia occurs by stem cells that reprogramme differentiation of cells rather than by transdifferentiation.
## Examples
Barrett's esophagus is an abnormal change in the cells of the lower esophagus, thought to be caused by damage from chronic stomach acid exposure.
Metaplasia of the cervix, which occurs in cervical erosion, can be detected by a cervical smear test. The normal endocervical columnar epithelium is replaced by a squamous epithelium in an area termed the transformation zone. This is a normal physiological event that takes place around puberty. The stimulus is believed to be a change in the vaginal environment, which becomes acidic.
The following table lists some common tissues susceptible to metaplasia, and the stimuli that can cause the change:
# Therapy
The medical significance of metaplasia is that in some sites cells may progress from metaplasia, to develop dysplasia, and then malignant neoplasia (cancer). Thus, at sites where metaplasia is detected, efforts are made to remove the causative irritant, thereby decreasing the risk of progression to malignancy. The metaplastic area must be carefully monitored to ensure that dysplastic change does not begin to occur. A progression to significant dysplasia indicates that the area could need removal to prevent the development of cancer. | https://www.wikidoc.org/index.php/Metaplasia | |
57f9f8f97b07e33a2b48d8fb4ef0214d14b844ea | wikidoc | Metatarsus | Metatarsus
# Overview
The metatarsus consists of the five long bones of the foot, which are numbered from the medial side (ossa metatarsalia I.-V.); each presents for examination a body and two extremities. These are analogous to the metacarpals of the hand.
Specifically, the bones are:
- First metatarsal bone
- Second metatarsal bone
- Third metatarsal bone
- Fourth metatarsal bone
- Fifth metatarsal bone
# Common characteristics of the metatarsal bones
- The body is prismoid in form, tapers gradually from the tarsal to the phalangeal extremity, and is curved longitudinally, so as to be concave below, slightly convex above.
- The base or posterior extremity is wedge-shaped, articulating proximally with the tarsal bones, and by its sides with the contiguous metatarsal bones: its dorsal and plantar surfaces are rough for the attachment of ligaments.
- The head or anterior extremity presents a convex articular surface, oblong from above downward, and extending farther backward below than above.
- Its sides are flattened, and on each is a depression, surmounted by a tubercle, for ligamentous attachment.
- Its plantar surface is grooved antero-posteriorly for the passage of the flexor tendons, and marked on either side by an articular eminence continuous with the terminal articular surface.
# Articulations
The base of each metatarsal bone articulates with one or more of the tarsal bones, and the head with one of the first row of phalanges.
- The first metatarsal articulates with the first cuneiform.
- the second with all three cuneiforms.
- the third with the third cuneiform.
- the fourth with the third cuneiform and the cuboid.
- The fifth with the cuboid.
# Injuries
The metatarsal bones are often broken by soccer players. These and other recent cases have been attributed to the modern lightweight design of football boots, which give less protection to the foot.
Stress fractures are thought to account for 16% of injuries related to sports preparation, and the metatarsals are most often involved. These fractures are commonly called march fractures, as they are commonly diagnosed among military recruits after long marches. They are also common among road runners, and even skimboarders. The second and third metatarsals are fixed while walking, thus these metatarsals are common sites of injury. The fifth metatarsal may be fractured if the foot is oversupinated during locomotion.
# Additional images
- CT 3D human Foot Skin and Bone
- Lower extremity
- X-ray of foot.
- Bones of the right foot. Dorsal surface.
- Skeleton of foot. Medial aspect.
- Oblique section of left intertarsal and tarsometatarsal articulations, showing the synovial cavities. | Metatarsus
Template:Infobox Bone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The metatarsus consists of the five long bones of the foot, which are numbered from the medial side (ossa metatarsalia I.-V.); each presents for examination a body and two extremities. These are analogous to the metacarpals of the hand.
Specifically, the bones are:
- First metatarsal bone
- Second metatarsal bone
- Third metatarsal bone
- Fourth metatarsal bone
- Fifth metatarsal bone
# Common characteristics of the metatarsal bones
- The body is prismoid in form, tapers gradually from the tarsal to the phalangeal extremity, and is curved longitudinally, so as to be concave below, slightly convex above.
- The base or posterior extremity is wedge-shaped, articulating proximally with the tarsal bones, and by its sides with the contiguous metatarsal bones: its dorsal and plantar surfaces are rough for the attachment of ligaments.
- The head or anterior extremity presents a convex articular surface, oblong from above downward, and extending farther backward below than above.
- Its sides are flattened, and on each is a depression, surmounted by a tubercle, for ligamentous attachment.
- Its plantar surface is grooved antero-posteriorly for the passage of the flexor tendons, and marked on either side by an articular eminence continuous with the terminal articular surface.
# Articulations
The base of each metatarsal bone articulates with one or more of the tarsal bones, and the head with one of the first row of phalanges.
- The first metatarsal articulates with the first cuneiform.
- the second with all three cuneiforms.
- the third with the third cuneiform.
- the fourth with the third cuneiform and the cuboid.
- The fifth with the cuboid.
# Injuries
The metatarsal bones are often broken by soccer players. These and other recent cases have been attributed to the modern lightweight design of football boots, which give less protection to the foot.
Stress fractures are thought to account for 16% of injuries related to sports preparation, and the metatarsals are most often involved. These fractures are commonly called march fractures, as they are commonly diagnosed among military recruits after long marches. They are also common among road runners, and even skimboarders. The second and third metatarsals are fixed while walking, thus these metatarsals are common sites of injury. The fifth metatarsal may be fractured if the foot is oversupinated during locomotion.[1]
# Additional images
- CT 3D human Foot Skin and Bone
- Lower extremity
- X-ray of foot.
- Bones of the right foot. Dorsal surface.
- Skeleton of foot. Medial aspect.
- Oblique section of left intertarsal and tarsometatarsal articulations, showing the synovial cavities. | https://www.wikidoc.org/index.php/Metatarsal | |
858d4bb318627a710163b73900f015d8825c56c6 | wikidoc | Metatheria | Metatheria
Metatheria is a grouping within the animal class Mammalia. First proposed by Thomas Henry Huxley in 1880, it is nearly synonymous with the earlier taxon Marsupialia (Illiger, 1811) though it is slightly wider since it also contains the nearest fossil relatives of marsupial mammals.
The earliest known representatives are from the uppermost Lower Cretaceous of North America.
The closest living relatives of the metatheres are the Eutheria (also erected by Huxley in 1880). Both are conventionally united as infraclasses within the subclass Theria (Parker and Haswell, 1897), which contains all living mammals except monotremes.
The Greek words meta- and theria mean the "changed beasts". | Metatheria
Metatheria is a grouping within the animal class Mammalia. First proposed by Thomas Henry Huxley in 1880, it is nearly synonymous with the earlier taxon Marsupialia (Illiger, 1811) though it is slightly wider since it also contains the nearest fossil relatives of marsupial mammals.
The earliest known representatives are from the uppermost Lower Cretaceous of North America.
The closest living relatives of the metatheres are the Eutheria (also erected by Huxley in 1880). Both are conventionally united as infraclasses within the subclass Theria (Parker and Haswell, 1897), which contains all living mammals except monotremes.
The Greek words meta- and theria mean the "changed beasts". | https://www.wikidoc.org/index.php/Metatheria | |
37bed58953979ec4748d4d222a5840451951ed82 | wikidoc | Metaxalone | Metaxalone
# 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
Metaxalone is a centrally acting skeletal muscle relaxant that is FDA approved for the {{{indicationType}}} of musculoskeletal pain. Common adverse reactions include drug-induced gastrointestinal disturbance, nausea, vomiting, dizziness, headache, somnolence, feeling nervous.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Metaxalone is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomforts associated with acute, painful musculoskeletal conditions. The mode of action of this drug has not been clearly identified, but may be related to its sedative properties. Metaxalone does not directly relax tense skeletal muscles in man.
- The recommended dose for adults is one 800 mg tablet three to four times a day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metaxalone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metaxalone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- The recommended dose for children over 12 years of age is one 800 mg tablet three to four times a day.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metaxalone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metaxalone in pediatric patients.
# Contraindications
- Known hypersensitivity to any components of this product.
- Known tendency to drug induced, hemolytic, or other anemias.
- Significantly impaired renal or hepatic function.
# Warnings
- Metaxalone may enhance the effects of alcohol and other CNS depressants.
### Precautions
- Metaxalone should be administered with great care to patients with pre-existing liver damage. Serial liver function studies should be performed in these patients.
- False-positive Benedict’s tests, due to an unknown reducing substance, have been noted. A glucose-specific test will differentiate findings.
- Taking metaxalone with food may enhance general CNS depression; elderly patients may be especially susceptible to this CNS effect.
# Adverse Reactions
## Clinical Trials Experience
- The most frequent reactions to metaxalone include:
Drowsiness, dizziness, headache, and nervousness or “irritability”;
Nausea, vomiting, gastrointestinal upset.
- Other adverse reactions are:
Hypersensitivity reaction, rash with or without pruritus;
Leukopenia; hemolytic anemia;
Jaundice.
- Though rare, anaphylactoid reactions have been reported with metaxalone.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Metaxalone in the drug label.
# Drug Interactions
- The sedative effects of metaxalone and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may be additive. Therefore, caution should be exercised with patients who take more than one of these CNS depressants simultaneously.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
- Reproduction studies in rats have not revealed evidence of impaired fertility or harm to the fetus due to metaxalone. Post marketing experience has not revealed evidence of fetal injury, but such experience cannot exclude the possibility of infrequent or subtle damage to the human fetus. Safe use of metaxalone has not been established with regard to possible adverse effects upon fetal development. Therefore, metaxalone tablets should not be used in women who are or may become pregnant and particularly during early pregnancy unless, in the judgement of the physician, the potential benefits outweigh the possible hazards.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Metaxalone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Metaxalone during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is secreted in human milk. As a general rule, nursing should not be undertaken while a patient is on a drug since many drugs are excreted in human milk.
### Pediatric Use
- Safety and effectiveness in children 12 years of age and below have not been established.
### Geriatic Use
There is no FDA guidance on the use of Metaxalone with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Metaxalone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Metaxalone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Metaxalone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Metaxalone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Metaxalone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Metaxalone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Metaxalone in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Metaxalone in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Deaths by deliberate or accidental overdose have occurred with metaxalone, particularly in combination with antidepressants, and have been reported with this class of drug in combination with alcohol.
- When determining the LD50 in rats and mice, progressive sedation, hypnosis and finally respiratory failure were noted as the dosage increased. In dogs, no LD50 could be determined as the higher doses produced an emetic action in 15 to 30 minutes.
### Management
- Gastric lavage and supportive therapy. Consultation with a regional poison control center is recommended.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Metaxalone in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism of action of metaxalone in humans has not been established, but may be due to general central nervous system depression. Metaxalone has no direct action on the contractile mechanism of striated muscle, the motor end plate or the nerve fiber.
## Structure
- Metaxalone is available as an 800 mg, light pink to pink, capsule shaped, scored uncoated tablet.
- Chemically, metaxalone is 5--2-oxazolidinone. The empirical formula is C12H15NO3, which corresponds to a molecular weight of 221.25. The structural formula is:
- Metaxalone is a white to almost white, odorless crystalline powder freely soluble in chloroform, soluble in methanol and in 96% ethanol, but practically insoluble in ether or water.
- Each tablet contains 800 mg metaxalone and the following inactive ingredients: calcium carbonate, FD&C Red #40, hypromellose, lactose monohydrate, microcrystalline cellulose, povidone, silicone dioxide, sodium starch glycolate and sodium stearyl fumarate.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Metaxalone in the drug label.
## Pharmacokinetics
- The pharmacokinetics of metaxalone have been evaluated in healthy adult volunteers after single dose administration of metaxalone under fasted and fed conditions at doses ranging from 400 mg to 800 mg.
- Absorption
- Peak plasma concentrations of metaxalone occur approximately 3 hours after a 400 mg oral dose under fasted conditions. Thereafter, metaxalone concentrations decline log-linearly with a terminal half-life of 9.0 ± 4.8 hours. Doubling the dose of metaxalone from 400 mg to 800 mg results in a roughly proportional increase in metaxalone exposure as indicated by peak plasma concentrations (Cmax) and area under the curve (AUC). Dose proportionality at doses above 800 mg has not been studied. The absolute bioavailability of metaxalone is not known.
- The single-dose pharmacokinetic parameters of metaxalone in two groups of healthy volunteers are shown in Table 1.
- Food Effects
- A randomized, two-way, crossover study was conducted in 42 healthy volunteers (31 males, 11 females) administered one 400 mg metaxalone tablet under fasted conditions and following a standard high-fat breakfast. Subjects ranged in age from 18 to 48 years (mean age = 23.5 ± 5.7 years). Compared to fasted conditions, the presence of a high fat meal at the time of drug administration increased Cmax by 177.5% and increased AUC (AUC0-t, AUC∞) by 123.5% and 115.4%, respectively. Time-to-peak concentration (Tmax) was also delayed (4.3 h versus 3.3 h) and terminal half-life was decreased (2.4 h versus 9.0 h) under fed conditions compared to fasted.
- In a second food effect study of similar design, two 400 mg metaxalone tablets (800 mg) were administered to healthy volunteers (N=59, 37 males, 22 females), ranging in age from 18 to 50 years (mean age = 25.6± 8.7 years). Compared to fasted conditions, the presence of a high fat meal at the time of drug administration increased Cmax by 193.6% and increased AUC (AUC0-t, AUC∞) by 146.4% and 142.2%, respectively. Time-to-peak concentration (Tmax) was also delayed (4.9 h versus 3.0 h) and terminal half-life was decreased (4.2 h versus 8.0 h) under fed conditions compared to fasted conditions. Similar food effect results were observed in the above study when one metaxalone 800 mg tablet was administered in place of two metaxalone 400 mg tablets. The increase in metaxalone exposure coinciding with a reduction in half-life may be attributed to more complete absorption of metaxalone in the presence of a high fat meal (Figure 1).
- Distribution, Metabolism, and Excretion
- Although plasma protein binding and absolute bioavailability of metaxalone are not known, the apparent volume of distribution (V/F ~ 800 L) and lipophilicity (log P = 2.42) of metaxalone suggest that the drug is extensively distributed in the tissues. Metaxalone is metabolized by the liver and excreted in the urine as unidentified metabolites. Hepatic Cytochrome P450 enzymes play a role in the metabolism of metaxalone. Specifically, CYP1A2, CYP2D6, CYP2E1, and CYP3A4 and, to a lesser extent, CYP2C8, CYP2C9, and CYP2C19 appear to metabolize metaxalone.
- Metaxalone does not significantly inhibit major CYP enzymes such as CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Metaxalone does not significantly induce major CYP enzymes such as CYP1A2, CYP2B6, and CYP3A4 in vitro.
- Pharmacokinetics in Special Populations
- Age:
- The effects of age on the pharmacokinetics of metaxalone were determined following single administration of two 400 mg tablets (800 mg) under fasted and fed conditions. The results were analyzed separately, as well as in combination with the results from three other studies. Using the combined data, the results indicate that the pharmacokinetics of metaxalone are significantly more affected by age under fasted conditions than under fed conditions, with bioavailability under fasted conditions increasing with age.
- The bioavailability of metaxalone under fasted and fed conditions in three groups of healthy volunteers of varying age is shown in Table 2.
- Gender:
- The effect of gender on the pharmacokinetics of metaxalone was assessed in an open label study, in which 48 healthy adult volunteers (24 males, 24 females) were administered two metaxalone 400 mg tablets (800 mg) under fasted conditions. The bioavailability of metaxalone was significantly higher in females compared to males as evidenced by Cmax (2115 ng/mL versus 1335 ng/mL) and AUC∞ (17884 ng·h/mL versus 10328 ng·h/mL). The mean half-life was 11.1 hours in females and 7.6 hours in males. The apparent volume of distribution of metaxalone was approximately 22% higher in males than in females, but not significantly different when adjusted for body weight. Similar findings were also seen when the previously described combined dataset was used in the analysis.
- Hepatic/Renal Insufficiency:
- The impact of hepatic and renal disease on the pharmacokinetics of metaxalone has not been determined. In the absence of such information, metaxalone should be used with caution in patients with hepatic and/or renal impairment.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Metaxalone in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Metaxalone in the drug label.
# How Supplied
- Metaxalone is available as an 800 mg, light pink to pink, capsule shaped, scored uncoated tablet with debossing ‘AN’ on the left side of the scoring and ‘553’ on the right side of the scoring. Other side of the tablet is plain.
- They are available as follows:
- Bottles of 100: NDC 68001-004-00
- Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).
## Storage
There is limited information regarding Metaxalone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Metaxalone may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle, especially when used with alcohol or other CNS depressants.
# Precautions with Alcohol
- Alcohol-Metaxalone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- METAXALONE®
# Look-Alike Drug Names
There is limited information regarding Metaxalone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Metaxalone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Metaxalone is a centrally acting skeletal muscle relaxant that is FDA approved for the {{{indicationType}}} of musculoskeletal pain. Common adverse reactions include drug-induced gastrointestinal disturbance, nausea, vomiting, dizziness, headache, somnolence, feeling nervous.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Metaxalone is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomforts associated with acute, painful musculoskeletal conditions. The mode of action of this drug has not been clearly identified, but may be related to its sedative properties. Metaxalone does not directly relax tense skeletal muscles in man.
- The recommended dose for adults is one 800 mg tablet three to four times a day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metaxalone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metaxalone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- The recommended dose for children over 12 years of age is one 800 mg tablet three to four times a day.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metaxalone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metaxalone in pediatric patients.
# Contraindications
- Known hypersensitivity to any components of this product.
- Known tendency to drug induced, hemolytic, or other anemias.
- Significantly impaired renal or hepatic function.
# Warnings
- Metaxalone may enhance the effects of alcohol and other CNS depressants.
### Precautions
- Metaxalone should be administered with great care to patients with pre-existing liver damage. Serial liver function studies should be performed in these patients.
- False-positive Benedict’s tests, due to an unknown reducing substance, have been noted. A glucose-specific test will differentiate findings.
- Taking metaxalone with food may enhance general CNS depression; elderly patients may be especially susceptible to this CNS effect.
# Adverse Reactions
## Clinical Trials Experience
- The most frequent reactions to metaxalone include:
Drowsiness, dizziness, headache, and nervousness or “irritability”;
Nausea, vomiting, gastrointestinal upset.
- Other adverse reactions are:
Hypersensitivity reaction, rash with or without pruritus;
Leukopenia; hemolytic anemia;
Jaundice.
- Though rare, anaphylactoid reactions have been reported with metaxalone.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Metaxalone in the drug label.
# Drug Interactions
- The sedative effects of metaxalone and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may be additive. Therefore, caution should be exercised with patients who take more than one of these CNS depressants simultaneously.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
- Reproduction studies in rats have not revealed evidence of impaired fertility or harm to the fetus due to metaxalone. Post marketing experience has not revealed evidence of fetal injury, but such experience cannot exclude the possibility of infrequent or subtle damage to the human fetus. Safe use of metaxalone has not been established with regard to possible adverse effects upon fetal development. Therefore, metaxalone tablets should not be used in women who are or may become pregnant and particularly during early pregnancy unless, in the judgement of the physician, the potential benefits outweigh the possible hazards.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Metaxalone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Metaxalone during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is secreted in human milk. As a general rule, nursing should not be undertaken while a patient is on a drug since many drugs are excreted in human milk.
### Pediatric Use
- Safety and effectiveness in children 12 years of age and below have not been established.
### Geriatic Use
There is no FDA guidance on the use of Metaxalone with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Metaxalone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Metaxalone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Metaxalone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Metaxalone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Metaxalone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Metaxalone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Metaxalone in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Metaxalone in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Deaths by deliberate or accidental overdose have occurred with metaxalone, particularly in combination with antidepressants, and have been reported with this class of drug in combination with alcohol.
- When determining the LD50 in rats and mice, progressive sedation, hypnosis and finally respiratory failure were noted as the dosage increased. In dogs, no LD50 could be determined as the higher doses produced an emetic action in 15 to 30 minutes.
### Management
- Gastric lavage and supportive therapy. Consultation with a regional poison control center is recommended.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Metaxalone in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism of action of metaxalone in humans has not been established, but may be due to general central nervous system depression. Metaxalone has no direct action on the contractile mechanism of striated muscle, the motor end plate or the nerve fiber.
## Structure
- Metaxalone is available as an 800 mg, light pink to pink, capsule shaped, scored uncoated tablet.
- Chemically, metaxalone is 5-[(3,5- dimethylphenoxy) methyl]-2-oxazolidinone. The empirical formula is C12H15NO3, which corresponds to a molecular weight of 221.25. The structural formula is:
- Metaxalone is a white to almost white, odorless crystalline powder freely soluble in chloroform, soluble in methanol and in 96% ethanol, but practically insoluble in ether or water.
- Each tablet contains 800 mg metaxalone and the following inactive ingredients: calcium carbonate, FD&C Red #40, hypromellose, lactose monohydrate, microcrystalline cellulose, povidone, silicone dioxide, sodium starch glycolate and sodium stearyl fumarate.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Metaxalone in the drug label.
## Pharmacokinetics
- The pharmacokinetics of metaxalone have been evaluated in healthy adult volunteers after single dose administration of metaxalone under fasted and fed conditions at doses ranging from 400 mg to 800 mg.
- Absorption
- Peak plasma concentrations of metaxalone occur approximately 3 hours after a 400 mg oral dose under fasted conditions. Thereafter, metaxalone concentrations decline log-linearly with a terminal half-life of 9.0 ± 4.8 hours. Doubling the dose of metaxalone from 400 mg to 800 mg results in a roughly proportional increase in metaxalone exposure as indicated by peak plasma concentrations (Cmax) and area under the curve (AUC). Dose proportionality at doses above 800 mg has not been studied. The absolute bioavailability of metaxalone is not known.
- The single-dose pharmacokinetic parameters of metaxalone in two groups of healthy volunteers are shown in Table 1.
- Food Effects
- A randomized, two-way, crossover study was conducted in 42 healthy volunteers (31 males, 11 females) administered one 400 mg metaxalone tablet under fasted conditions and following a standard high-fat breakfast. Subjects ranged in age from 18 to 48 years (mean age = 23.5 ± 5.7 years). Compared to fasted conditions, the presence of a high fat meal at the time of drug administration increased Cmax by 177.5% and increased AUC (AUC0-t, AUC∞) by 123.5% and 115.4%, respectively. Time-to-peak concentration (Tmax) was also delayed (4.3 h versus 3.3 h) and terminal half-life was decreased (2.4 h versus 9.0 h) under fed conditions compared to fasted.
- In a second food effect study of similar design, two 400 mg metaxalone tablets (800 mg) were administered to healthy volunteers (N=59, 37 males, 22 females), ranging in age from 18 to 50 years (mean age = 25.6± 8.7 years). Compared to fasted conditions, the presence of a high fat meal at the time of drug administration increased Cmax by 193.6% and increased AUC (AUC0-t, AUC∞) by 146.4% and 142.2%, respectively. Time-to-peak concentration (Tmax) was also delayed (4.9 h versus 3.0 h) and terminal half-life was decreased (4.2 h versus 8.0 h) under fed conditions compared to fasted conditions. Similar food effect results were observed in the above study when one metaxalone 800 mg tablet was administered in place of two metaxalone 400 mg tablets. The increase in metaxalone exposure coinciding with a reduction in half-life may be attributed to more complete absorption of metaxalone in the presence of a high fat meal (Figure 1).
- Distribution, Metabolism, and Excretion
- Although plasma protein binding and absolute bioavailability of metaxalone are not known, the apparent volume of distribution (V/F ~ 800 L) and lipophilicity (log P = 2.42) of metaxalone suggest that the drug is extensively distributed in the tissues. Metaxalone is metabolized by the liver and excreted in the urine as unidentified metabolites. Hepatic Cytochrome P450 enzymes play a role in the metabolism of metaxalone. Specifically, CYP1A2, CYP2D6, CYP2E1, and CYP3A4 and, to a lesser extent, CYP2C8, CYP2C9, and CYP2C19 appear to metabolize metaxalone.
- Metaxalone does not significantly inhibit major CYP enzymes such as CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Metaxalone does not significantly induce major CYP enzymes such as CYP1A2, CYP2B6, and CYP3A4 in vitro.
- Pharmacokinetics in Special Populations
- Age:
- The effects of age on the pharmacokinetics of metaxalone were determined following single administration of two 400 mg tablets (800 mg) under fasted and fed conditions. The results were analyzed separately, as well as in combination with the results from three other studies. Using the combined data, the results indicate that the pharmacokinetics of metaxalone are significantly more affected by age under fasted conditions than under fed conditions, with bioavailability under fasted conditions increasing with age.
- The bioavailability of metaxalone under fasted and fed conditions in three groups of healthy volunteers of varying age is shown in Table 2.
- Gender:
- The effect of gender on the pharmacokinetics of metaxalone was assessed in an open label study, in which 48 healthy adult volunteers (24 males, 24 females) were administered two metaxalone 400 mg tablets (800 mg) under fasted conditions. The bioavailability of metaxalone was significantly higher in females compared to males as evidenced by Cmax (2115 ng/mL versus 1335 ng/mL) and AUC∞ (17884 ng·h/mL versus 10328 ng·h/mL). The mean half-life was 11.1 hours in females and 7.6 hours in males. The apparent volume of distribution of metaxalone was approximately 22% higher in males than in females, but not significantly different when adjusted for body weight. Similar findings were also seen when the previously described combined dataset was used in the analysis.
- Hepatic/Renal Insufficiency:
- The impact of hepatic and renal disease on the pharmacokinetics of metaxalone has not been determined. In the absence of such information, metaxalone should be used with caution in patients with hepatic and/or renal impairment.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Metaxalone in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Metaxalone in the drug label.
# How Supplied
- Metaxalone is available as an 800 mg, light pink to pink, capsule shaped, scored uncoated tablet with debossing ‘AN’ on the left side of the scoring and ‘553’ on the right side of the scoring. Other side of the tablet is plain.
- They are available as follows:
- Bottles of 100: NDC 68001-004-00
- Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).
## Storage
There is limited information regarding Metaxalone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Metaxalone may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle, especially when used with alcohol or other CNS depressants.
# Precautions with Alcohol
- Alcohol-Metaxalone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- METAXALONE®[1]
# Look-Alike Drug Names
There is limited information regarding Metaxalone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Metaxalone | |
28765960a560a74a00651c9fe185e4aa18bec851 | wikidoc | Metenolone | Metenolone
# Overview
Metenolone (or methenolone) is a long-acting anabolic steroid with weak androgenic (testosterone or androsterone-like) properties. It is a naturally occurring drug, found within the adrenal glands of pregnant domesticated felines, and is supplied as the acetate ester for oral administration and as the enanthate ester for intramuscular injection. Adult doses for the treatment of aplastic anemia are usually in a range of 1–3 mg/kg per day.
# Side effects
Adverse side effects include fluid and electrolyte retention, hypercalcaemia, increased bone growth and skeletal weight. In men, additional side priapism, azoospermia, hirsutism, male pattern baldness, acne and oedema. In women, side effects include virilization, amenorrhoea, menstrual irregularities, suppressed lactation, and increased libido. In children, side effects may include virilization symptoms. Metenolone may enhance effects of antidiabetics, ciclosporin, levothyroxine, warfarin. Resistance to the effects of neuromuscular blockers may occur, and metenolone also has the potential to interfere with glucose tolerance and thyroid function tests.
# Use in sports
As an anabolic steroid, the use of metenolone is banned from use in sports governed by the World Anti-Doping Agency. Belarusian shot putter Nadzeya Ostapchuk was stripped of her gold medal after testing positive for metenolone at the London 2012 Olympic Games. She has been excluded from future IOC events.
The NBA and NBPA also banned the use of methenolone under the Anti-Drug Program. In February 2013, Hedo Türkoğlu of the Orlando Magic was suspended for 20 games without pay by the league after testing positive for methenolone.
In December 2013, Natalia Volgina was stripped of her 2013 Old Mutual Two Oceans Marathon title and received a two-year competition ban, subsequent to a final guilty verdict for using the steroid Metenolone. | Metenolone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Metenolone (or methenolone) is a long-acting anabolic steroid with weak androgenic (testosterone or androsterone-like) properties. It is a naturally occurring drug, found within the adrenal glands of pregnant domesticated felines, and is supplied as the acetate ester for oral administration and as the enanthate ester for intramuscular injection. Adult doses for the treatment of aplastic anemia are usually in a range of 1–3 mg/kg per day.
# Side effects
Adverse side effects include fluid and electrolyte retention, hypercalcaemia, increased bone growth and skeletal weight. In men, additional side priapism, azoospermia, hirsutism, male pattern baldness, acne and oedema. In women, side effects include virilization, amenorrhoea, menstrual irregularities, suppressed lactation, and increased libido. In children, side effects may include virilization symptoms. Metenolone may enhance effects of antidiabetics, ciclosporin, levothyroxine, warfarin. Resistance to the effects of neuromuscular blockers may occur, and metenolone also has the potential to interfere with glucose tolerance and thyroid function tests.
# Use in sports
As an anabolic steroid, the use of metenolone is banned from use in sports governed by the World Anti-Doping Agency.[1] Belarusian shot putter Nadzeya Ostapchuk was stripped of her gold medal after testing positive for metenolone at the London 2012 Olympic Games.[2] She has been excluded from future IOC events.
The NBA and NBPA also banned the use of methenolone under the Anti-Drug Program. In February 2013, Hedo Türkoğlu of the Orlando Magic was suspended for 20 games without pay by the league after testing positive for methenolone.[3]
In December 2013, Natalia Volgina was stripped of her 2013 Old Mutual Two Oceans Marathon title and received a two-year competition ban, subsequent to a final guilty verdict for using the steroid Metenolone.[4] | https://www.wikidoc.org/index.php/Metenolone | |
6a13f693465c86b533255564772acddbb32e371e | wikidoc | Meth mouth | Meth mouth
Meth mouth is an informal name for advanced tooth decay attributed to heavy methamphetamine use. According to the American Dental Association, meth mouth "is probably caused by a combination of drug-induced psychological and physiological changes resulting in xerostomia (dry mouth), extended periods of poor oral hygiene, frequent consumption of high calorie, carbonated beverages and tooth grinding and clenching."
Characteristics include:
- xerostomia (dry mouth): Methamphetamine use may decrease the production of saliva. A lack of saliva's natural protective effects directly leads to increased tooth decay, particularly at the gumline. Many users also smoke tobacco or consume highly sugared soft drinks, worsening the problem.
- cracked teeth: Methamphetamine induces clenching and grinding of the teeth, leading to wear or cracks.
- neglect of oral hygiene: This is likely among the most important causes of poor oral health among methamphetamine users. After a prolonged binge, users may sleep for a day or more with their mouths open, exacerbating the problems of poor saliva supply.
Meth mouth is "difficult to distinguish" from a simple case of poor oral hygiene. Dentists are advised to look for "unaccounted for and accelerated decay in teenagers and young adults" and "malnourished appearance in heavy users, because methamphetamine acts as an appetite suppressant."
Contrary to a number of media reports, meth mouth's contributing causes do not include the "corrosive", "acidic" or "caustic" effect of the drug itself on tooth enamel or gum tissue. Jack Shafer of Slate magazine has written a series of articles disputing the role of "chemical" or "contaminant" factors in causing meth mouth. | Meth mouth
Meth mouth is an informal name for advanced tooth decay attributed to heavy methamphetamine use. According to the American Dental Association, meth mouth "is probably caused by a combination of drug-induced psychological and physiological changes resulting in xerostomia (dry mouth), extended periods of poor oral hygiene, frequent consumption of high calorie, carbonated beverages and tooth grinding and clenching."[1]
Characteristics include:
- xerostomia (dry mouth): Methamphetamine use may decrease the production of saliva. A lack of saliva's natural protective effects directly leads to increased tooth decay, particularly at the gumline. Many users also smoke tobacco or consume highly sugared soft drinks, worsening the problem.
- cracked teeth: Methamphetamine induces clenching and grinding of the teeth, leading to wear or cracks.
- neglect of oral hygiene: This is likely among the most important causes of poor oral health among methamphetamine users. After a prolonged binge, users may sleep for a day or more with their mouths open, exacerbating the problems of poor saliva supply.
Meth mouth is "difficult to distinguish" from a simple case of poor oral hygiene.[2] Dentists are advised to look for "unaccounted for and accelerated decay in teenagers and young adults" and "malnourished appearance in heavy users, because methamphetamine acts as an appetite suppressant."[1]
Contrary to a number of media reports, meth mouth's contributing causes do not include the "corrosive", "acidic" or "caustic" effect of the drug itself on tooth enamel or gum tissue. Jack Shafer of Slate magazine has written a series of articles disputing the role of "chemical" or "contaminant" factors in causing meth mouth. | https://www.wikidoc.org/index.php/Meth_mouth | |
58587e5b16fa0c117032921c781f65ad6c7d3dab | wikidoc | Methanogen | Methanogen
# Overview
Methanogens are archaea that produce methane as a metabolic byproduct in anoxic conditions. They are common in wetlands, where they are responsible for marsh gas, and in the guts of animals such as ruminants and humans, where they are responsible for the methane content of flatulence . In marine sediments biomethanation is generally confined to where sulfates are depleted, below the top layers. Others are extremophiles, found in environments such as hot springs and submarine hydrothermal vents as well as in the "solid" rock of the earth's crust, kilometers below the surface. Methanogens are usually coccoid or rod shaped. There are over 50 described species of methanogens, which are paraphyletic and all included among the Euryarchaeota.
Methanogens are anaerobic. Although methanogens cannot function under aerobic conditions they can sustain oxygen stresses for prolonged times. An exception is Methanosarcina barkeri, which contains a superoxide dismutase (SOD) enzyme and may survive longer. Some, called hydrogenotrophic, use carbon dioxide (CO2) as a source of carbon, and hydrogen as a reducing agent. Some of the CO2 is reacted with the hydrogen to produce methane, which produces an electrochemical gradient across a membrane, used to generate ATP through chemiosmosis. In contrast, plants and algae use water as their reducing agent.
Methanogens do not have a polymer that is found in cell walls of prokaryotes. Some methanogens have a cell wall that is composed of pseudomurein. Other methanogens that don't have a pseudomurein have at least one paracrystalline array (S-layer) which is made up of proteins that fit together like a puzzle.
Although most marine biogenic methane is the result of CO2 reduction, a small amount is derived from acetate (CH3COO-). Archaea that catabolize this for energy are referred to as acetotrophic or aceticlastic. Methylotrophic archaea utilize methylated compounds such as methylamines, methanol, and methanethiol as well.
Ecologically, methanogens play the vital role in anaerobic environments of removing excess hydrogen and fermentation products that have been produced by other forms of anaerobic respiration. Methanogens typically thrive in environments in which all other electron acceptors (such as oxygen, nitrate, sulfate, and trivalent iron) have been depleted. In the deep rock they obtain their hydrogen from the thermal and radioactive breakdown of water.
Methanogens have been found in several extreme environments on Earth - buried under kilometres of ice in Greenland and living in hot, dry desert soil. They can still reproduce from temperatures of 15 to 100 degrees celcius.They are known to be the most common prokaryotes archaebacteria in deep subteranean habitats.
Live microbes making methane were found in a glacial ice core sample retrieved from three kilometres under Greenland by researchers from the University of California, Berkeley, US.
Another study has also discovered methanogens in a harsh environment on Earth. Researchers studied dozens of soil and vapour samples from five different desert environments in Utah, Idaho and California in the US, and in Canada and Chile. Of these, five soil samples and three vapour samples from the vicinity of the Mars Desert Research Station in Utah were found to have signs of viable methanogens.
Some scientists have proposed that the presence of methane in the Martian atmosphere may be indicative of native methanogens on that planet.
Closely related to the methanogens are the anaerobic methane oxidizers, which utilize methane as a substrate in conjunction with the reduction of sulfate and nitrate.
Methanogens are autotrophic producers.
# Examples
- Methanobacterium formicum
- Methanobacterium bryantii
- Methanobacterium thermo-autotrophicum
- Methanogenium cariaci
- Methanogenium frigidum
- Methanothrix sochngenii | Methanogen
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Methanogens are archaea that produce methane as a metabolic byproduct in anoxic conditions. They are common in wetlands, where they are responsible for marsh gas, and in the guts of animals such as ruminants and humans, where they are responsible for the methane content of flatulence[1] . In marine sediments biomethanation is generally confined to where sulfates are depleted, below the top layers.[2] Others are extremophiles, found in environments such as hot springs and submarine hydrothermal vents as well as in the "solid" rock of the earth's crust, kilometers below the surface. Methanogens are usually coccoid or rod shaped. There are over 50 described species of methanogens, which are paraphyletic and all included among the Euryarchaeota.
Methanogens are anaerobic. Although methanogens cannot function under aerobic conditions they can sustain oxygen stresses for prolonged times[3]. An exception is Methanosarcina barkeri, which contains a superoxide dismutase (SOD) enzyme and may survive longer.[4] Some, called hydrogenotrophic, use carbon dioxide (CO2) as a source of carbon, and hydrogen as a reducing agent. Some of the CO2 is reacted with the hydrogen to produce methane, which produces an electrochemical gradient across a membrane, used to generate ATP through chemiosmosis. In contrast, plants and algae use water as their reducing agent.
Methanogens do not have a polymer that is found in cell walls of prokaryotes. Some methanogens have a cell wall that is composed of pseudomurein. Other methanogens that don't have a pseudomurein have at least one paracrystalline array (S-layer) which is made up of proteins that fit together like a puzzle.
Although most marine biogenic methane is the result of CO2 reduction, a small amount is derived from acetate (CH3COO-).[5] Archaea that catabolize this for energy are referred to as acetotrophic or aceticlastic. Methylotrophic archaea utilize methylated compounds such as methylamines, methanol, and methanethiol as well.
Ecologically, methanogens play the vital role in anaerobic environments of removing excess hydrogen and fermentation products that have been produced by other forms of anaerobic respiration. Methanogens typically thrive in environments in which all other electron acceptors (such as oxygen, nitrate, sulfate, and trivalent iron) have been depleted. In the deep rock they obtain their hydrogen from the thermal and radioactive breakdown of water.
Methanogens have been found in several extreme environments on Earth - buried under kilometres of ice in Greenland and living in hot, dry desert soil. They can still reproduce from temperatures of 15 to 100 degrees celcius.They are known to be the most common prokaryotes archaebacteria in deep subteranean habitats.
Live microbes making methane were found in a glacial ice core sample retrieved from three kilometres under Greenland by researchers from the University of California, Berkeley, US.[6]
Another study[7] has also discovered methanogens in a harsh environment on Earth. Researchers studied dozens of soil and vapour samples from five different desert environments in Utah, Idaho and California in the US, and in Canada and Chile. Of these, five soil samples and three vapour samples from the vicinity of the Mars Desert Research Station in Utah were found to have signs of viable methanogens.[8]
Some scientists have proposed that the presence of methane in the Martian atmosphere may be indicative of native methanogens on that planet.[9]
Closely related to the methanogens are the anaerobic methane oxidizers, which utilize methane as a substrate in conjunction with the reduction of sulfate and nitrate.[10]
Methanogens are autotrophic producers.
# Examples
- Methanobacterium formicum
- Methanobacterium bryantii
- Methanobacterium thermo-autotrophicum
- Methanogenium cariaci
- Methanogenium frigidum
- Methanothrix sochngenii | https://www.wikidoc.org/index.php/Methanogen | |
22f0ed9f4f78950b11853c5095092526fd1f262e | wikidoc | Methionine | Methionine
Methionine (abbreviated as Met or M) is an α-amino acid with the chemical formula HO2CCH(NH2)CH2CH2SCH3. This essential amino acid is classified as nonpolar. Together with cysteine, methionine is one of two sulfur-containing proteinogenic amino acids. Its derivative S-adenosyl methionine (SAM) serves as a methyl donor. Methionine is an intermediate in the biosynthesis of cysteine, carnitine, taurine, lecithin, phosphatidylcholine, and other phospholipids. Improper conversion of methionine can lead to atherosclerosis.
Methionine is one of only two amino acids encoded by a single codon (AUG) in the standard genetic code (tryptophan, encoded by UGG, is the other). The codon AUG is also significant, in that it carries the "Start" message for a ribosome that signals the initiation of protein translation from mRNA. As a consequence, methionine is incorporated into the N-terminal position of all proteins in eukaryotes and archaea during translation, although it is usually removed by post-translational modification.
# Biosynthesis
As an essential amino acid, methionine is not synthesized in humans, hence we must ingest methionine or methionine-containing proteins. In plants and microorganisms, methionine is synthesized via a pathway that uses both aspartic acid and cysteine. First, aspartic acid is converted via β-aspartyl-semialdehyde into homoserine, introducing the pair of contiguous methylene groups. Homoserine converts to O-succinyl homoserine, which then reacts with cysteine to produce cystathionine, which is cleaved to yield homocysteine. Subsequent methylation of the thiol group by folates affords methionine. Both cystathionine-γ-synthase and cystathionine-β-lyase require Pyridoxyl-5'-phosphate as a cofactor, whereas homocysteine methyltransferase requires Vitamin B12 as a cofactor.
Enzymes involved in methionine biosynthesis:
- aspartokinase
- β-aspartate semialdehyde dehydrogenase
- homoserine dehydrogenase
- homoserine acyltransferase
- cystathionine-γ-synthase
- cystathionine-β-lyase
- methionine synthase (in mammals, this step is performed by homocysteine methyltransferase)
# Other biochemical pathways
Although mammals cannot synthesize methionine, they can still utilize it in a variety of biochemical pathways:
Methionine is converted to S-adenosylmethionine (SAM) by (1) methionine adenosyltransferase. SAM serves as a methyl-donor in many (2) methyltransferase reactions and is converted to S-adenosylhomocysteine (SAH). (3) adenosylhomocysteinase converts SAH to homocysteine.
There are two fates of homocysteine:
- Methionine can be regenerated from homocysteine via (4) methionine synthase. It can also be remethylated using glycine betaine (NNN-trimethyl glycine) to methionine via the enzyme Betaine-homocysteine methyltransferase (E.C.2.1.1.5, BHMT). BHMT makes up to 1.5% of all the soluble protein of the liver, and recent evidence suggests that it may have a greater influence on methionine and homocysteine homeostasis than Methionine sythase.
- Homocysteine can be converted to cysteine. (5) Cystathionine-β-synthase (a PLP-dependent enzyme) combines homocysteine and serine to produce cystathionine. Instead of degrading cystathionine via cystathionine-β-lyase, as in the biosynthetic pathway, cystathionine is broken down to cysteine and α-ketobutyrate via (6) cystathionine-γ-lyase. (7) α-ketoacid dehydrogenase converts α-ketobutyrate to propionyl-CoA, which is metabolized to succinyl-CoA in a three-step process (see propionyl-CoA for pathway).
# Synthesis
Racemic methionine can be synthesized from diethyl sodium phthalimidomalonate by alkylation with chloroethylmethylsulfide (ClCH2CH2SCH3) followed by hydrolysis and decarboxylation.
# Dietary aspects
High levels of methionine can be found in sesame seeds, Brazil nuts, fish, meats, and some other plant seeds. Most fruit and vegetables contain very little; however, some have significant amounts, such as spinach, potatoes, and boiled corn.st DL-methionine is sometimes added as an ingredient to pet foods. Methionine, cysteine, and soy protein heated in a small amount of water creates a meat-like aroma. | Methionine
Template:NatOrganicBox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Methionine (abbreviated as Met or M)[1] is an α-amino acid with the chemical formula HO2CCH(NH2)CH2CH2SCH3. This essential amino acid is classified as nonpolar. Together with cysteine, methionine is one of two sulfur-containing proteinogenic amino acids. Its derivative S-adenosyl methionine (SAM) serves as a methyl donor. Methionine is an intermediate in the biosynthesis of cysteine, carnitine, taurine, lecithin, phosphatidylcholine, and other phospholipids. Improper conversion of methionine can lead to atherosclerosis.
Methionine is one of only two amino acids encoded by a single codon (AUG) in the standard genetic code (tryptophan, encoded by UGG, is the other). The codon AUG is also significant, in that it carries the "Start" message for a ribosome that signals the initiation of protein translation from mRNA. As a consequence, methionine is incorporated into the N-terminal position of all proteins in eukaryotes and archaea during translation, although it is usually removed by post-translational modification.
# Biosynthesis
As an essential amino acid, methionine is not synthesized in humans, hence we must ingest methionine or methionine-containing proteins. In plants and microorganisms, methionine is synthesized via a pathway that uses both aspartic acid and cysteine. First, aspartic acid is converted via β-aspartyl-semialdehyde into homoserine, introducing the pair of contiguous methylene groups. Homoserine converts to O-succinyl homoserine, which then reacts with cysteine to produce cystathionine, which is cleaved to yield homocysteine. Subsequent methylation of the thiol group by folates affords methionine. Both cystathionine-γ-synthase and cystathionine-β-lyase require Pyridoxyl-5'-phosphate as a cofactor, whereas homocysteine methyltransferase requires Vitamin B12 as a cofactor.[2]
Enzymes involved in methionine biosynthesis:
- aspartokinase
- β-aspartate semialdehyde dehydrogenase
- homoserine dehydrogenase
- homoserine acyltransferase
- cystathionine-γ-synthase
- cystathionine-β-lyase
- methionine synthase (in mammals, this step is performed by homocysteine methyltransferase)
# Other biochemical pathways
Although mammals cannot synthesize methionine, they can still utilize it in a variety of biochemical pathways:
Methionine is converted to S-adenosylmethionine (SAM) by (1) methionine adenosyltransferase. SAM serves as a methyl-donor in many (2) methyltransferase reactions and is converted to S-adenosylhomocysteine (SAH). (3) adenosylhomocysteinase converts SAH to homocysteine.
There are two fates of homocysteine:
- Methionine can be regenerated from homocysteine via (4) methionine synthase. It can also be remethylated using glycine betaine (NNN-trimethyl glycine) to methionine via the enzyme Betaine-homocysteine methyltransferase (E.C.2.1.1.5, BHMT). BHMT makes up to 1.5% of all the soluble protein of the liver, and recent evidence suggests that it may have a greater influence on methionine and homocysteine homeostasis than Methionine sythase.
- Homocysteine can be converted to cysteine. (5) Cystathionine-β-synthase (a PLP-dependent enzyme) combines homocysteine and serine to produce cystathionine. Instead of degrading cystathionine via cystathionine-β-lyase, as in the biosynthetic pathway, cystathionine is broken down to cysteine and α-ketobutyrate via (6) cystathionine-γ-lyase. (7) α-ketoacid dehydrogenase converts α-ketobutyrate to propionyl-CoA, which is metabolized to succinyl-CoA in a three-step process (see propionyl-CoA for pathway).
# Synthesis
Racemic methionine can be synthesized from diethyl sodium phthalimidomalonate by alkylation with chloroethylmethylsulfide (ClCH2CH2SCH3) followed by hydrolysis and decarboxylation.[3]
# Dietary aspects
High levels of methionine can be found in sesame seeds, Brazil nuts, fish, meats, and some other plant seeds. Most fruit and vegetables contain very little; however, some have significant amounts, such as spinach, potatoes, and boiled corn.st DL-methionine is sometimes added as an ingredient to pet foods.[4] Methionine, cysteine, and soy protein heated in a small amount of water creates a meat-like aroma. | https://www.wikidoc.org/index.php/Methionine | |
9aa0a28e343e28975d9c2bb71fc34845bc77e5db | wikidoc | Methorphan | Methorphan
Methorphan comes in two forms
- Dextromethorphan - An over-the-counter cough suppressant
- Levomethorphan - The left hand isomer of the above, a potent acting opioid.
# Racemethorphan
Racemethorphan is a racemic mixture of the stereoisomers of methorphan, namely dextromethorphan, which is the active ingredient in "DM" cough syrups, and the lesser known levomethorphan which is described as a controlled substance in The Merck Index - likely because it has more potential for abuse than its dextro enantiomer .
Levomethorphan is the methyl ether analog of levorphanol and these two substances are related in the same way that codeine (which is the methyl ether of morphine) is related to morphine . | Methorphan
Methorphan comes in two forms
- Dextromethorphan - An over-the-counter cough suppressant
- Levomethorphan - The left hand isomer of the above, a potent acting opioid.
# Racemethorphan
Racemethorphan is a racemic mixture of the stereoisomers of methorphan, namely dextromethorphan, which is the active ingredient in "DM" cough syrups, and the lesser known levomethorphan which is described as a controlled substance in The Merck Index - likely because it has more potential for abuse than its dextro enantiomer .
Levomethorphan is the methyl ether analog of levorphanol and these two substances are related in the same way that codeine (which is the methyl ether of morphine) is related to morphine .
Template:Pharma-stub
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Methorphan | |
ea320e85124cad887cb107c91bdeceed961a367e | wikidoc | Methyl red | Methyl red
# Overview
Methyl Red, also called C.I. Acid Red 2, is an indicator dye that turns red in acidic solutions. It is an azo dye, and is a dark red crystalline powder.
Methyl red is a pH indicator; it is red in pH under 4.4, yellow in pH over 6.2, and orange in between.
In microbiology, methyl red is used in the Methyl Red (MR) Test, used to identify bacteria producing stable acids by mechanisms of mixed acid fermentation of glucose. Cf. Voges-Proskauer (VP) test.
Murexide and methyl red are investigated as promising enhancers of sonochemical destruction of chlorinated hydrocarbon pollutants.
Methyl red is classed by the IARC in group 3 - unclassified as to carcinogenic potential in humans. Its risk phrases are Template:R20 Template:R21 Template:R22 Template:R36 Template:R37 Template:R38 Template:R40. | Methyl red
Template:Chembox new
# Overview
Template:PH indicator template
Methyl Red, also called C.I. Acid Red 2, is an indicator dye that turns red in acidic solutions. It is an azo dye, and is a dark red crystalline powder.
Methyl red is a pH indicator; it is red in pH under 4.4, yellow in pH over 6.2, and orange in between.
In microbiology, methyl red is used in the Methyl Red (MR) Test, used to identify bacteria producing stable acids by mechanisms of mixed acid fermentation of glucose. Cf. Voges-Proskauer (VP) test.
Murexide and methyl red are investigated as promising enhancers of sonochemical destruction of chlorinated hydrocarbon pollutants. [1]
Methyl red is classed by the IARC in group 3 - unclassified as to carcinogenic potential in humans. Its risk phrases are Template:R20 Template:R21 Template:R22 Template:R36 Template:R37 Template:R38 Template:R40. | https://www.wikidoc.org/index.php/Methyl_red | |
3342dea54335b1d1617137ed2743800feef9e798 | wikidoc | Metirosine | Metirosine
# 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
Metirosine is an antihypertensive that is FDA approved for the treatment of pheochromocytoma. Common adverse reactions include diarrhea, sedation, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- DEMSER is indicated in the treatment of patients with pheochromocytoma for:
- Preoperative preparation of patients for surgery
- Management of patients when surgery is contraindicated
- Chronic treatment of patients with malignant pheochromocytoma.
- DEMSER is not recommended for the control of essential hypertension.
- The recommended initial dosage of DEMSER for adults is 250 mg orally four times daily. This may be increased by 250 mg to 500 mg every day to a maximum of 4.0 g/day in divided doses. When used for preoperative preparation, the optimally effective dosage of DEMSER should be given for at least five to seven days.
- Optimally effective dosages of DEMSER usually are between 2.0 and 3.0 g/day, and the dose should be titrated by monitoring clinical symptoms and catecholamine excretion. In patients who are hypertensive, dosage should be titrated to achieve normalization of blood pressure and control of clinical symptoms. In patients who are usually normotensive, dosage should be titrated to the amount that will reduce urinary metanephrines and/or vanillylmandelic acid by 50 percent or more.
- If patients are not adequately controlled by the use of DEMSER, an alpha-adrenergic blocking agent (phenoxybenzamine) should be added.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metirosine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metirosine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- DEMSER is indicated in the treatment of patients with pheochromocytoma for:
- Preoperative preparation of patients for surgery
- Management of patients when surgery is contraindicated
- Chronic treatment of patients with malignant pheochromocytoma.
- DEMSER is not recommended for the control of essential hypertension.
- The recommended initial dosage of DEMSER for children 12 years of age and older is 250 mg orally four times daily. This may be increased by 250 mg to 500 mg every day to a maximum of 4.0 g/day in divided doses. When used for preoperative preparation, the optimally effective dosage of DEMSER should be given for at least five to seven days.
- Optimally effective dosages of DEMSER usually are between 2.0 and 3.0 g/day, and the dose should be titrated by monitoring clinical symptoms and catecholamine excretion. In patients who are hypertensive, dosage should be titrated to achieve normalization of blood pressure and control of clinical symptoms. In patients who are usually normotensive, dosage should be titrated to the amount that will reduce urinary metanephrines and/or vanillylmandelic acid by 50 percent or more.
- If patients are not adequately controlled by the use of DEMSER, an alpha-adrenergic blocking agent (phenoxybenzamine) should be added.
- Use of DEMSER in children under 12 years of age has been limited and a dosage schedule for this age group cannot be given.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metirosine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metirosine in pediatric patients.
# Contraindications
- DEMSER is contraindicated in persons known to be hypersensitive to this compound.
# Warnings
- Maintain Fluid Volume During and After Surgery
- When DEMSER is used preoperatively, alone or especially in combination with alpha-adrenergic blocking drugs, adequate intravascular volume must be maintained intraoperatively (especially after tumor removal) and postoperatively to avoid hypotension and decreased perfusion of vital organs resulting from vasodilatation and expanded volume capacity. Following tumor removal, large volumes of plasma may be needed to maintain blood pressure and central venous pressure within the normal range.
- In addition, life-threatening arrhythmias may occur during anesthesia and surgery, and may require treatment with a beta-blocker or lidocaine. During surgery, patients should have continuous monitoring of blood pressure and electrocardiogram.
- Intraoperative Effects
- While the preoperative use of DEMSER in patients with pheochromocytoma is thought to decrease intraoperative problems with blood pressure control, DEMSER does not eliminate the danger of hypertensive crises or arrhythmias during manipulation of the tumor, and the alpha-adrenergic blocking drug, phentolamine, may be needed.
- Interaction with Alcohol
- DEMSER may add to the sedative effects of alcohol and other CNS depressants, e.g., hypnotics, sedatives, and tranquilizers.
### Precautions
- Metyrosine Crystalluria
- Crystalluria and urolithiasis have been found in dogs treated with DEMSER (Metyrosine) at doses similar to those used in humans, and crystalluria has also been observed in a few patients. To minimize the risk of crystalluria, patients should be urged to maintain water intake sufficient to achieve a daily urine volume of 2000 mL or more, particularly when doses greater than 2 g per day are given. Routine examination of the urine should be carried out. Metyrosine will crystallize as needles or rods. If metyrosine crystalluria occurs, fluid intake should be increased further. If crystalluria persists, the dosage should be reduced or the drug discontinued.
- Relatively Little Data Regarding Long-term Use
- The total human experience with the drug is quite limited and few patients have been studied long-term. Chronic animal studies have not been carried out. Therefore, suitable laboratory tests should be carried out periodically in patients requiring prolonged use of DEMSER and caution should be observed in patients with impaired hepatic or renal function.
# Adverse Reactions
## Clinical Trials Experience
- Central Nervous System
- Sedation:
- The most common adverse reaction to DEMSER is moderate to severe sedation, which has been observed in almost all patients. It occurs at both low and high dosages. Sedative effects begin within the first 24 hours of therapy, are maximal after two to three days, and tend to wane during the next few days. Sedation usually is not obvious after one week unless the dosage is increased, but at dosages greater than 2000 mg/day some degree of sedation or fatigue may persist.
- In most patients who experience sedation, temporary changes in sleep pattern occur following withdrawal of the drug. Changes consist of insomnia that may last for two or three days and feelings of increased alertness and ambition. Even patients who do not experience sedation while on DEMSER may report symptoms of psychic stimulation when the drug is discontinued.
- Extrapyramidal Signs:
- Extrapyramidal signs such as drooling, speech difficulty, and tremor have been reported in approximately 10 percent of patients. These occasionally have been accompanied by trismus and frank parkinsonism.
- Anxiety and Psychic Disturbances:
- Anxiety and psychic disturbances such as depression, hallucinations, disorientation, and confusion may occur. These effects seem to be dose-dependent and may disappear with reduction of dosage.
- Diarrhea
- Diarrhea occurs in about 10 percent of patients and may be severe. Anti-diarrheal agents may be required if continuation of DEMSER is necessary.
- Miscellaneous
- Infrequently, slight swelling of the breast, galactorrhea, nasal stuffiness, decreased salivation, dry mouth, headache, nausea, vomiting, abdominal pain, and impotence or failure of ejaculation may occur. Crystalluria and transient dysuria and hematuria have been observed in a few patients. Hematologic disorders (including eosinophilia, anemia, thrombocytopenia, and thrombocytosis), increased SGOT levels, peripheral edema, and hypersensitivity reactions such as urticaria and pharyngeal edema have been reported rarely.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Metirosine in the drug label.
# Drug Interactions
- Caution should be observed in administering DEMSER to patients receiving phenothiazines or haloperidol because the extrapyramidal effects of these drugs can be expected to be potentiated by inhibition of catecholamine synthesis.
- Concurrent use of DEMSER with alcohol or other CNS depressants can increase their sedative effects.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Animal reproduction studies have not been conducted with DEMSER. It is also not known whether DEMSER can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. DEMSER should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Metirosine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Metirosine during labor and delivery.
### Nursing Mothers
- It is not known whether DEMSER is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when DEMSER is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 12 years have not been established.
### Geriatic Use
- Clinical studies of DEMSER did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Metirosine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Metirosine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Metirosine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Metirosine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Metirosine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Metirosine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Metirosine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Metirosine in the drug label.
# Overdosage
## Acute Overdose
- Signs of metyrosine overdosage include those central nervous system effects observed in some patients even at low dosages.
- At doses exceeding 2000 mg/day, some degree of sedation or feeling of fatigue may persist. Doses of 2000-4000 mg/day can result in anxiety or agitated depression, neuromuscular effects (including fine tremor of the hands, gross tremor of the trunk, tightening of the jaw with trismus), diarrhea, and decreased salivation with dry mouth.
- Reduction of drug dose or cessation of treatment results in the disappearance of these symptoms.
- The acute toxicity of metyrosine was 442 mg/kg and 752 mg/kg in the female mouse and rat respectively.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Metirosine in the drug label.
# Pharmacology
## Mechanism of Action
- DEMSER inhibits tyrosine hydroxylase, which catalyzes the first transformation in catecholamine biosynthesis, i.e., the conversion of tyrosine to dihydroxyphenylalanine (DOPA). Because the first step is also the rate-limiting step, blockade of tyrosine hydroxylase activity results in decreased endogenous levels of catecholamines, usually measured as decreased urinary excretion of catecholamines and their metabolites.
## Structure
- DEMSER1 (Metyrosine) is (–)-α-methyl-L-tyrosine or (α-MPT). It has the following structural formula:
- Metyrosine is a white, crystalline compound of molecular weight 195. It is very slightly soluble in water, acetone, and methanol, and insoluble in chloroform and benzene. It is soluble in acidic aqueous solutions. It is also soluble in alkaline aqueous solutions, but is subject to oxidative degradation under these conditions.
- DEMSER is supplied as capsules, for oral administration. Each capsule contains 250 mg metyrosine. Inactive ingredients are colloidal silicon dioxide, gelatin, hydroxypropyl cellulose, magnesium stearate, titanium dioxide, and FD&C Blue 2.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Metirosine in the drug label.
## Pharmacokinetics
- In patients with pheochromocytoma, who produce excessive amounts of norepinephrine and epinephrine, administration of one to four grams of DEMSER per day has reduced catecholamine biosynthesis from about 35 to 80 percent as measured by the total excretion of catecholamines and their metabolites (metanephrine and vanillylmandelic acid). The maximum biochemical effect usually occurs within two to three days, and the urinary concentration of catecholamines and their metabolites usually returns to pretreatment levels within three to four days after DEMSER is discontinued. In some patients the total excretion of catecholamines and catecholamine metabolites may be lowered to normal or near normal levels (less than 10 mg/24 hours). In most patients the duration of treatment has been two to eight weeks, but several patients have received DEMSER for periods of one to 10 years. Most patients with pheochromocytoma treated with DEMSER experience decreased frequency and severity of hypertensive attacks with their associated headache, nausea, sweating, and tachycardia. In patients who respond, blood pressure decreases progressively during the first two days of therapy with DEMSER; after withdrawal, blood pressure usually increases gradually to pretreatment values within two to three days.
- Metyrosine is well absorbed from the gastrointestinal tract. From 53 to 88 percent (mean 69 percent) was recovered in the urine as unchanged drug following maintenance oral doses of 600 to 4000 mg/24 hours in patients with pheochromocytoma or essential hypertension. Less than 1% of the dose was recovered as catechol metabolites. These metabolites are probably not present in sufficient amounts to contribute to the biochemical effects of metyrosine. The quantities excreted, however, are sufficient to interfere with accurate determination of urinary catecholamines determined by routine techniques.
- Plasma half-life of metyrosine determined over an 8-hour period after single oral doses was 3-3.7 hours in three patients.
## Nonclinical Toxicology
- Long-term carcinogenic studies in animals and studies on mutagenesis and impairment of fertility have not been performed with metyrosine.
# Clinical Studies
There is limited information regarding Clinical Studies of Metirosine in the drug label.
# How Supplied
- Capsules DEMSER, 250 mg, are opaque, two-toned blue capsules coded Aton 305 on one side and DEMSER on the other. They are supplied as follows:
- NDC 25010-305-15 bottles of 100.
## Storage
There is limited information regarding Metirosine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- When receiving DEMSER, patients should be warned about engaging in activities requiring mental alertness and motor coordination, such as driving a motor vehicle or operating machinery. DEMSER may have additive sedative effects with alcohol and other CNS depressants, e.g., hypnotics, sedatives, and tranquilizers.
- Patients should be advised to maintain a liberal fluid intake.
# Precautions with Alcohol
- Alcohol-Metirosine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- DEMSER®
# Look-Alike Drug Names
There is limited information regarding Metirosine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Metirosine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Metirosine is an antihypertensive that is FDA approved for the treatment of pheochromocytoma. Common adverse reactions include diarrhea, sedation, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- DEMSER is indicated in the treatment of patients with pheochromocytoma for:
- Preoperative preparation of patients for surgery
- Management of patients when surgery is contraindicated
- Chronic treatment of patients with malignant pheochromocytoma.
- DEMSER is not recommended for the control of essential hypertension.
- The recommended initial dosage of DEMSER for adults is 250 mg orally four times daily. This may be increased by 250 mg to 500 mg every day to a maximum of 4.0 g/day in divided doses. When used for preoperative preparation, the optimally effective dosage of DEMSER should be given for at least five to seven days.
- Optimally effective dosages of DEMSER usually are between 2.0 and 3.0 g/day, and the dose should be titrated by monitoring clinical symptoms and catecholamine excretion. In patients who are hypertensive, dosage should be titrated to achieve normalization of blood pressure and control of clinical symptoms. In patients who are usually normotensive, dosage should be titrated to the amount that will reduce urinary metanephrines and/or vanillylmandelic acid by 50 percent or more.
- If patients are not adequately controlled by the use of DEMSER, an alpha-adrenergic blocking agent (phenoxybenzamine) should be added.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metirosine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metirosine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- DEMSER is indicated in the treatment of patients with pheochromocytoma for:
- Preoperative preparation of patients for surgery
- Management of patients when surgery is contraindicated
- Chronic treatment of patients with malignant pheochromocytoma.
- DEMSER is not recommended for the control of essential hypertension.
- The recommended initial dosage of DEMSER for children 12 years of age and older is 250 mg orally four times daily. This may be increased by 250 mg to 500 mg every day to a maximum of 4.0 g/day in divided doses. When used for preoperative preparation, the optimally effective dosage of DEMSER should be given for at least five to seven days.
- Optimally effective dosages of DEMSER usually are between 2.0 and 3.0 g/day, and the dose should be titrated by monitoring clinical symptoms and catecholamine excretion. In patients who are hypertensive, dosage should be titrated to achieve normalization of blood pressure and control of clinical symptoms. In patients who are usually normotensive, dosage should be titrated to the amount that will reduce urinary metanephrines and/or vanillylmandelic acid by 50 percent or more.
- If patients are not adequately controlled by the use of DEMSER, an alpha-adrenergic blocking agent (phenoxybenzamine) should be added.
- Use of DEMSER in children under 12 years of age has been limited and a dosage schedule for this age group cannot be given.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metirosine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metirosine in pediatric patients.
# Contraindications
- DEMSER is contraindicated in persons known to be hypersensitive to this compound.
# Warnings
- Maintain Fluid Volume During and After Surgery
- When DEMSER is used preoperatively, alone or especially in combination with alpha-adrenergic blocking drugs, adequate intravascular volume must be maintained intraoperatively (especially after tumor removal) and postoperatively to avoid hypotension and decreased perfusion of vital organs resulting from vasodilatation and expanded volume capacity. Following tumor removal, large volumes of plasma may be needed to maintain blood pressure and central venous pressure within the normal range.
- In addition, life-threatening arrhythmias may occur during anesthesia and surgery, and may require treatment with a beta-blocker or lidocaine. During surgery, patients should have continuous monitoring of blood pressure and electrocardiogram.
- Intraoperative Effects
- While the preoperative use of DEMSER in patients with pheochromocytoma is thought to decrease intraoperative problems with blood pressure control, DEMSER does not eliminate the danger of hypertensive crises or arrhythmias during manipulation of the tumor, and the alpha-adrenergic blocking drug, phentolamine, may be needed.
- Interaction with Alcohol
- DEMSER may add to the sedative effects of alcohol and other CNS depressants, e.g., hypnotics, sedatives, and tranquilizers.
### Precautions
- Metyrosine Crystalluria
- Crystalluria and urolithiasis have been found in dogs treated with DEMSER (Metyrosine) at doses similar to those used in humans, and crystalluria has also been observed in a few patients. To minimize the risk of crystalluria, patients should be urged to maintain water intake sufficient to achieve a daily urine volume of 2000 mL or more, particularly when doses greater than 2 g per day are given. Routine examination of the urine should be carried out. Metyrosine will crystallize as needles or rods. If metyrosine crystalluria occurs, fluid intake should be increased further. If crystalluria persists, the dosage should be reduced or the drug discontinued.
- Relatively Little Data Regarding Long-term Use
- The total human experience with the drug is quite limited and few patients have been studied long-term. Chronic animal studies have not been carried out. Therefore, suitable laboratory tests should be carried out periodically in patients requiring prolonged use of DEMSER and caution should be observed in patients with impaired hepatic or renal function.
# Adverse Reactions
## Clinical Trials Experience
- Central Nervous System
- Sedation:
- The most common adverse reaction to DEMSER is moderate to severe sedation, which has been observed in almost all patients. It occurs at both low and high dosages. Sedative effects begin within the first 24 hours of therapy, are maximal after two to three days, and tend to wane during the next few days. Sedation usually is not obvious after one week unless the dosage is increased, but at dosages greater than 2000 mg/day some degree of sedation or fatigue may persist.
- In most patients who experience sedation, temporary changes in sleep pattern occur following withdrawal of the drug. Changes consist of insomnia that may last for two or three days and feelings of increased alertness and ambition. Even patients who do not experience sedation while on DEMSER may report symptoms of psychic stimulation when the drug is discontinued.
- Extrapyramidal Signs:
- Extrapyramidal signs such as drooling, speech difficulty, and tremor have been reported in approximately 10 percent of patients. These occasionally have been accompanied by trismus and frank parkinsonism.
- Anxiety and Psychic Disturbances:
- Anxiety and psychic disturbances such as depression, hallucinations, disorientation, and confusion may occur. These effects seem to be dose-dependent and may disappear with reduction of dosage.
- Diarrhea
- Diarrhea occurs in about 10 percent of patients and may be severe. Anti-diarrheal agents may be required if continuation of DEMSER is necessary.
- Miscellaneous
- Infrequently, slight swelling of the breast, galactorrhea, nasal stuffiness, decreased salivation, dry mouth, headache, nausea, vomiting, abdominal pain, and impotence or failure of ejaculation may occur. Crystalluria and transient dysuria and hematuria have been observed in a few patients. Hematologic disorders (including eosinophilia, anemia, thrombocytopenia, and thrombocytosis), increased SGOT levels, peripheral edema, and hypersensitivity reactions such as urticaria and pharyngeal edema have been reported rarely.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Metirosine in the drug label.
# Drug Interactions
- Caution should be observed in administering DEMSER to patients receiving phenothiazines or haloperidol because the extrapyramidal effects of these drugs can be expected to be potentiated by inhibition of catecholamine synthesis.
- Concurrent use of DEMSER with alcohol or other CNS depressants can increase their sedative effects.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Animal reproduction studies have not been conducted with DEMSER. It is also not known whether DEMSER can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. DEMSER should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Metirosine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Metirosine during labor and delivery.
### Nursing Mothers
- It is not known whether DEMSER is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when DEMSER is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 12 years have not been established.
### Geriatic Use
- Clinical studies of DEMSER did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Metirosine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Metirosine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Metirosine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Metirosine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Metirosine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Metirosine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Metirosine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Metirosine in the drug label.
# Overdosage
## Acute Overdose
- Signs of metyrosine overdosage include those central nervous system effects observed in some patients even at low dosages.
- At doses exceeding 2000 mg/day, some degree of sedation or feeling of fatigue may persist. Doses of 2000-4000 mg/day can result in anxiety or agitated depression, neuromuscular effects (including fine tremor of the hands, gross tremor of the trunk, tightening of the jaw with trismus), diarrhea, and decreased salivation with dry mouth.
- Reduction of drug dose or cessation of treatment results in the disappearance of these symptoms.
- The acute toxicity of metyrosine was 442 mg/kg and 752 mg/kg in the female mouse and rat respectively.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Metirosine in the drug label.
# Pharmacology
## Mechanism of Action
- DEMSER inhibits tyrosine hydroxylase, which catalyzes the first transformation in catecholamine biosynthesis, i.e., the conversion of tyrosine to dihydroxyphenylalanine (DOPA). Because the first step is also the rate-limiting step, blockade of tyrosine hydroxylase activity results in decreased endogenous levels of catecholamines, usually measured as decreased urinary excretion of catecholamines and their metabolites.
## Structure
- DEMSER1 (Metyrosine) is (–)-α-methyl-L-tyrosine or (α-MPT). It has the following structural formula:
- Metyrosine is a white, crystalline compound of molecular weight 195. It is very slightly soluble in water, acetone, and methanol, and insoluble in chloroform and benzene. It is soluble in acidic aqueous solutions. It is also soluble in alkaline aqueous solutions, but is subject to oxidative degradation under these conditions.
- DEMSER is supplied as capsules, for oral administration. Each capsule contains 250 mg metyrosine. Inactive ingredients are colloidal silicon dioxide, gelatin, hydroxypropyl cellulose, magnesium stearate, titanium dioxide, and FD&C Blue 2.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Metirosine in the drug label.
## Pharmacokinetics
- In patients with pheochromocytoma, who produce excessive amounts of norepinephrine and epinephrine, administration of one to four grams of DEMSER per day has reduced catecholamine biosynthesis from about 35 to 80 percent as measured by the total excretion of catecholamines and their metabolites (metanephrine and vanillylmandelic acid). The maximum biochemical effect usually occurs within two to three days, and the urinary concentration of catecholamines and their metabolites usually returns to pretreatment levels within three to four days after DEMSER is discontinued. In some patients the total excretion of catecholamines and catecholamine metabolites may be lowered to normal or near normal levels (less than 10 mg/24 hours). In most patients the duration of treatment has been two to eight weeks, but several patients have received DEMSER for periods of one to 10 years. Most patients with pheochromocytoma treated with DEMSER experience decreased frequency and severity of hypertensive attacks with their associated headache, nausea, sweating, and tachycardia. In patients who respond, blood pressure decreases progressively during the first two days of therapy with DEMSER; after withdrawal, blood pressure usually increases gradually to pretreatment values within two to three days.
- Metyrosine is well absorbed from the gastrointestinal tract. From 53 to 88 percent (mean 69 percent) was recovered in the urine as unchanged drug following maintenance oral doses of 600 to 4000 mg/24 hours in patients with pheochromocytoma or essential hypertension. Less than 1% of the dose was recovered as catechol metabolites. These metabolites are probably not present in sufficient amounts to contribute to the biochemical effects of metyrosine. The quantities excreted, however, are sufficient to interfere with accurate determination of urinary catecholamines determined by routine techniques.
- Plasma half-life of metyrosine determined over an 8-hour period after single oral doses was 3-3.7 hours in three patients.
## Nonclinical Toxicology
- Long-term carcinogenic studies in animals and studies on mutagenesis and impairment of fertility have not been performed with metyrosine.
# Clinical Studies
There is limited information regarding Clinical Studies of Metirosine in the drug label.
# How Supplied
- Capsules DEMSER, 250 mg, are opaque, two-toned blue capsules coded Aton 305 on one side and DEMSER on the other. They are supplied as follows:
- NDC 25010-305-15 bottles of 100.
## Storage
There is limited information regarding Metirosine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- When receiving DEMSER, patients should be warned about engaging in activities requiring mental alertness and motor coordination, such as driving a motor vehicle or operating machinery. DEMSER may have additive sedative effects with alcohol and other CNS depressants, e.g., hypnotics, sedatives, and tranquilizers.
- Patients should be advised to maintain a liberal fluid intake.
# Precautions with Alcohol
- Alcohol-Metirosine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- DEMSER®[1]
# Look-Alike Drug Names
There is limited information regarding Metirosine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Metirosine | |
a2d96892eb86cf93a42666159f4c8b51e909428f | wikidoc | Metolazone | Metolazone
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Metolazone is a thiazide-like diuretic that is FDA approved for the {{{indicationType}}} of edema associated with congestive heart failure or renal disease. Metolazone is also indicated for the treatment of hypertension, alone or in combination with other antihypertensive agents. There is a Black Box Warning for this drug as shown here. Common adverse reactions include orthostatic hypotension, electrolyte disturbances, hyperuricemia, dizziness, and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Effective dosage of Zaroxolyn should be individualized according to indication and patient response. A single daily dose is recommended. Therapy with Zaroxolyn should be titrated to gain an initial therapeutic response and to determine the minimal dose possible to maintain the desired therapeutic response.
- Dosing Information
- 5–20 mg PO qd
- The time interval required for the initial dosage to produce an effect may vary. Diuresis and saluresis usually begin within one hour and persist for 24 hours or longer. When a desired therapeutic effect has been obtained, it may be advisable to reduce the dose if possible. The daily dose depends on the severity of the patient's condition, sodium intake, and responsiveness. A decision to change the daily dose should be based on the results of thorough clinical and laboratory evaluations. If antihypertensive drugs or diuretics are given concurrently with Zaroxolyn, more careful dosage adjustment may be necessary. For patients who tend to experience paroxysmal nocturnal dyspnea, it may be advisable to employ a larger dose to ensure prolongation of diuresis and saluresis for a full 24-hour period.
- Dosing Information
- 2.5–5 mg PO qd
- The time interval required for the initial dosage regimen to show effect may vary from three or four days to three to six weeks in the treatment of elevated blood pressure. Doses should be adjusted at appropriate intervals to achieve maximum therapeutic effect.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metolazone in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 2.5–10 mg PO qd
- Dosing Information
- 5–20 mg PO qd
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness in pediatric patients have not been established in controlled clinical trials.
- There is limited experience with the use of Zaroxolyn in pediatric patients with congestive heart failure, hypertension, bronchopulmonary dysplasia, nephrotic syndrome and nephrogenic diabetes insipidus.
- Doses used generally ranged from 0.05 to 0.1 mg/kg administered once daily and usually resulted in a 1 to 2.8 kg weight loss and 150 to 300 cc increase in urine output. Not all patients responded and some gained weight. Those patients who did respond did so in the first few days of treatment. Prolonged use (beyond a few days) was generally associated with no further beneficial effect or a return to baseline status and is not recommended.
- Dosing Information
- 0.05–0.1 mg/kg qd
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metolazone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metolazone in pediatric patients.
# Contraindications
- Anuria
- Hepatic coma or precoma
- Allergy or hypersensitivity to metolazone
# Warnings
- Rapid Onset Hyponatremia And/Or Hypokalemia
- Rarely, the rapid onset of severe hyponatremia and/or hypokalemia has been reported following initial doses of thiazide and non-thiazide diuretics. When symptoms consistent with severe electrolyte imbalance appear rapidly, drug should be discontinued and supportive measures should be initiated immediately. Parenteral electrolytes may be required. Appropriateness of therapy with this class of drugs should be carefully reevaluated.
- Hypokalemia
- Hypokalemia may occur with consequent weakness, cramps, and cardiac dysrhythmias. Serum potassium should be determined at regular and appropriate intervals, and dose reduction, potassium supplementation or addition of a potassium-sparing diuretic instituted whenever indicated. Hypokalemia is a particular hazard in patients who are digitalized or who have or have had a ventricular arrhythmia; dangerous or fatal arrhythmias may be precipitated. Hypokalemia is dose related.
- Concomitant Therapy
- Lithium
- In general, diuretics should not be given concomitantly with lithium because they reduce its renal clearance and add a high risk of lithium toxicity. Read prescribing information for lithium preparations before use of such concomitant therapy.
- Furosemide
- Unusually large or prolonged losses of fluids and electrolytes may result when Zaroxolyn is administered concomitantly to patients receiving furosemide.
- Other Antihypertensive Drugs
- When Zaroxolyn is used with other antihypertensive drugs, particular care must be taken to avoid excessive reduction of blood pressure, especially during initial therapy.
- Cross-Allergy
- Cross-allergy may occur when Zaroxolyn is given to patients known to be allergic to sulfonamide-derived drugs, thiazides, or quinethazone.
- Sensitivity Reactions
- Sensitivity reactions (e.g., angioedema, bronchospasm) may occur with or without a history of allergy or bronchial asthma and may occur with the first dose of Zaroxolyn.
### Precautions
- Fluid And Electrolytes
- All patients receiving therapy with Zaroxolyn Tablets should have serum electrolyte measurements done at appropriate intervals and be observed for clinical signs of fluid and/or electrolyte imbalance: namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. In patients with severe edema accompanying cardiac failure or renal disease, a low-salt syndrome may be produced, especially with hot weather and a low-salt diet. Serum and urine electrolyte determinations are particularly important when the patient has protracted vomiting, severe diarrhea, or is receiving parenteral fluids. Warning signs of imbalance are: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Hyponatremia may occur at any time during long term therapy and, on rare occasions, may be life threatening.
- The risk of hypokalemia is increased when larger doses are used, when diuresis is rapid, when severe liver disease is present, when corticosteroids are given concomitantly, when oral intake is inadequate or when excess potassium is being lost extrarenally, such as with vomiting or diarrhea.
- Thiazide-like diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.
- Glucose Tolerance
- Metolazone may raise blood glucose concentrations possibly causing hyperglycemia and glycosuria in patients with diabetes or latent diabetes.
- Hyperuricemia
- Zaroxolyn regularly causes an increase in serum uric acid and can occasionally precipitate gouty attacks even in patients without a prior history of them.
- Azotemia
- Azotemia, presumably prerenal azotemia, may be precipitated during the administration of Zaroxolyn. If azotemia and oliguria worsen during treatment of patients with severe renal disease, Zaroxolyn should be discontinued.
- Renal Impairment
- Use caution when administering Zaroxolyn Tablets to patients with severely impaired renal function. As most of the drug is excreted by the renal route, accumulation may occur.
- Orthostatic Hypotension
- Orthostatic hypotension may occur; this may be potentiated by alcohol, barbiturates, narcotics, or concurrent therapy with other antihypertensive drugs.
- Hypercalcemia
- Hypercalcemia may infrequently occur with metolazone, especially in patients taking high doses of vitamin D or with high bone turnover states, and may signify hidden hyperparathyroidism. Metolazone should be discontinued before tests for parathyroid function are performed.
- Systemic Lupus Erythematosus
- Thiazide diuretics have exacerbated or activated systemic lupus erythematosus and this possibility should be considered with Zaroxolyn Tablets.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Metolazone in the drug label.
## Postmarketing Experience
- Zaroxolyn is usually well tolerated, and most reported adverse reactions have been mild and transient. Many Zaroxolyn related adverse reactions represent extensions of its expected pharmacologic activity and can be attributed to either its antihypertensive action or its renal/metabolic actions. The following adverse reactions have been reported. Several are single or comparably rare occurrences. Adverse reactions are listed in decreasing order of severity within body systems.
Chest pain/discomfort, orthostatic hypotension, excessive volume depletion, hemoconcentration, venous thrombosis, palpitations.
Syncope, neuropathy, vertigo, paresthesias, psychotic depression, impotence, dizziness/lightheadedness, drowsiness, fatigue, weakness, restlessness (sometimes resulting in insomnia), headache.
Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, necrotizing angiitis (cutaneous vasculitis), skin necrosis, purpura, petechiae, dermatitis (photosensitivity), urticaria, pruritus, skin rashes.
Hepatitis, intrahepatic cholestatic jaundice, pancreatitis, vomiting, nausea, epigastric distress, diarrhea, constipation, anorexia, abdominal bloating, abdominal pain.
Aplastic/hypoplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.
Hypokalemia, hyponatremia, hyperuricemia, hypochloremia, hypochloremic alkalosis, hyperglycemia, glycosuria, increase in serum urea nitrogen (BUN) or creatinine, hypophosphatemia, hypomagnesemia, hypercalcemia.
Joint pain, acute gouty attacks, muscle cramps or spasm.
Transient blurred vision, chills, dry mouth.
- In addition, adverse reactions reported with similar antihypertensive-diuretics, but which have not been reported to date for Zaroxolyn include: bitter taste, sialadenitis, xanthopsia, respiratory distress (including pneumonitis), and anaphylactic reactions. These reactions should be considered as possible occurrences with clinical usage of Zaroxolyn.
- Whenever adverse reactions are moderate or severe, Zaroxolyn dosage should be reduced or therapy withdrawn.
# Drug Interactions
- Diuretics
- Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes.
- Other Antihypertensives
- When Zaroxolyn Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary.
- Alcohol, Barbiturates, And Narcotics
- The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy.
- Digitalis Glycosides
- Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result.
- Corticosteroids Or ACTH
- May increase the risk of hypokalemia and increase salt and water retention.
- Lithium
- Serum lithium levels may increase.
- Curariform Drugs
- Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) – the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue Zaroxolyn three days before elective surgery.
- Salicylates And Other Non-Steroidal Anti-Inflammatory Drugs
- May decrease the antihypertensive effects of Zaroxolyn Tablets.
- Sympathomimetics
- Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.
- Insulin And Oral Antidiabetic Agents
- Methenamine
- Efficacy may be decreased due to urinary alkalizing effect of metolazone.
- Anticoagulants
- Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Teratogenic Effects
- Reproduction studies performed in mice, rabbits, and rats treated during the appropriate period of gestation at doses up to 50 mg/kg/day have revealed no evidence of harm to the fetus due to metolazone. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Zaroxolyn Tablets (metolazone tablets, USP) should be used during pregnancy only if clearly needed. Metolazone crosses the placental barrier and appears in cord blood.
- Non-Teratogenic Effects
- The use of Zaroxolyn Tablets in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult. It is not known what effect the use of the drug during pregnancy has on the later growth, development, and functional maturation of the child. No such effects have been reported with metolazone.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Metolazone in women who are pregnant.
### Labor and Delivery
- Based on clinical studies in which women received metolazone in late pregnancy until the time of delivery, there is no evidence that the drug has any adverse effects on the normal course of labor or delivery.
### Nursing Mothers
- Metolazone appears in breast milk. Because of the potential for serious adverse reactions in nursing infants from metolazone, 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 in controlled clinical trials. There is limited experience with the use of Zaroxolyn in pediatric patients with congestive heart failure, hypertension, bronchopulmonary dysplasia, nephrotic syndrome and nephrogenic diabetes insipidus. Doses used generally ranged from 0.05 to 0.1 mg/kg administered once daily and usually resulted in a 1 to 2.8 kg weight loss and 150 to 300 cc increase in urine output. Not all patients responded and some gained weight. Those patients who did respond did so in the first few days of treatment. Prolonged use (beyond a few days) was generally associated with no further beneficial effect or a return to baseline status and is not recommended.
- There is limited experience with the combination of Zaroxolyn and furosemide in pediatric patients with furosemide-resistant edema. Some benefited while others did not or had an exaggerated response with hypovolemia, tachycardia, and orthostatic hypotension requiring fluid replacement. Severe hypokalemia was reported and there was a tendency for diuresis to persist for up to 24 hours after Zaroxolyn was discontinued. Hyperbilirubinemia has been reported in 1 neonate. Close clinical and laboratory monitoring of all children treated with diuretics is indicated.
### Geriatic Use
- Clinical studies of Zaroxolyn did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
- This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Metolazone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Metolazone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Metolazone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Metolazone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Metolazone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Metolazone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Close clinical and laboratory monitoring of all children treated with diuretics is indicated.
- 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.
# IV Compatibility
There is limited information regarding IV Compatibility of Metolazone in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Intentional overdosage has been reported rarely with metolazone and similar diuretic drugs.
- Orthostatic hypotension, dizziness, drowsiness, syncope, electrolyte abnormalities, hemoconcentration and hemodynamic changes due to plasma volume depletion may occur. In some instances depressed respiration may be observed. At high doses, lethargy of varying degree may progress to coma within a few hours. The mechanism of CNS depression with thiazide overdosage is unknown. Also, GI irritation and hypermotility may occur. Temporary elevation of BUN has been reported, especially in patients with impairment of renal function. Serum electrolyte changes and cardiovascular and renal function should be closely monitored.
### Management
- There is no specific antidote available but immediate evacuation of stomach contents is advised. Dialysis is not likely to be effective. Care should be taken when evacuating the gastric contents to prevent aspiration, especially in the stuporous or comatose patient. Supportive measures should be initiated as required to maintain hydration, electrolyte balance, respiration, and cardiovascular and renal function.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Metolazone in the drug label.
# Pharmacology
## Mechanism of Action
- Zaroxolyn (metolazone) is a quinazoline diuretic, with properties generally similar to the thiazide diuretics. The actions of Zaroxolyn result from interference with the renal tubular mechanism of electrolyte reabsorption. Zaroxolyn acts primarily to inhibit sodium reabsorption at the cortical diluting site and to a lesser extent in the proximal convoluted tubule. Sodium and chloride ions are excreted in approximately equivalent amounts. The increased delivery of sodium to the distal tubular exchange site results in increased potassium excretion. Zaroxolyn does not inhibit carbonic anhydrase. A proximal action of metolazone has been shown in humans by increased excretion of phosphate and magnesium ions and by a markedly increased fractional excretion of sodium in patients with severely compromised glomerular filtration. This action has been demonstrated in animals by micropuncture studies.
## Structure
- Zaroxolyn Tablets (metolazone tablets, USP) for oral administration contain 2½ or 5 mg of metolazone, USP, a diuretic/saluretic/antihypertensive drug of the quinazoline class.
- Metolazone has the molecular formula C16H16ClN3S, the chemical name 7-chloro-1, 2, 3, 4-tetrahydro-2-methyl-3-(2-methylphenyl)-4-oxo-6-quinazolinesulfonamide, and a molecular weight of 365.83. The structural formula is:
- Metolazone is only sparingly soluble in water, but more soluble in plasma, blood, alkali, and organic solvents.
- Inactive Ingredients: Magnesium stearate, microcrystalline cellulose and dye: 2½ mg-D&C Red No. 33; 5 mg-FD&C Blue No. 2.
## Pharmacodynamics
- When Zaroxolyn Tablets are given, diuresis and saluresis usually begin within one hour and may persist for 24 hours or more. For most patients, the duration of effect can be varied by adjusting the daily dose. High doses may prolong the effect. A single daily dose is recommended. When a desired therapeutic effect has been obtained, it may be possible to reduce dosage to a lower maintenance level.
- The diuretic potency of Zaroxolyn at maximum therapeutic dosage is approximately equal to thiazide diuretics. However, unlike thiazides, Zaroxolyn may produce diuresis in patients with glomerular filtration rates below 20 mL/min.
- Zaroxolyn and furosemide administered concurrently have produced marked diuresis in some patients where edema or ascites was refractory to treatment with maximum recommended doses of these or other diuretics administered alone. The mechanism of this interaction is unknown
## Pharmacokinetics
- Maximum blood levels of metolazone are found approximately eight hours after dosing. A small fraction of metolazone is metabolized. Most of the drug is excreted in the unconverted form in the urine.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment Of Fertility
- Mice and rats administered metolazone 5 days/week for up to 18 and 24 months, respectively, at daily doses of 2, 10, and 50 mg/kg, exhibited no evidence of a tumorigenic effect of the drug. The small number of animals examined histologically and poor survival in the mice limit the conclusions that can be reached from these studies.
- Metolazone was not mutagenic in vitro in the Ames Test using Salmonella typhimurium strains TA-97, TA-98, TA-100, TA-102, and TA-1535.
- Reproductive performance has been evaluated in mice and rats. There is no evidence that metolazone possesses the potential for altering reproductive capacity in mice. In a rat study, in which males were treated orally with metolazone at doses of 2, 10, and 50 mg/kg for 127 days prior to mating with untreated females, an increased number of resorption sites was observed in dams mated with males from the 50 mg/kg group. In addition, the birth weight of offspring was decreased and the pregnancy rate was reduced in dams mated with males from the 10 and 50 mg/kg groups.
# Clinical Studies
There is limited information regarding Clinical Studies of Metolazone in the drug label.
# How Supplied
- Zaroxolyn Tablets (metolazone tablets, USP) are shallow biconvex, round tablets, and are available in two strengths:
- Storage
- Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) .
- Protect from light. Keep out of the reach of children.
## Storage
There is limited information regarding Metolazone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be informed of possible adverse effects, advised to take the medication as directed, and promptly report any possible adverse reactions to the treating physician.
# Precautions with Alcohol
- The hypotensive effects of alcohol may be potentiated by the volume contraction associated with metolazone therapy.
# Brand Names
- Mykrox®
- Zaroxolyn®
# Look-Alike Drug Names
- metolazone — methimazole
- metolazone — metoclopramide
# Drug Shortage Status
# Price | Metolazone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Metolazone is a thiazide-like diuretic that is FDA approved for the {{{indicationType}}} of edema associated with congestive heart failure or renal disease. Metolazone is also indicated for the treatment of hypertension, alone or in combination with other antihypertensive agents. There is a Black Box Warning for this drug as shown here. Common adverse reactions include orthostatic hypotension, electrolyte disturbances, hyperuricemia, dizziness, and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Effective dosage of Zaroxolyn should be individualized according to indication and patient response. A single daily dose is recommended. Therapy with Zaroxolyn should be titrated to gain an initial therapeutic response and to determine the minimal dose possible to maintain the desired therapeutic response.
- Dosing Information
- 5–20 mg PO qd
- The time interval required for the initial dosage to produce an effect may vary. Diuresis and saluresis usually begin within one hour and persist for 24 hours or longer. When a desired therapeutic effect has been obtained, it may be advisable to reduce the dose if possible. The daily dose depends on the severity of the patient's condition, sodium intake, and responsiveness. A decision to change the daily dose should be based on the results of thorough clinical and laboratory evaluations. If antihypertensive drugs or diuretics are given concurrently with Zaroxolyn, more careful dosage adjustment may be necessary. For patients who tend to experience paroxysmal nocturnal dyspnea, it may be advisable to employ a larger dose to ensure prolongation of diuresis and saluresis for a full 24-hour period.
- Dosing Information
- 2.5–5 mg PO qd
- The time interval required for the initial dosage regimen to show effect may vary from three or four days to three to six weeks in the treatment of elevated blood pressure. Doses should be adjusted at appropriate intervals to achieve maximum therapeutic effect.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metolazone in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 2.5–10 mg PO qd[1]
- Dosing Information
- 5–20 mg PO qd[2]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness in pediatric patients have not been established in controlled clinical trials.
- There is limited experience with the use of Zaroxolyn in pediatric patients with congestive heart failure, hypertension, bronchopulmonary dysplasia, nephrotic syndrome and nephrogenic diabetes insipidus.
- Doses used generally ranged from 0.05 to 0.1 mg/kg administered once daily and usually resulted in a 1 to 2.8 kg weight loss and 150 to 300 cc increase in urine output. Not all patients responded and some gained weight. Those patients who did respond did so in the first few days of treatment. Prolonged use (beyond a few days) was generally associated with no further beneficial effect or a return to baseline status and is not recommended.
- Dosing Information
- 0.05–0.1 mg/kg qd
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metolazone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metolazone in pediatric patients.
# Contraindications
- Anuria
- Hepatic coma or precoma
- Allergy or hypersensitivity to metolazone
# Warnings
- Rapid Onset Hyponatremia And/Or Hypokalemia
- Rarely, the rapid onset of severe hyponatremia and/or hypokalemia has been reported following initial doses of thiazide and non-thiazide diuretics. When symptoms consistent with severe electrolyte imbalance appear rapidly, drug should be discontinued and supportive measures should be initiated immediately. Parenteral electrolytes may be required. Appropriateness of therapy with this class of drugs should be carefully reevaluated.
- Hypokalemia
- Hypokalemia may occur with consequent weakness, cramps, and cardiac dysrhythmias. Serum potassium should be determined at regular and appropriate intervals, and dose reduction, potassium supplementation or addition of a potassium-sparing diuretic instituted whenever indicated. Hypokalemia is a particular hazard in patients who are digitalized or who have or have had a ventricular arrhythmia; dangerous or fatal arrhythmias may be precipitated. Hypokalemia is dose related.
- Concomitant Therapy
- Lithium
- In general, diuretics should not be given concomitantly with lithium because they reduce its renal clearance and add a high risk of lithium toxicity. Read prescribing information for lithium preparations before use of such concomitant therapy.
- Furosemide
- Unusually large or prolonged losses of fluids and electrolytes may result when Zaroxolyn is administered concomitantly to patients receiving furosemide.
- Other Antihypertensive Drugs
- When Zaroxolyn is used with other antihypertensive drugs, particular care must be taken to avoid excessive reduction of blood pressure, especially during initial therapy.
- Cross-Allergy
- Cross-allergy may occur when Zaroxolyn is given to patients known to be allergic to sulfonamide-derived drugs, thiazides, or quinethazone.
- Sensitivity Reactions
- Sensitivity reactions (e.g., angioedema, bronchospasm) may occur with or without a history of allergy or bronchial asthma and may occur with the first dose of Zaroxolyn.
### Precautions
- Fluid And Electrolytes
- All patients receiving therapy with Zaroxolyn Tablets should have serum electrolyte measurements done at appropriate intervals and be observed for clinical signs of fluid and/or electrolyte imbalance: namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. In patients with severe edema accompanying cardiac failure or renal disease, a low-salt syndrome may be produced, especially with hot weather and a low-salt diet. Serum and urine electrolyte determinations are particularly important when the patient has protracted vomiting, severe diarrhea, or is receiving parenteral fluids. Warning signs of imbalance are: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Hyponatremia may occur at any time during long term therapy and, on rare occasions, may be life threatening.
- The risk of hypokalemia is increased when larger doses are used, when diuresis is rapid, when severe liver disease is present, when corticosteroids are given concomitantly, when oral intake is inadequate or when excess potassium is being lost extrarenally, such as with vomiting or diarrhea.
- Thiazide-like diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.
- Glucose Tolerance
- Metolazone may raise blood glucose concentrations possibly causing hyperglycemia and glycosuria in patients with diabetes or latent diabetes.
- Hyperuricemia
- Zaroxolyn regularly causes an increase in serum uric acid and can occasionally precipitate gouty attacks even in patients without a prior history of them.
- Azotemia
- Azotemia, presumably prerenal azotemia, may be precipitated during the administration of Zaroxolyn. If azotemia and oliguria worsen during treatment of patients with severe renal disease, Zaroxolyn should be discontinued.
- Renal Impairment
- Use caution when administering Zaroxolyn Tablets to patients with severely impaired renal function. As most of the drug is excreted by the renal route, accumulation may occur.
- Orthostatic Hypotension
- Orthostatic hypotension may occur; this may be potentiated by alcohol, barbiturates, narcotics, or concurrent therapy with other antihypertensive drugs.
- Hypercalcemia
- Hypercalcemia may infrequently occur with metolazone, especially in patients taking high doses of vitamin D or with high bone turnover states, and may signify hidden hyperparathyroidism. Metolazone should be discontinued before tests for parathyroid function are performed.
- Systemic Lupus Erythematosus
- Thiazide diuretics have exacerbated or activated systemic lupus erythematosus and this possibility should be considered with Zaroxolyn Tablets.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Metolazone in the drug label.
## Postmarketing Experience
- Zaroxolyn is usually well tolerated, and most reported adverse reactions have been mild and transient. Many Zaroxolyn related adverse reactions represent extensions of its expected pharmacologic activity and can be attributed to either its antihypertensive action or its renal/metabolic actions. The following adverse reactions have been reported. Several are single or comparably rare occurrences. Adverse reactions are listed in decreasing order of severity within body systems.
Chest pain/discomfort, orthostatic hypotension, excessive volume depletion, hemoconcentration, venous thrombosis, palpitations.
Syncope, neuropathy, vertigo, paresthesias, psychotic depression, impotence, dizziness/lightheadedness, drowsiness, fatigue, weakness, restlessness (sometimes resulting in insomnia), headache.
Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, necrotizing angiitis (cutaneous vasculitis), skin necrosis, purpura, petechiae, dermatitis (photosensitivity), urticaria, pruritus, skin rashes.
Hepatitis, intrahepatic cholestatic jaundice, pancreatitis, vomiting, nausea, epigastric distress, diarrhea, constipation, anorexia, abdominal bloating, abdominal pain.
Aplastic/hypoplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.
Hypokalemia, hyponatremia, hyperuricemia, hypochloremia, hypochloremic alkalosis, hyperglycemia, glycosuria, increase in serum urea nitrogen (BUN) or creatinine, hypophosphatemia, hypomagnesemia, hypercalcemia.
Joint pain, acute gouty attacks, muscle cramps or spasm.
Transient blurred vision, chills, dry mouth.
- In addition, adverse reactions reported with similar antihypertensive-diuretics, but which have not been reported to date for Zaroxolyn include: bitter taste, sialadenitis, xanthopsia, respiratory distress (including pneumonitis), and anaphylactic reactions. These reactions should be considered as possible occurrences with clinical usage of Zaroxolyn.
- Whenever adverse reactions are moderate or severe, Zaroxolyn dosage should be reduced or therapy withdrawn.
# Drug Interactions
- Diuretics
- Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes.
- Other Antihypertensives
- When Zaroxolyn Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary.
- Alcohol, Barbiturates, And Narcotics
- The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy.
- Digitalis Glycosides
- Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result.
- Corticosteroids Or ACTH
- May increase the risk of hypokalemia and increase salt and water retention.
- Lithium
- Serum lithium levels may increase.
- Curariform Drugs
- Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) – the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue Zaroxolyn three days before elective surgery.
- Salicylates And Other Non-Steroidal Anti-Inflammatory Drugs
- May decrease the antihypertensive effects of Zaroxolyn Tablets.
- Sympathomimetics
- Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.
- Insulin And Oral Antidiabetic Agents
- Methenamine
- Efficacy may be decreased due to urinary alkalizing effect of metolazone.
- Anticoagulants
- Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Teratogenic Effects
- Reproduction studies performed in mice, rabbits, and rats treated during the appropriate period of gestation at doses up to 50 mg/kg/day have revealed no evidence of harm to the fetus due to metolazone. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Zaroxolyn Tablets (metolazone tablets, USP) should be used during pregnancy only if clearly needed. Metolazone crosses the placental barrier and appears in cord blood.
- Non-Teratogenic Effects
- The use of Zaroxolyn Tablets in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult. It is not known what effect the use of the drug during pregnancy has on the later growth, development, and functional maturation of the child. No such effects have been reported with metolazone.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Metolazone in women who are pregnant.
### Labor and Delivery
- Based on clinical studies in which women received metolazone in late pregnancy until the time of delivery, there is no evidence that the drug has any adverse effects on the normal course of labor or delivery.
### Nursing Mothers
- Metolazone appears in breast milk. Because of the potential for serious adverse reactions in nursing infants from metolazone, 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 in controlled clinical trials. There is limited experience with the use of Zaroxolyn in pediatric patients with congestive heart failure, hypertension, bronchopulmonary dysplasia, nephrotic syndrome and nephrogenic diabetes insipidus. Doses used generally ranged from 0.05 to 0.1 mg/kg administered once daily and usually resulted in a 1 to 2.8 kg weight loss and 150 to 300 cc increase in urine output. Not all patients responded and some gained weight. Those patients who did respond did so in the first few days of treatment. Prolonged use (beyond a few days) was generally associated with no further beneficial effect or a return to baseline status and is not recommended.
- There is limited experience with the combination of Zaroxolyn and furosemide in pediatric patients with furosemide-resistant edema. Some benefited while others did not or had an exaggerated response with hypovolemia, tachycardia, and orthostatic hypotension requiring fluid replacement. Severe hypokalemia was reported and there was a tendency for diuresis to persist for up to 24 hours after Zaroxolyn was discontinued. Hyperbilirubinemia has been reported in 1 neonate. Close clinical and laboratory monitoring of all children treated with diuretics is indicated.
### Geriatic Use
- Clinical studies of Zaroxolyn did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
- This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Metolazone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Metolazone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Metolazone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Metolazone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Metolazone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Metolazone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Close clinical and laboratory monitoring of all children treated with diuretics is indicated.
- 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.
# IV Compatibility
There is limited information regarding IV Compatibility of Metolazone in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Intentional overdosage has been reported rarely with metolazone and similar diuretic drugs.
- Orthostatic hypotension, dizziness, drowsiness, syncope, electrolyte abnormalities, hemoconcentration and hemodynamic changes due to plasma volume depletion may occur. In some instances depressed respiration may be observed. At high doses, lethargy of varying degree may progress to coma within a few hours. The mechanism of CNS depression with thiazide overdosage is unknown. Also, GI irritation and hypermotility may occur. Temporary elevation of BUN has been reported, especially in patients with impairment of renal function. Serum electrolyte changes and cardiovascular and renal function should be closely monitored.
### Management
- There is no specific antidote available but immediate evacuation of stomach contents is advised. Dialysis is not likely to be effective. Care should be taken when evacuating the gastric contents to prevent aspiration, especially in the stuporous or comatose patient. Supportive measures should be initiated as required to maintain hydration, electrolyte balance, respiration, and cardiovascular and renal function.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Metolazone in the drug label.
# Pharmacology
## Mechanism of Action
- Zaroxolyn (metolazone) is a quinazoline diuretic, with properties generally similar to the thiazide diuretics. The actions of Zaroxolyn result from interference with the renal tubular mechanism of electrolyte reabsorption. Zaroxolyn acts primarily to inhibit sodium reabsorption at the cortical diluting site and to a lesser extent in the proximal convoluted tubule. Sodium and chloride ions are excreted in approximately equivalent amounts. The increased delivery of sodium to the distal tubular exchange site results in increased potassium excretion. Zaroxolyn does not inhibit carbonic anhydrase. A proximal action of metolazone has been shown in humans by increased excretion of phosphate and magnesium ions and by a markedly increased fractional excretion of sodium in patients with severely compromised glomerular filtration. This action has been demonstrated in animals by micropuncture studies.
## Structure
- Zaroxolyn Tablets (metolazone tablets, USP) for oral administration contain 2½ or 5 mg of metolazone, USP, a diuretic/saluretic/antihypertensive drug of the quinazoline class.
- Metolazone has the molecular formula C16H16ClN3S, the chemical name 7-chloro-1, 2, 3, 4-tetrahydro-2-methyl-3-(2-methylphenyl)-4-oxo-6-quinazolinesulfonamide, and a molecular weight of 365.83. The structural formula is:
- Metolazone is only sparingly soluble in water, but more soluble in plasma, blood, alkali, and organic solvents.
- Inactive Ingredients: Magnesium stearate, microcrystalline cellulose and dye: 2½ mg-D&C Red No. 33; 5 mg-FD&C Blue No. 2.
## Pharmacodynamics
- When Zaroxolyn Tablets are given, diuresis and saluresis usually begin within one hour and may persist for 24 hours or more. For most patients, the duration of effect can be varied by adjusting the daily dose. High doses may prolong the effect. A single daily dose is recommended. When a desired therapeutic effect has been obtained, it may be possible to reduce dosage to a lower maintenance level.
- The diuretic potency of Zaroxolyn at maximum therapeutic dosage is approximately equal to thiazide diuretics. However, unlike thiazides, Zaroxolyn may produce diuresis in patients with glomerular filtration rates below 20 mL/min.
- Zaroxolyn and furosemide administered concurrently have produced marked diuresis in some patients where edema or ascites was refractory to treatment with maximum recommended doses of these or other diuretics administered alone. The mechanism of this interaction is unknown
## Pharmacokinetics
- Maximum blood levels of metolazone are found approximately eight hours after dosing. A small fraction of metolazone is metabolized. Most of the drug is excreted in the unconverted form in the urine.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment Of Fertility
- Mice and rats administered metolazone 5 days/week for up to 18 and 24 months, respectively, at daily doses of 2, 10, and 50 mg/kg, exhibited no evidence of a tumorigenic effect of the drug. The small number of animals examined histologically and poor survival in the mice limit the conclusions that can be reached from these studies.
- Metolazone was not mutagenic in vitro in the Ames Test using Salmonella typhimurium strains TA-97, TA-98, TA-100, TA-102, and TA-1535.
- Reproductive performance has been evaluated in mice and rats. There is no evidence that metolazone possesses the potential for altering reproductive capacity in mice. In a rat study, in which males were treated orally with metolazone at doses of 2, 10, and 50 mg/kg for 127 days prior to mating with untreated females, an increased number of resorption sites was observed in dams mated with males from the 50 mg/kg group. In addition, the birth weight of offspring was decreased and the pregnancy rate was reduced in dams mated with males from the 10 and 50 mg/kg groups.
# Clinical Studies
There is limited information regarding Clinical Studies of Metolazone in the drug label.
# How Supplied
- Zaroxolyn Tablets (metolazone tablets, USP) are shallow biconvex, round tablets, and are available in two strengths:
- Storage
- Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].
- Protect from light. Keep out of the reach of children.
## Storage
There is limited information regarding Metolazone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be informed of possible adverse effects, advised to take the medication as directed, and promptly report any possible adverse reactions to the treating physician.
# Precautions with Alcohol
- The hypotensive effects of alcohol may be potentiated by the volume contraction associated with metolazone therapy.
# Brand Names
- Mykrox®
- Zaroxolyn®[3]
# Look-Alike Drug Names
- metolazone — methimazole[4]
- metolazone — metoclopramide[4]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Metolazone | |
5a8b2b9e1ba4d1d5b5fe3680f91f90c5ab6b8389 | wikidoc | Metyrapone | Metyrapone
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# Overview
Metyrapone is a inhibitor of endogenous adrenal corticosteriod synthesis that is FDA approved for the diagnosis of adrenal insufficiency and testing hypothalamic‑pituitary ACTH function. Common adverse reactions include acute adrenal insufficiency in patients with reduced adrenal secretory capacity.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- This test, usually given on an outpatient basis, determines plasma 11-desoxycortisol and/or ACTH levels after a single dose of Metopirone. The patient is given 30 mg/kg (maximum 3 g Metopirone) at midnight with yogurt or milk. The same dose is recommended in children. The blood sample for the assay is taken early the following morning (7:30-8:00 a.m.). The plasma should be frozen as soon as possible. The patient is then given a prophylactic dose of 50 mg cortisone acetate.
- Normal values will depend on the method used to determine ACTH and 11‑desoxycortisol levels. An intact ACTH reserve is generally indicated by an increase in plasma ACTH to at least 44 pmol/L (200 ng/L) or by an increase in 11‑desoxycortisol to over 0.2 µmol/L (70µg/L). Patients with suspected adrenocortical insufficiency should be hospitalized overnight as a precautionary measure.
- Day 1: Control period - Collect 24-hour urine for measurement of 17-OHCS or 17-KGS.
- Day 2: ACTH test to determine the ability of adrenals to respond - Standard ACTH test such as infusion of 50 units ACTH over 8 hours and measurement of 24-hour urinary steroids. If results indicate adequate response, the Metopirone test may proceed.
- Day 3-4: Rest period.
- Day 5: Administration of Metopirone: Recommended with milk or snack.
Dosage:
Adults: 750 mg orally, every 4 hours for 6 doses. A single dose is approximately equivalent to 15 mg/kg.
- Dosage:
Adults: 750 mg orally, every 4 hours for 6 doses. A single dose is approximately equivalent to 15 mg/kg.
- Adults: 750 mg orally, every 4 hours for 6 doses. A single dose is approximately equivalent to 15 mg/kg.
- Day 6: After administration of Metopirone - Determination of 24-hour urinary steroids for effect.
The normal 24-hour urinary excretion of 17-OHCS ranges from 3 to 12 mg. Following continuous intravenous infusion of 50 units ACTH over a period of 8 hours, 17-OHCS excretion increases to 15 to 45 mg per 24 hours.
- Metopirone
Normal response: In patients with a normally functioning pituitary, administration of Metopirone is followed by a two‑ to four‑fold increase of 17-OHCS excretion or doubling of 17-KGS excretion.
Subnormal response: Subnormal response in patients without adrenal insufficiency is indicative of some degree of impairment of pituitary function, either panhypopituitarism or partial hypopituitarism (limited pituitary reserve).
Panhypopituitarism is readily diagnosed by the classical clinical and chemical evidences of hypogonadism, hypothyroidism, and hypoadrenocorticism. These patients usually have subnormal basal urinary steroid levels. Depending upon the duration of the disease and degree of adrenal atrophy, they may fail to respond to exogenous ACTH in the normal manner. Administration of Metopirone is not essential in the diagnosis, but if given, it will not induce an appreciable increase in urinary steroids.
Partial hypopituitarism or limited pituitary reserve is the more difficult diagnosis as these patients do not present the classical signs and symptoms of hypopituitarism. Measurements of target organ functions often are normal under basal conditions. The response to exogenous ACTH is usually normal, producing the expected rise of urinary steroids (17-OHCS or 17-KGS). The response, however, to Metopirone is subnormal; that is, no significant increase in 17‑OHCS or 17‑KGS excretion occurs.
- Normal response: In patients with a normally functioning pituitary, administration of Metopirone is followed by a two‑ to four‑fold increase of 17-OHCS excretion or doubling of 17-KGS excretion.
- Subnormal response: Subnormal response in patients without adrenal insufficiency is indicative of some degree of impairment of pituitary function, either panhypopituitarism or partial hypopituitarism (limited pituitary reserve).
Panhypopituitarism is readily diagnosed by the classical clinical and chemical evidences of hypogonadism, hypothyroidism, and hypoadrenocorticism. These patients usually have subnormal basal urinary steroid levels. Depending upon the duration of the disease and degree of adrenal atrophy, they may fail to respond to exogenous ACTH in the normal manner. Administration of Metopirone is not essential in the diagnosis, but if given, it will not induce an appreciable increase in urinary steroids.
Partial hypopituitarism or limited pituitary reserve is the more difficult diagnosis as these patients do not present the classical signs and symptoms of hypopituitarism. Measurements of target organ functions often are normal under basal conditions. The response to exogenous ACTH is usually normal, producing the expected rise of urinary steroids (17-OHCS or 17-KGS). The response, however, to Metopirone is subnormal; that is, no significant increase in 17‑OHCS or 17‑KGS excretion occurs.
- Panhypopituitarism is readily diagnosed by the classical clinical and chemical evidences of hypogonadism, hypothyroidism, and hypoadrenocorticism. These patients usually have subnormal basal urinary steroid levels. Depending upon the duration of the disease and degree of adrenal atrophy, they may fail to respond to exogenous ACTH in the normal manner. Administration of Metopirone is not essential in the diagnosis, but if given, it will not induce an appreciable increase in urinary steroids.
- Partial hypopituitarism or limited pituitary reserve is the more difficult diagnosis as these patients do not present the classical signs and symptoms of hypopituitarism. Measurements of target organ functions often are normal under basal conditions. The response to exogenous ACTH is usually normal, producing the expected rise of urinary steroids (17-OHCS or 17-KGS). The response, however, to Metopirone is subnormal; that is, no significant increase in 17‑OHCS or 17‑KGS excretion occurs.
- This failure to respond to metyrapone may be interpreted as evidence of impaired pituitary‑adrenal reserve. In view of the normal response to exogenous ACTH, the failure to respond to metyrapone is inferred to be related to a defect in the CNS‑pituitary mechanisms which normally regulate ACTH secretions. Presumably the ACTH secreting mechanisms of these individuals are already working at their maximal rates to meet everyday conditions and possess limited “reserve” capacities to secrete additional ACTH either in response to stress or to decreased cortisol levels occurring as a result of metyrapone administration. Subnormal response in patients with Cushing’s syndrome is suggestive of either autonomous adrenal tumors that suppress the ACTH-releasing capacity of the pituitary or non endocrine ACTH-secreting tumors.
- Excessive response: An excessive excretion of 17-OHCS or 17-KGS after administration of Metopirone is suggestive of Cushing’s syndrome associated with adrenal hyperplasia. These patients have an elevated excretion of urinary corticosteroids under basal conditions and will often, but not invariably, show a “supernormal” response to ACTH and also to Metopirone, excreting more than 35 mg per 24 hours of either 17-OHCS or 17-KGS.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metyrapone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metyrapone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- This test, usually given on an outpatient basis, determines plasma 11-desoxycortisol and/or ACTH levels after a single dose of Metopirone. The patient is given 30 mg/kg (maximum 3 g Metopirone) at midnight with yogurt or milk. The same dose is recommended in children. The blood sample for the assay is taken early the following morning (7:30-8:00 a.m.). The plasma should be frozen as soon as possible. The patient is then given a prophylactic dose of 50 mg cortisone acetate.
- Normal values will depend on the method used to determine ACTH and 11‑desoxycortisol levels. An intact ACTH reserve is generally indicated by an increase in plasma ACTH to at least 44 pmol/L (200 ng/L) or by an increase in 11‑desoxycortisol to over 0.2 µmol/L (70µg/L). Patients with suspected adrenocortical insufficiency should be hospitalized overnight as a precautionary measure.
- Day 1: Control period - Collect 24-hour urine for measurement of 17-OHCS or 17-KGS.
- Day 2: ACTH test to determine the ability of adrenals to respond - Standard ACTH test such as infusion of 50 units ACTH over 8 hours and measurement of 24-hour urinary steroids. If results indicate adequate response, the Metopirone test may proceed.
- Day 3-4: Rest period.
- Day 5: Administration of Metopirone: Recommended with milk or snack.
Dosage:
Children: 15 mg/kg orally every 4 hours for 6 doses. A minimal single dose of 250 mg is recommended.
- Dosage:
Children: 15 mg/kg orally every 4 hours for 6 doses. A minimal single dose of 250 mg is recommended.
- Children: 15 mg/kg orally every 4 hours for 6 doses. A minimal single dose of 250 mg is recommended.
- Day 6: After administration of Metopirone - Determination of 24-hour urinary steroids for effect.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metyrapone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metyrapone in pediatric patients.
# Contraindications
- Metopirone is contraindicated in patients with adrenal cortical insufficiency, or hypersensitivity to Metopirone or to any of its excipients.
# Warnings
- Metopirone may induce acute adrenal insufficiency in patients with reduced adrenal secretory capacity.
# Adverse Reactions
## Clinical Trials Experience
- Cardiovascular System: Hypotension.
- Gastrointestinal System: Nausea, vomiting, abdominal discomfort or pain.
- Central Nervous System: Headache, dizziness, sedation.
- Dermatologic System: Allergic rash.
- Hematologic System: Rarely, decreased white blood cell count or bone marrow depression.
## Postmarketing Experience
There is limited information regarding Metyrapone Postmarketing Experience in the drug label.
# Drug Interactions
- Drugs affecting pituitary or adrenocortical function, including all corticosteroid therapy, must be discontinued prior to and during testing with Metopirone.
- The metabolism of Metopirone is accelerated by phenytoin; therefore, results of the test may be inaccurate in patients taking phenytoin within two weeks before. A subnormal response may occur in patients on estrogen therapy.
- Metopirone inhibits the glucuronidation of acetaminophen and could possibly potentiate acetaminophen toxicity.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- A subnormal response to Metopirone may occur in pregnant women. Animal reproduction studies have not been conducted with Metopirone. The Metopirone test was administered to 20 pregnant women in their second and third trimester of pregnancy and evidence was found that the fetal pituitary responded to the enzymatic block. It is not known if Metopirone can affect reproduction capacity. Metopirone should be given to a pregnant woman only if clearly needed.
- Animal reproduction studies adequate to evaluate teratogenicity and postnatal development have not been conducted with Metopirone.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Metyrapone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Metyrapone during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Metopirone is administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Metyrapone in pediatric settings.
### Geriatic Use
- Clinical studies of Metopirone did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Metyrapone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Metyrapone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Metyrapone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Metyrapone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Metyrapone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Metyrapone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Metyrapone Administration in the drug label.
### Monitoring
There is limited information regarding Metyrapone Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Metyrapone and IV administrations.
# Overdosage
- One case has been recorded in which a 6‑year‑old girl died after two doses of Metopirone, 2 g.
- Oral LD50 in animals (mg/kg): rats, 521; maximum tolerated intravenous dose in one dog, 300.
- The clinical picture of poisoning with Metopirone is characterized by gastrointestinal symptoms and by signs of acute adrenocortical insufficiency.
- Cardiovascular System: Cardiac arrhythmias, hypotension, dehydration.
- Nervous System and Muscles: Anxiety, confusion, weakness, impairment of consciousness.
- Gastrointestinal System: Nausea, vomiting, epigastric pain, diarrhea.
- Laboratory Findings: Hyponatremia, hypochloremia, hyperkalemia.
- In patients under treatment with insulin or oral antidiabetics, the signs and symptoms of acute poisoning with Metopirone may be aggravated or modified.
- There is no specific antidote. Besides general measures to eliminate the drug and reduce its absorption, a large dose of hydrocortisone should be administered at once, together with saline and glucose infusions.
Surveillance: For a few days blood pressure and fluid and electrolyte balance should be monitored.
# Pharmacology
## Mechanism of Action
- Inhibition of the 11-beta-hydroxylation reaction in the adrenal cortex.
## Structure
- Metopirone, metyrapone USP, is an inhibitor of endogenous adrenal corticosteriod synthesis, available as 250-mg capsules for oral administration. Its chemical name is 2-methyl-1, 2-di-3-pyridyl-1-propanone, and its structural formula is:
## Pharmacodynamics
- The pharmacological effect of Metopirone is to reduce cortisol and corticosterone production by inhibiting the 11-beta-hydroxylation reaction in the adrenal cortex. Removal of the strong inhibitory feedback mechanism exerted by cortisol results in an increase in adrenocorticotropic hormone (ACTH) production by the pituitary. With continued blockade of the enzymatic steps leading to production of cortisol and corticosterone, there is a marked increase in adrenocortical secretion of their immediate precursors, 11-desoxycortisol and desoxycorticosterone, which are weak suppressors of ACTH release, and a corresponding elevation of these steroids in the plasma and of their metabolites in the urine. These metabolites are readily determined by measuring urinary 17‑hydroxycorticosteroids (17-OHCS) or 17-ketogenic steroids (17-KGS). Because of these actions, Metopirone is used as a diagnostic test, with urinary 17-OHCS measured as an index of pituitary ACTH responsiveness. Metopirone may also suppress biosynthesis of aldosterone, resulting in a mild natriuresis.
- The response to Metopirone does not occur immediately. Following oral administration, peak steroid excretion occurs during the subsequent 24-hour period.
## Pharmacokinetics
- Metopirone is absorbed rapidly and well when administered orally as prescribed. Peak plasma concentrations are usually reached 1 hour after administration. After administration of 750 mg, mean peak plasma concentrations are 3.7 μg/mL, falling to 0.5 μg/mL 4 hours after administration. Following a single 2000-mg dose, mean peak plasma concentrations of metyrapone in plasma are 7.3 μg/mL.
- The major biotransformation is reduction of the ketone to metyrapol, an active alcohol metabolite. Eight hours after a single oral dose, the ratio of metyrapone to metyrapol in the plasma is 1:1.5. Metyrapone and metyrapol are both conjugated with glucuronide.
- Metyrapone is rapidly eliminated from the plasma. The mean ± SD terminal elimination half‑life is 1.9 ± 0.7 hours. Metyrapol takes about twice as long as metyrapone to be eliminated from the plasma. After administration of 4.5 g metyrapone (750 mg every 4 hours), an average of 5.3% of the dose was excreted in the urine in the form of metyrapone (9.2% free and 90.8% as glucuronide) and 38.5% in the form of metyrapol (8.1% free and 91.9% as glucuronide) within 72 hours after the first dose was given.
## Nonclinical Toxicology
There is limited information regarding Metyrapone Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Metyrapone Clinical Studies in the drug label.
# How Supplied
Capsules 250 mg -- soft gelatin, white to yellowish‑white, oblong, opaque, imprinted HRA on one side in red ink.
Bottles of 18............................................................................................NDC 76336‑455‑18
## Storage
- Do not store above 30ºC (86ºF).
- Protect from moisture and heat.
- Dispense in tight container (USP
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Metyrapone Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Metyrapone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Metopirone
- Metopiron
# Look-Alike Drug Names
There is limited information regarding Metyrapone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Metyrapone
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
Metyrapone is a inhibitor of endogenous adrenal corticosteriod synthesis that is FDA approved for the diagnosis of adrenal insufficiency and testing hypothalamic‑pituitary ACTH function. Common adverse reactions include acute adrenal insufficiency in patients with reduced adrenal secretory capacity.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- This test, usually given on an outpatient basis, determines plasma 11-desoxycortisol and/or ACTH levels after a single dose of Metopirone. The patient is given 30 mg/kg (maximum 3 g Metopirone) at midnight with yogurt or milk. The same dose is recommended in children. The blood sample for the assay is taken early the following morning (7:30-8:00 a.m.). The plasma should be frozen as soon as possible. The patient is then given a prophylactic dose of 50 mg cortisone acetate.
- Normal values will depend on the method used to determine ACTH and 11‑desoxycortisol levels. An intact ACTH reserve is generally indicated by an increase in plasma ACTH to at least 44 pmol/L (200 ng/L) or by an increase in 11‑desoxycortisol to over 0.2 µmol/L (70µg/L). Patients with suspected adrenocortical insufficiency should be hospitalized overnight as a precautionary measure.
- Day 1: Control period - Collect 24-hour urine for measurement of 17-OHCS or 17-KGS.
- Day 2: ACTH test to determine the ability of adrenals to respond - Standard ACTH test such as infusion of 50 units ACTH over 8 hours and measurement of 24-hour urinary steroids. If results indicate adequate response, the Metopirone test may proceed.
- Day 3-4: Rest period.
- Day 5: Administration of Metopirone: Recommended with milk or snack.
Dosage:
Adults: 750 mg orally, every 4 hours for 6 doses. A single dose is approximately equivalent to 15 mg/kg.
- Dosage:
Adults: 750 mg orally, every 4 hours for 6 doses. A single dose is approximately equivalent to 15 mg/kg.
- Adults: 750 mg orally, every 4 hours for 6 doses. A single dose is approximately equivalent to 15 mg/kg.
- Day 6: After administration of Metopirone - Determination of 24-hour urinary steroids for effect.
The normal 24-hour urinary excretion of 17-OHCS ranges from 3 to 12 mg. Following continuous intravenous infusion of 50 units ACTH over a period of 8 hours, 17-OHCS excretion increases to 15 to 45 mg per 24 hours.
- Metopirone
Normal response: In patients with a normally functioning pituitary, administration of Metopirone is followed by a two‑ to four‑fold increase of 17-OHCS excretion or doubling of 17-KGS excretion.
Subnormal response: Subnormal response in patients without adrenal insufficiency is indicative of some degree of impairment of pituitary function, either panhypopituitarism or partial hypopituitarism (limited pituitary reserve).
Panhypopituitarism is readily diagnosed by the classical clinical and chemical evidences of hypogonadism, hypothyroidism, and hypoadrenocorticism. These patients usually have subnormal basal urinary steroid levels. Depending upon the duration of the disease and degree of adrenal atrophy, they may fail to respond to exogenous ACTH in the normal manner. Administration of Metopirone is not essential in the diagnosis, but if given, it will not induce an appreciable increase in urinary steroids.
Partial hypopituitarism or limited pituitary reserve is the more difficult diagnosis as these patients do not present the classical signs and symptoms of hypopituitarism. Measurements of target organ functions often are normal under basal conditions. The response to exogenous ACTH is usually normal, producing the expected rise of urinary steroids (17-OHCS or 17-KGS). The response, however, to Metopirone is subnormal; that is, no significant increase in 17‑OHCS or 17‑KGS excretion occurs.
- Normal response: In patients with a normally functioning pituitary, administration of Metopirone is followed by a two‑ to four‑fold increase of 17-OHCS excretion or doubling of 17-KGS excretion.
- Subnormal response: Subnormal response in patients without adrenal insufficiency is indicative of some degree of impairment of pituitary function, either panhypopituitarism or partial hypopituitarism (limited pituitary reserve).
Panhypopituitarism is readily diagnosed by the classical clinical and chemical evidences of hypogonadism, hypothyroidism, and hypoadrenocorticism. These patients usually have subnormal basal urinary steroid levels. Depending upon the duration of the disease and degree of adrenal atrophy, they may fail to respond to exogenous ACTH in the normal manner. Administration of Metopirone is not essential in the diagnosis, but if given, it will not induce an appreciable increase in urinary steroids.
Partial hypopituitarism or limited pituitary reserve is the more difficult diagnosis as these patients do not present the classical signs and symptoms of hypopituitarism. Measurements of target organ functions often are normal under basal conditions. The response to exogenous ACTH is usually normal, producing the expected rise of urinary steroids (17-OHCS or 17-KGS). The response, however, to Metopirone is subnormal; that is, no significant increase in 17‑OHCS or 17‑KGS excretion occurs.
- Panhypopituitarism is readily diagnosed by the classical clinical and chemical evidences of hypogonadism, hypothyroidism, and hypoadrenocorticism. These patients usually have subnormal basal urinary steroid levels. Depending upon the duration of the disease and degree of adrenal atrophy, they may fail to respond to exogenous ACTH in the normal manner. Administration of Metopirone is not essential in the diagnosis, but if given, it will not induce an appreciable increase in urinary steroids.
- Partial hypopituitarism or limited pituitary reserve is the more difficult diagnosis as these patients do not present the classical signs and symptoms of hypopituitarism. Measurements of target organ functions often are normal under basal conditions. The response to exogenous ACTH is usually normal, producing the expected rise of urinary steroids (17-OHCS or 17-KGS). The response, however, to Metopirone is subnormal; that is, no significant increase in 17‑OHCS or 17‑KGS excretion occurs.
- This failure to respond to metyrapone may be interpreted as evidence of impaired pituitary‑adrenal reserve. In view of the normal response to exogenous ACTH, the failure to respond to metyrapone is inferred to be related to a defect in the CNS‑pituitary mechanisms which normally regulate ACTH secretions. Presumably the ACTH secreting mechanisms of these individuals are already working at their maximal rates to meet everyday conditions and possess limited “reserve” capacities to secrete additional ACTH either in response to stress or to decreased cortisol levels occurring as a result of metyrapone administration. Subnormal response in patients with Cushing’s syndrome is suggestive of either autonomous adrenal tumors that suppress the ACTH-releasing capacity of the pituitary or non endocrine ACTH-secreting tumors.
- Excessive response: An excessive excretion of 17-OHCS or 17-KGS after administration of Metopirone is suggestive of Cushing’s syndrome associated with adrenal hyperplasia. These patients have an elevated excretion of urinary corticosteroids under basal conditions and will often, but not invariably, show a “supernormal” response to ACTH and also to Metopirone, excreting more than 35 mg per 24 hours of either 17-OHCS or 17-KGS.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metyrapone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metyrapone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- This test, usually given on an outpatient basis, determines plasma 11-desoxycortisol and/or ACTH levels after a single dose of Metopirone. The patient is given 30 mg/kg (maximum 3 g Metopirone) at midnight with yogurt or milk. The same dose is recommended in children. The blood sample for the assay is taken early the following morning (7:30-8:00 a.m.). The plasma should be frozen as soon as possible. The patient is then given a prophylactic dose of 50 mg cortisone acetate.
- Normal values will depend on the method used to determine ACTH and 11‑desoxycortisol levels. An intact ACTH reserve is generally indicated by an increase in plasma ACTH to at least 44 pmol/L (200 ng/L) or by an increase in 11‑desoxycortisol to over 0.2 µmol/L (70µg/L). Patients with suspected adrenocortical insufficiency should be hospitalized overnight as a precautionary measure.
- Day 1: Control period - Collect 24-hour urine for measurement of 17-OHCS or 17-KGS.
- Day 2: ACTH test to determine the ability of adrenals to respond - Standard ACTH test such as infusion of 50 units ACTH over 8 hours and measurement of 24-hour urinary steroids. If results indicate adequate response, the Metopirone test may proceed.
- Day 3-4: Rest period.
- Day 5: Administration of Metopirone: Recommended with milk or snack.
Dosage:
Children: 15 mg/kg orally every 4 hours for 6 doses. A minimal single dose of 250 mg is recommended.
- Dosage:
Children: 15 mg/kg orally every 4 hours for 6 doses. A minimal single dose of 250 mg is recommended.
- Children: 15 mg/kg orally every 4 hours for 6 doses. A minimal single dose of 250 mg is recommended.
- Day 6: After administration of Metopirone - Determination of 24-hour urinary steroids for effect.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metyrapone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metyrapone in pediatric patients.
# Contraindications
- Metopirone is contraindicated in patients with adrenal cortical insufficiency, or hypersensitivity to Metopirone or to any of its excipients.
# Warnings
- Metopirone may induce acute adrenal insufficiency in patients with reduced adrenal secretory capacity.
# Adverse Reactions
## Clinical Trials Experience
- Cardiovascular System: Hypotension.
- Gastrointestinal System: Nausea, vomiting, abdominal discomfort or pain.
- Central Nervous System: Headache, dizziness, sedation.
- Dermatologic System: Allergic rash.
- Hematologic System: Rarely, decreased white blood cell count or bone marrow depression.
## Postmarketing Experience
There is limited information regarding Metyrapone Postmarketing Experience in the drug label.
# Drug Interactions
- Drugs affecting pituitary or adrenocortical function, including all corticosteroid therapy, must be discontinued prior to and during testing with Metopirone.
- The metabolism of Metopirone is accelerated by phenytoin; therefore, results of the test may be inaccurate in patients taking phenytoin within two weeks before. A subnormal response may occur in patients on estrogen therapy.
- Metopirone inhibits the glucuronidation of acetaminophen and could possibly potentiate acetaminophen toxicity.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- A subnormal response to Metopirone may occur in pregnant women. Animal reproduction studies have not been conducted with Metopirone. The Metopirone test was administered to 20 pregnant women in their second and third trimester of pregnancy and evidence was found that the fetal pituitary responded to the enzymatic block. It is not known if Metopirone can affect reproduction capacity. Metopirone should be given to a pregnant woman only if clearly needed.
- Animal reproduction studies adequate to evaluate teratogenicity and postnatal development have not been conducted with Metopirone.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Metyrapone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Metyrapone during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Metopirone is administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Metyrapone in pediatric settings.
### Geriatic Use
- Clinical studies of Metopirone did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Metyrapone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Metyrapone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Metyrapone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Metyrapone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Metyrapone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Metyrapone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Metyrapone Administration in the drug label.
### Monitoring
There is limited information regarding Metyrapone Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Metyrapone and IV administrations.
# Overdosage
- One case has been recorded in which a 6‑year‑old girl died after two doses of Metopirone, 2 g.
- Oral LD50 in animals (mg/kg): rats, 521; maximum tolerated intravenous dose in one dog, 300.
- The clinical picture of poisoning with Metopirone is characterized by gastrointestinal symptoms and by signs of acute adrenocortical insufficiency.
- Cardiovascular System: Cardiac arrhythmias, hypotension, dehydration.
- Nervous System and Muscles: Anxiety, confusion, weakness, impairment of consciousness.
- Gastrointestinal System: Nausea, vomiting, epigastric pain, diarrhea.
- Laboratory Findings: Hyponatremia, hypochloremia, hyperkalemia.
- In patients under treatment with insulin or oral antidiabetics, the signs and symptoms of acute poisoning with Metopirone may be aggravated or modified.
- There is no specific antidote. Besides general measures to eliminate the drug and reduce its absorption, a large dose of hydrocortisone should be administered at once, together with saline and glucose infusions.
Surveillance: For a few days blood pressure and fluid and electrolyte balance should be monitored.
# Pharmacology
## Mechanism of Action
- Inhibition of the 11-beta-hydroxylation reaction in the adrenal cortex.
## Structure
- Metopirone, metyrapone USP, is an inhibitor of endogenous adrenal corticosteriod synthesis, available as 250-mg capsules for oral administration. Its chemical name is 2-methyl-1, 2-di-3-pyridyl-1-propanone, and its structural formula is:
## Pharmacodynamics
- The pharmacological effect of Metopirone is to reduce cortisol and corticosterone production by inhibiting the 11-beta-hydroxylation reaction in the adrenal cortex. Removal of the strong inhibitory feedback mechanism exerted by cortisol results in an increase in adrenocorticotropic hormone (ACTH) production by the pituitary. With continued blockade of the enzymatic steps leading to production of cortisol and corticosterone, there is a marked increase in adrenocortical secretion of their immediate precursors, 11-desoxycortisol and desoxycorticosterone, which are weak suppressors of ACTH release, and a corresponding elevation of these steroids in the plasma and of their metabolites in the urine. These metabolites are readily determined by measuring urinary 17‑hydroxycorticosteroids (17-OHCS) or 17-ketogenic steroids (17-KGS). Because of these actions, Metopirone is used as a diagnostic test, with urinary 17-OHCS measured as an index of pituitary ACTH responsiveness. Metopirone may also suppress biosynthesis of aldosterone, resulting in a mild natriuresis.
- The response to Metopirone does not occur immediately. Following oral administration, peak steroid excretion occurs during the subsequent 24-hour period.
## Pharmacokinetics
- Metopirone is absorbed rapidly and well when administered orally as prescribed. Peak plasma concentrations are usually reached 1 hour after administration. After administration of 750 mg, mean peak plasma concentrations are 3.7 μg/mL, falling to 0.5 μg/mL 4 hours after administration. Following a single 2000-mg dose, mean peak plasma concentrations of metyrapone in plasma are 7.3 μg/mL.
- The major biotransformation is reduction of the ketone to metyrapol, an active alcohol metabolite. Eight hours after a single oral dose, the ratio of metyrapone to metyrapol in the plasma is 1:1.5. Metyrapone and metyrapol are both conjugated with glucuronide.
- Metyrapone is rapidly eliminated from the plasma. The mean ± SD terminal elimination half‑life is 1.9 ± 0.7 hours. Metyrapol takes about twice as long as metyrapone to be eliminated from the plasma. After administration of 4.5 g metyrapone (750 mg every 4 hours), an average of 5.3% of the dose was excreted in the urine in the form of metyrapone (9.2% free and 90.8% as glucuronide) and 38.5% in the form of metyrapol (8.1% free and 91.9% as glucuronide) within 72 hours after the first dose was given.
## Nonclinical Toxicology
There is limited information regarding Metyrapone Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Metyrapone Clinical Studies in the drug label.
# How Supplied
Capsules 250 mg -- soft gelatin, white to yellowish‑white, oblong, opaque, imprinted HRA on one side in red ink.
Bottles of 18............................................................................................NDC 76336‑455‑18
## Storage
- Do not store above 30ºC (86ºF).
- Protect from moisture and heat.
- Dispense in tight container (USP
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Metyrapone Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Metyrapone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Metopirone
- Metopiron
# Look-Alike Drug Names
There is limited information regarding Metyrapone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Metopiron | |
49c0a3a24482f6a7e8b5da9098e5628c5f668d31 | wikidoc | Metyrosine | Metyrosine
# 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
Metyrosine is an antihypertensive and tyrosine hydroxylase inhibitor that is FDA approved for the treatment of pheochromocytoma. Common adverse reactions include diarrhea, sedation and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Metyrosine is indicated in the treatment of patients with pheochromocytoma for:
- Preoperative preparation of patients for surgery
- Management of patients when surgery is contraindicated
- Chronic treatment of patients with malignant pheochromocytoma.
- Metyrosine is not recommended for the control of essential hypertension.
### Dosing Information
- The recommended initial dosage of Metyrosine for adults and children 12 years of age and older is 250 mg orally four times daily. This may be increased by 250 mg to 500 mg every day to a maximum of 4.0 g/day in divided doses. When used for preoperative preparation, the optimally effective dosage of Metyrosine should be given for at least five to seven days.
- Optimally effective dosages of Metyrosine usually are between 2.0 and 3.0 g/day, and the dose should be titrated by monitoring clinical symptoms and catecholamine excretion. In patients who are hypertensive, dosage should be titrated to achieve normalization of blood pressure and control of clinical symptoms. In patients who are usually normotensive, dosage should be titrated to the amount that will reduce urinary
metanephrines and/or vanillylmandelic acid by 50 percent or more.
- If patients are not adequately controlled by the use of Metyrosine, an alpha-adrenergic blocking agent (phenoxybenzamine) should be added.
- Use of Metyrosine in children under 12 years of age has been limited and a dosage schedule for this age group cannot be given.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metyrosine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metyrosine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Metyrosine 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 Metyrosine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metyrosine in pediatric patients.
# Contraindications
- Metyrosine is contraindicated in persons known to be hypersensitive to this compound.
# Warnings
- When Metyrosine is used preoperatively, alone or especially in combination with alpha-adrenergic blocking drugs, adequate intravascular volume must be maintained intraoperatively (especially after tumor removal) and postoperatively to avoid hypotension and decreased perfusion of vital organs resulting from vasodilatation and expanded volume capacity. Following tumor removal, large volumes of plasma may be needed to maintain blood pressure and central venous pressure within the normal range.
- In addition, life-threatening arrhythmias may occur during anesthesia and surgery, and may require treatment with a beta-blocker or lidocaine. During surgery, patients should have continuous monitoring of blood pressure and electrocardiogram.
- While the preoperative use of Metyrosine in patients with pheochromocytoma is thought to decrease intraoperative problems with blood pressure control, Metyrosine does not eliminate the danger of hypertensive crises or arrhythmias during manipulation of the tumor, and the alpha-adrenergic blocking drug, phentolamine, may be needed.
- Metyrosine may add to the sedative effects of alcohol and other CNS depressants, e.g., hypnotics, sedatives, and tranquilizers.
### PRECAUTIONS
- Crystalluria and urolithiasis have been found in dogs treated with Metyrosine at doses similar to those used in humans, and crystalluria has also been observed in a few patients. To minimize the risk of crystalluria, patients should be urged to maintain water intake sufficient to achieve a daily urine volume of 2000 mL or more, particularly when doses greater than 2 g per day are given. Routine examination of the urine should be carried out. Metyrosine will crystallize as needles or rods. If metyrosine crystalluria occurs, fluid intake should be increased further. If crystalluria persists, the dosage should be reduced or the drug discontinued.
- The total human experience with the drug is quite limited and few patients have been studied long-term. Chronic animal studies have not been carried out. Therefore, suitable laboratory tests should be carried out periodically in patients requiring prolonged use of Metyrosine and caution should be observed in patients with impaired hepatic or renal function.
# Adverse Reactions
## Clinical Trials Experience
- The most common adverse reaction to Metyrosine is moderate to severe sedation, which has been observed in almost all patients. It occurs at both low and high dosages. Sedative effects begin within the first 24 hours of therapy, are maximal after two to three days, and tend to wane during the next few days. Sedation usually is not obvious after one week unless the dosage is increased, but at dosages greater than 2000 mg/day some degree of sedation or fatigue may persist.
- In most patients who experience sedation, temporary changes in sleep pattern occur following withdrawal of the drug. Changes consist of insomnia that may last for two or three days and feelings of increased alertness and ambition. Even patients who do not experience sedation while on Metyrosine may report symptoms of psychic stimulation when the drug is discontinued.
- Extrapyramidal signs such as drooling, speech difficulty, and tremor have been reported in approximately 10 percent of patients. These occasionally have been accompanied by trismus and frank parkinsonism.
- Anxiety and psychic disturbances such as depression, hallucinations, disorientation, and confusion may occur. These effects seem to be dose-dependent and may disappear with reduction of dosage.
- Diarrhea occurs in about 10 percent of patients and may be severe. Anti-diarrheal agents may be required if continuation of Metyrosine is necessary.
- Infrequently, slight swelling of the breast, galactorrhea, nasal stuffiness, decreased salivation, dry mouth, headache, nausea, vomiting, abdominal pain, and impotence or failure of ejaculation may occur. Crystalluria and transient dysuria and hematuria have been observed in a few patients. Hematologic disorders (including eosinophilia, anemia, thrombocytopenia, and thrombocytosis), increased SGOT levels, peripheral edema, and hypersensitivity reactions such as urticaria and pharyngeal edema have been reported rarely.
## Postmarketing Experience
There is limited information regarding Metyrosine Postmarketing Experience in the drug label.
# Drug Interactions
- Caution should be observed in administering Metyrosine to patients receiving phenothiazines or haloperidol because the extrapyramidal effects of these drugs can be expected to be potentiated by inhibition of catecholamine synthesis.
- Concurrent use of Metyrosine with alcohol or other CNS depressants can increase their sedative effects.
- Spurious increases in urinary catecholamines may be observed in patients receiving Metyrosine due to the presence of metabolites of the drug.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with Metyrosine. It is also not known whether Metyrosine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Metyrosine should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Metyrosine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Metyrosine during labor and delivery.
### Nursing Mothers
- It is not known whether Metyrosine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Metyrosine is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 12 years have not been established.
### Geriatic Use
- Clinical studies of Metyrosine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Metyrosine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Metyrosine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Metyrosine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Metyrosine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Metyrosine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Metyrosine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Metyrosine Administration in the drug label.
### Monitoring
There is limited information regarding Metyrosine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Metyrosine and IV administrations.
# Overdosage
- Signs of metyrosine overdosage include those central nervous system effects observed in some patients even at low dosages.
- At doses exceeding 2000 mg/day, some degree of sedation or feeling of fatigue may persist. Doses of 2000-4000 mg/day can result in anxiety or agitated depression, neuromuscular effects (including fine tremor of the hands, gross tremor of the trunk, tightening of the jaw with trismus), diarrhea, and decreased salivation with dry mouth.
- Reduction of drug dose or cessation of treatment results in the disappearance of these symptoms.
- The acute toxicity of metyrosine was 442 mg/kg and 752 mg/kg in the female mouse and rat respectively.
# Pharmacology
## Mechanism of Action
- Metyrosine inhibits tyrosine hydroxylase, which catalyzes the first transformation in catecholamine biosynthesis, i.e., the conversion of tyrosine to dihydroxyphenylalanine (DOPA). Because the first step is also the rate-limiting step, blockade of tyrosine hydroxylase activity results in decreased endogenous levels of catecholamines, usually measured as decreased urinary excretion of catecholamines and their metabolites.
## Structure
Metyrosine1 (Metyrosine) is (–)-α-methyl-L-tyrosine or (α-MPT). It has the following structural formula:
- Metyrosine is a white, crystalline compound of molecular weight 195. It is very slightly soluble in water, acetone, and methanol, and insoluble in chloroform and benzene. It is soluble in acidic aqueous solutions. It is also soluble in alkaline aqueous solutions, but is subject to oxidative degradation under these conditions.
- Metyrosine is supplied as capsules, for oral administration. Each capsule contains 250 mg metyrosine. Inactive ingredients are colloidal silicon dioxide, gelatin, hydroxypropyl cellulose, magnesium stearate, titanium dioxide, and FD&C Blue 2.
## Pharmacodynamics
There is limited information regarding Metyrosine Pharmacodynamics in the drug label.
## Pharmacokinetics
- In patients with pheochromocytoma, who produce excessive amounts of norepinephrine and epinephrine, administration of one to four grams of Metyrosine per day has reduced catecholamine biosynthesis from about 35 to 80 percent as measured by the total excretion of catecholamines and their metabolites (metanephrine and vanillylmandelic acid). The maximum biochemical effect usually occurs within two to three days, and the urinary concentration of catecholamines and their metabolites usually returns to pretreatment levels within three to four days after Metyrosine is discontinued. In some patients the total excretion of catecholamines and catecholamine metabolites may be lowered to normal or near normal levels (less than 10 mg/24 hours). In most patients the duration of treatment has been two to eight weeks, but several patients have received Metyrosine for periods of one to 10 years. Most patients with pheochromocytoma treated with Metyrosine experience decreased frequency and severity of hypertensive attacks with their associated headache, nausea, sweating, and tachycardia. In patients who respond, blood pressure decreases progressively during the first two days of therapy with Metyrosine; after withdrawal, blood pressure usually increases gradually to pretreatment values within two to three days.
- Metyrosine is well absorbed from the gastrointestinal tract. From 53 to 88 percent (mean 69 percent) was recovered in the urine as unchanged drug following maintenance oral doses of 600 to 4000 mg/24 hours in patients with pheochromocytoma or essential hypertension. Less than 1% of the dose was recovered as catechol metabolites. These metabolites are probably not present in sufficient amounts to contribute to the biochemical effects of metyrosine. The quantities excreted, however, are sufficient to interfere with accurate determination of urinary catecholamines determined by routine techniques.
- Plasma half-life of metyrosine determined over an 8-hour period after single oral doses was 3-3.7 hours in three patients.
## Nonclinical Toxicology
- Long-term carcinogenic studies in animals and studies on mutagenesis and impairment of fertility have not been performed with metyrosine.
# Clinical Studies
There is limited information regarding Metyrosine Clinical Studies in the drug label.
# How Supplied
Capsules Metyrosine, 250 mg, are opaque, two-toned blue capsules coded Aton 305 on one side and Metyrosine on the other. They are supplied as follows:
NDC 25010-305-15 bottles of 100.
## Storage
There is limited information regarding Metyrosine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
Metyrosine® 250 mg
(Metyrosine)
NDC 25010-305-15
Distributed by:
ATON PHARMA, INC.
LAWRENCEVILLE, NJ 08648, USA
Rx only
USUAL ADULT DOSAGE:
See accompanying circular.
This is a bulk package and not intended
for dispensing.
Package not child resistant.
Dispense in a well-closed container.
100 Capsules
# Patient Counseling Information
- When receiving Metyrosine, patients should be warned about engaging in activities requiring mental alertness and motor coordination, such as driving a motor vehicle or operating machinery. Metyrosine may have additive sedative effects with alcohol and other CNS depressants, e.g., hypnotics, sedatives, and tranquilizers.
- Patients should be advised to maintain a liberal fluid intake.
# Precautions with Alcohol
Alcohol-Metyrosine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Demser®
# Look-Alike Drug Names
There is limited information regarding Metyrosine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Metyrosine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Metyrosine is an antihypertensive and tyrosine hydroxylase inhibitor that is FDA approved for the treatment of pheochromocytoma. Common adverse reactions include diarrhea, sedation and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Metyrosine is indicated in the treatment of patients with pheochromocytoma for:
- Preoperative preparation of patients for surgery
- Management of patients when surgery is contraindicated
- Chronic treatment of patients with malignant pheochromocytoma.
- Metyrosine is not recommended for the control of essential hypertension.
### Dosing Information
- The recommended initial dosage of Metyrosine for adults and children 12 years of age and older is 250 mg orally four times daily. This may be increased by 250 mg to 500 mg every day to a maximum of 4.0 g/day in divided doses. When used for preoperative preparation, the optimally effective dosage of Metyrosine should be given for at least five to seven days.
- Optimally effective dosages of Metyrosine usually are between 2.0 and 3.0 g/day, and the dose should be titrated by monitoring clinical symptoms and catecholamine excretion. In patients who are hypertensive, dosage should be titrated to achieve normalization of blood pressure and control of clinical symptoms. In patients who are usually normotensive, dosage should be titrated to the amount that will reduce urinary
metanephrines and/or vanillylmandelic acid by 50 percent or more.
- If patients are not adequately controlled by the use of Metyrosine, an alpha-adrenergic blocking agent (phenoxybenzamine) should be added.
- Use of Metyrosine in children under 12 years of age has been limited and a dosage schedule for this age group cannot be given.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metyrosine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metyrosine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Metyrosine 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 Metyrosine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metyrosine in pediatric patients.
# Contraindications
- Metyrosine is contraindicated in persons known to be hypersensitive to this compound.
# Warnings
- When Metyrosine is used preoperatively, alone or especially in combination with alpha-adrenergic blocking drugs, adequate intravascular volume must be maintained intraoperatively (especially after tumor removal) and postoperatively to avoid hypotension and decreased perfusion of vital organs resulting from vasodilatation and expanded volume capacity. Following tumor removal, large volumes of plasma may be needed to maintain blood pressure and central venous pressure within the normal range.
- In addition, life-threatening arrhythmias may occur during anesthesia and surgery, and may require treatment with a beta-blocker or lidocaine. During surgery, patients should have continuous monitoring of blood pressure and electrocardiogram.
- While the preoperative use of Metyrosine in patients with pheochromocytoma is thought to decrease intraoperative problems with blood pressure control, Metyrosine does not eliminate the danger of hypertensive crises or arrhythmias during manipulation of the tumor, and the alpha-adrenergic blocking drug, phentolamine, may be needed.
- Metyrosine may add to the sedative effects of alcohol and other CNS depressants, e.g., hypnotics, sedatives, and tranquilizers.
### PRECAUTIONS
- Crystalluria and urolithiasis have been found in dogs treated with Metyrosine at doses similar to those used in humans, and crystalluria has also been observed in a few patients. To minimize the risk of crystalluria, patients should be urged to maintain water intake sufficient to achieve a daily urine volume of 2000 mL or more, particularly when doses greater than 2 g per day are given. Routine examination of the urine should be carried out. Metyrosine will crystallize as needles or rods. If metyrosine crystalluria occurs, fluid intake should be increased further. If crystalluria persists, the dosage should be reduced or the drug discontinued.
- The total human experience with the drug is quite limited and few patients have been studied long-term. Chronic animal studies have not been carried out. Therefore, suitable laboratory tests should be carried out periodically in patients requiring prolonged use of Metyrosine and caution should be observed in patients with impaired hepatic or renal function.
# Adverse Reactions
## Clinical Trials Experience
- The most common adverse reaction to Metyrosine is moderate to severe sedation, which has been observed in almost all patients. It occurs at both low and high dosages. Sedative effects begin within the first 24 hours of therapy, are maximal after two to three days, and tend to wane during the next few days. Sedation usually is not obvious after one week unless the dosage is increased, but at dosages greater than 2000 mg/day some degree of sedation or fatigue may persist.
- In most patients who experience sedation, temporary changes in sleep pattern occur following withdrawal of the drug. Changes consist of insomnia that may last for two or three days and feelings of increased alertness and ambition. Even patients who do not experience sedation while on Metyrosine may report symptoms of psychic stimulation when the drug is discontinued.
- Extrapyramidal signs such as drooling, speech difficulty, and tremor have been reported in approximately 10 percent of patients. These occasionally have been accompanied by trismus and frank parkinsonism.
- Anxiety and psychic disturbances such as depression, hallucinations, disorientation, and confusion may occur. These effects seem to be dose-dependent and may disappear with reduction of dosage.
- Diarrhea occurs in about 10 percent of patients and may be severe. Anti-diarrheal agents may be required if continuation of Metyrosine is necessary.
- Infrequently, slight swelling of the breast, galactorrhea, nasal stuffiness, decreased salivation, dry mouth, headache, nausea, vomiting, abdominal pain, and impotence or failure of ejaculation may occur. Crystalluria and transient dysuria and hematuria have been observed in a few patients. Hematologic disorders (including eosinophilia, anemia, thrombocytopenia, and thrombocytosis), increased SGOT levels, peripheral edema, and hypersensitivity reactions such as urticaria and pharyngeal edema have been reported rarely.
## Postmarketing Experience
There is limited information regarding Metyrosine Postmarketing Experience in the drug label.
# Drug Interactions
- Caution should be observed in administering Metyrosine to patients receiving phenothiazines or haloperidol because the extrapyramidal effects of these drugs can be expected to be potentiated by inhibition of catecholamine synthesis.
- Concurrent use of Metyrosine with alcohol or other CNS depressants can increase their sedative effects.
- Spurious increases in urinary catecholamines may be observed in patients receiving Metyrosine due to the presence of metabolites of the drug.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with Metyrosine. It is also not known whether Metyrosine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Metyrosine should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Metyrosine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Metyrosine during labor and delivery.
### Nursing Mothers
- It is not known whether Metyrosine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Metyrosine is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 12 years have not been established.
### Geriatic Use
- Clinical studies of Metyrosine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Metyrosine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Metyrosine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Metyrosine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Metyrosine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Metyrosine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Metyrosine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Metyrosine Administration in the drug label.
### Monitoring
There is limited information regarding Metyrosine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Metyrosine and IV administrations.
# Overdosage
- Signs of metyrosine overdosage include those central nervous system effects observed in some patients even at low dosages.
- At doses exceeding 2000 mg/day, some degree of sedation or feeling of fatigue may persist. Doses of 2000-4000 mg/day can result in anxiety or agitated depression, neuromuscular effects (including fine tremor of the hands, gross tremor of the trunk, tightening of the jaw with trismus), diarrhea, and decreased salivation with dry mouth.
- Reduction of drug dose or cessation of treatment results in the disappearance of these symptoms.
- The acute toxicity of metyrosine was 442 mg/kg and 752 mg/kg in the female mouse and rat respectively.
# Pharmacology
## Mechanism of Action
- Metyrosine inhibits tyrosine hydroxylase, which catalyzes the first transformation in catecholamine biosynthesis, i.e., the conversion of tyrosine to dihydroxyphenylalanine (DOPA). Because the first step is also the rate-limiting step, blockade of tyrosine hydroxylase activity results in decreased endogenous levels of catecholamines, usually measured as decreased urinary excretion of catecholamines and their metabolites.
## Structure
Metyrosine1 (Metyrosine) is (–)-α-methyl-L-tyrosine or (α-MPT). It has the following structural formula:
- Metyrosine is a white, crystalline compound of molecular weight 195. It is very slightly soluble in water, acetone, and methanol, and insoluble in chloroform and benzene. It is soluble in acidic aqueous solutions. It is also soluble in alkaline aqueous solutions, but is subject to oxidative degradation under these conditions.
- Metyrosine is supplied as capsules, for oral administration. Each capsule contains 250 mg metyrosine. Inactive ingredients are colloidal silicon dioxide, gelatin, hydroxypropyl cellulose, magnesium stearate, titanium dioxide, and FD&C Blue 2.
## Pharmacodynamics
There is limited information regarding Metyrosine Pharmacodynamics in the drug label.
## Pharmacokinetics
- In patients with pheochromocytoma, who produce excessive amounts of norepinephrine and epinephrine, administration of one to four grams of Metyrosine per day has reduced catecholamine biosynthesis from about 35 to 80 percent as measured by the total excretion of catecholamines and their metabolites (metanephrine and vanillylmandelic acid). The maximum biochemical effect usually occurs within two to three days, and the urinary concentration of catecholamines and their metabolites usually returns to pretreatment levels within three to four days after Metyrosine is discontinued. In some patients the total excretion of catecholamines and catecholamine metabolites may be lowered to normal or near normal levels (less than 10 mg/24 hours). In most patients the duration of treatment has been two to eight weeks, but several patients have received Metyrosine for periods of one to 10 years. Most patients with pheochromocytoma treated with Metyrosine experience decreased frequency and severity of hypertensive attacks with their associated headache, nausea, sweating, and tachycardia. In patients who respond, blood pressure decreases progressively during the first two days of therapy with Metyrosine; after withdrawal, blood pressure usually increases gradually to pretreatment values within two to three days.
- Metyrosine is well absorbed from the gastrointestinal tract. From 53 to 88 percent (mean 69 percent) was recovered in the urine as unchanged drug following maintenance oral doses of 600 to 4000 mg/24 hours in patients with pheochromocytoma or essential hypertension. Less than 1% of the dose was recovered as catechol metabolites. These metabolites are probably not present in sufficient amounts to contribute to the biochemical effects of metyrosine. The quantities excreted, however, are sufficient to interfere with accurate determination of urinary catecholamines determined by routine techniques.
- Plasma half-life of metyrosine determined over an 8-hour period after single oral doses was 3-3.7 hours in three patients.
## Nonclinical Toxicology
- Long-term carcinogenic studies in animals and studies on mutagenesis and impairment of fertility have not been performed with metyrosine.
# Clinical Studies
There is limited information regarding Metyrosine Clinical Studies in the drug label.
# How Supplied
Capsules Metyrosine, 250 mg, are opaque, two-toned blue capsules coded Aton 305 on one side and Metyrosine on the other. They are supplied as follows:
NDC 25010-305-15 bottles of 100.
## Storage
There is limited information regarding Metyrosine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
Metyrosine® 250 mg
(Metyrosine)
NDC 25010-305-15
Distributed by:
ATON PHARMA, INC.
LAWRENCEVILLE, NJ 08648, USA
Rx only
USUAL ADULT DOSAGE:
See accompanying circular.
This is a bulk package and not intended
for dispensing.
Package not child resistant.
Dispense in a well-closed container.
100 Capsules
# Patient Counseling Information
- When receiving Metyrosine, patients should be warned about engaging in activities requiring mental alertness and motor coordination, such as driving a motor vehicle or operating machinery. Metyrosine may have additive sedative effects with alcohol and other CNS depressants, e.g., hypnotics, sedatives, and tranquilizers.
- Patients should be advised to maintain a liberal fluid intake.
# Precautions with Alcohol
Alcohol-Metyrosine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Demser®
# Look-Alike Drug Names
There is limited information regarding Metyrosine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Metyrosine | |
08864781fe903a0c5a654f626943c435d10e924b | wikidoc | Mevastatin | Mevastatin
# Overview
Mevastatin, compactin, ML-236B is a hypolipidemic agent that belongs to the statins class.
It was the first compound isolated in the 1970s during research into HMG-CoA reductase inhibitors produced by a mould Penicillium citrinum.
Nowadays, Mevastatin is not used in therapy of hyperlipidemias because of multiple side effects but it is the only source for production of other statin - pravastatin.
# Mechanisms of Action
Mevastatin inhibits isoprenoid biosynthesis by inhibition of HMG-CoA reductase (Ki for acid form is 1 nM)1 and therefore blocks protein isoprenylation and reduces plasma cholesterol levels in humans. It causes cells to arrest early in the G1 phase.
Mevastatin is a close structural analog of lovastatin and both agents have the same biochemical and pharmacological activities.
Mevastatin is inactive in cell-free assays. In cells however, it is hydrolyzed to the active free acid form by intracellular esterases. | Mevastatin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Mevastatin, compactin, ML-236B is a hypolipidemic agent that belongs to the statins class.
It was the first compound isolated in the 1970s during research into HMG-CoA reductase inhibitors produced by a mould Penicillium citrinum.
Nowadays, Mevastatin is not used in therapy of hyperlipidemias because of multiple side effects but it is the only source for production of other statin - pravastatin.
# Mechanisms of Action
Mevastatin inhibits isoprenoid biosynthesis by inhibition of HMG-CoA reductase (Ki for acid form is 1 nM)1 and therefore blocks protein isoprenylation and reduces plasma cholesterol levels in humans.[1] It causes cells to arrest early in the G1 phase. [2] [3]
Mevastatin is a close structural analog of lovastatin and both agents have the same biochemical and pharmacological activities.
Mevastatin is inactive in cell-free assays. In cells however, it is hydrolyzed to the active free acid form by intracellular esterases. | https://www.wikidoc.org/index.php/Mevacor | |
b23652ecd518fd72db16b5e995cd500defdca0fb | wikidoc | Mexiletine | Mexiletine
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Mexiletine is an antiarrhythmic that is FDA approved for the {{{indicationType}}} of ventricular arrhythmias, such as sustained ventricular tachycardia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include heartburn, nausea, vomiting, coordination problem, dizziness, lightheadedness, tremor, blurred vision, visual disturbance, and anxiety.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Loading Dose
- When rapid control of ventricular arrhythmia is essential, an initial loading dose of 400 mg of mexiletine hydrochloride may be administered, followed by a 200 mg dose in eight hours. Onset of therapeutic effect is usually observed within 30 minutes to two hours.
- Q12H Dosage Schedule
- Some patients responding to mexiletine may be transferred to a 12 hour dosage schedule to improve convenience and compliance. If adequate suppression is achieved on a mexiletine hydrochloride dose of 300 mg or less every eight hours, the same total daily dose may be given in divided doses every 12 hours while carefully monitoring the degree of suppression of ventricular ectopy. This dose may be adjusted up to a maximum of 450 mg every 12 hours to achieve the desired response.
- Transferring to Mexiletine Hydrochloride
- The following dosage schedule, based on theoretical considerations rather than experimental data, is suggested for transferring patients from other Class I oral antiarrhythmic agents to mexiletine: mexiletine hydrochloride treatment may be initiated with a 200 mg dose, and titrated to response as described above, 6 to 12 hours after the last dose of quinidine sulfate, 3 to 6 hours after the last dose of procainamide, 6 to 12 hours after the last dose of disopryramide or 8 to 12 hours after the last dose of tocainide.
- In patients in whom withdrawal of the previous antiarrhythmic agent is likely to produce life-threatening arrhythmias, hospitalization of the patient is recommended.
- When transferring from lidocaine to mexiletine, the lidocaine infusion should be stopped when the first oral dose of mexiletine hydrochloride is administered. The infusion line should be left open until suppression of the arrhythmia appears to be satisfactorily maintained. Consideration should be given to the similarity of the adverse effects of lidocaine and mexiletine and the possibility that they may be additive.
- Dosing Information
- The dosage of mexiletine hydrochloride must be individualized on the basis of response and tolerance, both of which are dose-related. Administration with food or antacid is recommended. Initiate mexiletine therapy with 200 mg every eight hours when rapid control of arrhythmia is not essential. A minimum of two to three days between dose adjustments is recommended. Dose may be adjusted in 50 or 100 mg increments up or down.
- As with any antiarrhythmic drug, clinical and electrocardiographic evaluation (including Holter monitoring if necessary for evaluation) are needed to determine whether the desired antiarrhythmic effect has been obtained and to guide titration and dose adjustment.
- Satisfactory control can be achieved in most patients by 200 to 300 mg given every eight hours with food or antacid. If satisfactory response has not been achieved at 300 mg q8h, and the patient tolerates mexiletine well, a dose of 400 mg q8h may be tried. As the severity of CNS side effects increases with total daily dose, the dose should not exceed 1200 mg/day.
- In general, patients with renal failure will require the usual doses of mexiletine hydrochloride. Patients with severe liver disease, however, may require lower doses and must be monitored closely. Similarly, marked right-sided congestive heart failure can reduce hepatic metabolism and reduce the needed dose. Plasma level may also be affected by certain concomitant drugs
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mexiletine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mexiletine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mexiletine in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- 1.4 to 5 mg/kg (mean 3.3 mg/kg) every 8 hours
# Contraindications
- Mexiletine hydrochloride capsules are contraindicated in the presence of cardiogenic shock or pre-existing second-or third-degree AV block (if no pacemaker is present).
# Warnings
### Precautions
- General
- If a ventricular pacemaker is operative, patients with second or third degree heart block may be treated with mexiletine hydrochloride if continuously monitored. A limited number of patients (45 of 475 in controlled clinical trials) with pre-existing first degree AV block were treated with mexiletine; none of these patients developed second or third degree AV block. Caution should be exercised when it is used in such patients or in patients with pre-existing sinus node dysfunction or intraventricular conduction abnormalities.
- Like other antiarrhythmics mexiletine hydrochloride can cause worsening of arrhythmias. This has been uncommon in patients with less serious arrhythmias (frequent premature beats or nonsustained ventricular tachycardia), but is of greater concern in patients with life-threatening arrhythmias such as sustained ventricular tachycardia. In patients with such arrhythmias subjected to programmed electrical stimulation or to exercise provocation, 10 to 15% of patients had exacerbation of the arrhythmia, a rate not greater than that of other agents.
- Mexiletine should be used with caution in patients with hypotension and severe congestive heart failure because of the potential for aggravating these conditions.
- Since mexiletine is metabolized in the liver, and hepatic impairment has been reported to prolong the elimination half-life of mexiletine, patients with liver disease should be followed carefully while receiving mexiletine. The same caution should be observed in patients with hepatic dysfunction secondary to congestive heart failure.
- Concurrent drug therapy or dietary regimens which may markedly alter urinary pH should be avoided during mexiletine hydrochloride therapy. The minor fluctuations in urinary pH associated with normal diet do not affect the excretion of mexiletine.
- SGOT Elevation and Liver Injury
- In three month controlled trials, elevations of SGOT greater than three times the upper limit of normal occurred in about 1% of both mexiletine-treated and control patients. Approximately 2% of patients in the mexiletine compassionate use program had elevations of SGOT greater than or equal to three times the upper limit of normal. These elevations frequently occurred in association with identifiable clinical events and therapeutic measures such as congestive heart failure, acute myocardial infarction, blood transfusions and other medications. These elevations were often asymptomatic and transient, usually not associated with elevated bilirubin levels and usually did not require discontinuation of therapy. Marked elevations of SGOT (> 1000 U/L) were seen before death in four patients with end-stage cardiac disease (severe congestive heart failure, cardiogenic shock).
- Rare instances of severe liver injury, including hepatic necrosis, have been reported in association with mexiletine treatment. It is recommended that patients in whom an abnormal liver test has occurred, or who have signs of symptoms suggesting liver dysfunction, be carefully evaluated. If persistent or worsening elevation of hepatic enzymes is detected, consideration should be given to discontinuing therapy.
- Blood Dyscrasias
- Among 10,867 patients treated with mexiletine in the compassionate use program, marked leukopenia (neutrophils less than 1000/mm3) or agranulocytosis were seen in 0.06% and milder depressions of leukocytes were seen in 0.08%, and thrombocytopenia was observed in 0.16%. Many of these patients were seriously ill and receiving concomitant medications with known hematologic adverse effects. Rechallenge with mexiletine in several cases was negative. Marked leukopenia or agranulocytosis did not occur in any patient receiving mexiletine alone; five of the six cases of agranulocytosis were associated with procainamide (sustained release preparations in four) and one with vinblastine. If significant hematologic changes are observed, the patient should be carefully evaluated, and, if warranted, mexiletine should be discontinued. Blood counts usually return to normal within a month of discontinuation.
- Convulsions (seizures) did not occur in mexiletine controlled clinical trials. In the compassionate use program, convulsions were reported in about 2 of 1000 patients. Twenty-eight percent of these patients discontinued therapy. Convulsions were reported in patients with and without a prior history of seizures. Mexiletine should be used with caution in patients with known seizure disorder.
# Adverse Reactions
## Clinical Trials Experience
- Mexiletine hydrochloride commonly produces reversible gastrointestinal and nervous system adverse reactions but is otherwise well tolerated. Mexiletine has been evaluated in 483 patients in one month and three month controlled studies and in over 10,000 patients in a large compassionate use program. Dosages in the controlled studies ranged from 600 to 1200 mg/day; some patients (8%) in the compassionate use program were treated with higher daily doses (1600 to 3200 mg/day). In the three month controlled trials comparing mexiletine to quinidine, procainamide and disopyramide, the most frequent adverse reactions were upper gastrointestinal distress (41%), lightheadedness (10.5%), tremor (12.6%) and coordination difficulties (10.2%). Similar frequency and incidence were observed in the one month placebo-controlled trial. Although these reactions were generally not serious, and were dose-related and reversible with a reduction in dosage, by taking the drug with food or antacid or by therapy discontinuation, they led to therapy discontinuation in 40% of patients in the controlled trials. Table 1 presents the adverse events reported in the one-month placebo-controlled trial.
- Table 2 presents the adverse reactions occurring in one percent or more of patients in the three month controlled studies.
- Less than 1%: Syncope, edema, hot flashes, hypertension, short-term memory loss, loss of consciousness, other psychological changes, diaphoresis, urinary hesitancy/retention, malaise, impotence/decreased libido, pharyngitis, and congestive heart failure.
- An additional group of over 10,000 patients has been treated in a program allowing administration of mexiletine hydrochloride under compassionate use circumstances. These patients were seriously ill with the large majority on multiple drug therapy. Twenty-four percent of the patients continued in the program for one year or longer. Adverse reactions leading to therapy discontinuation occurred in 15 percent of patients (usually upper gastrointestinal system or nervous system effects). In general, the more common adverse reactions were similar to those in the controlled trials. Less common adverse events possibly related to mexiletine use include:
Syncope and hypotension, each about 6 in 1000; bradycardia, about 4 in 1000; angina/angina-like pain, about 3 in 1000; edema, atrioventricular block/conduction disturbances and hot flashes, each about 2 in 1000; atrial arrhythmias, hypertension and cardiogenic shock, each about 1 in 1000.
Dysphagia, about 2 in 1000; peptic ulcer, about 8 in 10,000; upper gastrointestinal bleeding, about 7 in 10,000; esophageal ulceration, about 1 in 10,000. Rare cases of severe hepatitis/acute hepatic necrosis.
Blood dyscrasias were not seen in the controlled trials but did occur among 10,867 patients treated with mexiletine in the compassionate use program.
Myelofibrosis was reported in two patients in the compassionate use program; one was receiving long-term thiotepa therapy and the other had pretreatment myeloid abnormalities.
In postmarketing experience, there have been isolated, spontaneous reports of pulmonary changes including pulmonary infiltration and pulmonary fibrosis during mexiletine therapy with or without other drugs or diseases that are known to produce pulmonary toxicity. A causal relationship to mexiletine therapy has not been established. In addition, there have been isolated reports of drowsiness, nystagmus, ataxia, dyspepsia, hypersensitivity reaction, and exacerbation of congestive heart failure in patients with pre-existing compromised ventricular function. There have been rare reports of pancreatitis associated with mexiletine treatment.
Short-term memory loss, about 9 in 1000 patients; hallucinations and other psychological changes, each about 3 in 1000; psychosis and convulsions/seizures, each about 2 in 1000; loss of consciousness, about 6 in 10,000.
Rare cases of exfoliative dermatitis and Stevens-Johnson syndrome with mexiletine treatment have been reported.
Abnormal liver function tests, about 5 in 1000; positive ANA and thrombocytopenia, each about 2 in 1000; leukopenia (including neutropenia and agranulocytosis), about 1 in 1000; myelofibrosis, about 2 in 10,000 patients.
Diaphoresis, about 6 in 1000; altered taste, about 5 in 1000; salivary changes, hair loss and impotence/decreased libido, each about 4 in 1000; malaise, about 3 in 1000; urinary hesitancy/retention, each about 2 in 1000; hiccups, dry skin, laryngeal and pharyngeal changes and changes in oral mucous membranes, each about 1 in 1000; SLE syndrome, about 4 in 10,000.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Mexiletine in the drug label.
# Drug Interactions
- Since mexiletine hydrochloride is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs is initiated, the dose of mexiletine should be slowly titrated to desired effect.
- In a large compassionate use program mexiletine has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with mexiletine, lowered mexiletine plasma levels have been reported. Monitoring of mexiletine plasma levels is recommended during such concurrent use to avoid ineffective therapy.
- In a formal study, benzodiazepines were shown not to affect mexiletine plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent mexiletine and digoxin, diuretics, or propranolol.
- Concurrent administration of cimetidine and mexiletine has been reported to increase, decrease, or leave unchanged mexiletine plasma levels; therefore patients should be followed carefully during concurrent therapy.
- Mexiletine does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to mexiletine, has been reported to lower serum digoxin levels.
- Concurrent use of mexiletine and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35 to 136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting mexiletine. Theophylline plasma levels returned to pre-mexiletine values within 48 hours after discontinuing mexiletine. If mexiletine and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the mexiletine dose is changed. An appropriate adjustment in theophylline dose should be considered.
- Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of mexiletine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Reproduction studies performed with mexiletine in rats, mice and rabbits at doses up to four times the maximum human oral dose (24 mg/kg in a 50 kg patient) revealed no evidence of teratogenicity or impaired fertility but did show an increase in fetal resorption. There are no adequate and well-controlled studies in pregnant women; this drug should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mexiletine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Mexiletine during labor and delivery.
### Nursing Mothers
- Mexiletine appears in human milk in concentrations similar to those observed in plasma. Therefore, if the use of mexiletine hydrochloride is deemed essential, an alternative method of infant feeding should be considered.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
There is no FDA guidance on the use of Mexiletine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Mexiletine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Mexiletine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Mexiletine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Mexiletine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Mexiletine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Mexiletine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- As with any antiarrhythmic drug, clinical and electrocardiographic evaluation (including Holter monitoring if necessary for evaluation) are needed to determine whether the desired antiarrhythmic effect has been obtained and to guide titration and dose adjustment.
# IV Compatibility
There is limited information regarding IV Compatibility of Mexiletine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Clinical findings associated with mexiletine overdosage have included drowsiness, confusion, nausea, hypotension, sinus bradycardia, paresthesia, seizures, bundle branch block, AV heart block, asystole, ventricular tachyarrythmia, including ventricular fibrillation, cardiovascular collapse and coma. The lowest known dose in a fatality case was 4.4 g with postmortem serum mexiletine level of 34 to 37 mcg/mL (Jequier P. et. al., Lancet 1976: 1 (7956): 429). Patients have recovered from ingestion of 4 g to 18 g of mexiletine (Frank S. E. et. al., Am J Emerg Med 1991: 9:43-48).
### Management
- In postmarketing experience, there have been isolated, spontaneous reports of pulmonary changes including pulmonary infiltration and pulmonary fibrosis during mexiletine therapy with or without other drugs or diseases that are known to produce pulmonary toxicity. A causal relationship to mexiletine therapy has not been established. In addition, there have been isolated reports of drowsiness, nystagmus, ataxia, dyspepsia, hypersensitivity reaction, and exacerbation of congestive heart failure in patients with pre-existing compromised ventricular function. There have been rare reports of pancreatitis associated with mexiletine treatment.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Mexiletine in the drug label.
# Pharmacology
## Mechanism of Action
- Mexiletine hydrochloride is a local anesthetic, antiarrhythmic agent, structurally similar to lidocaine, but orally active. In animal studies, mexiletine has been shown to be effective in the suppression of induced ventricular arrhythmias, including those induced by glycoside toxicity and coronary artery ligation. Mexiletine, like lidocaine, inhibits the inward sodium current, thus reducing the rate of rise of the action potential, Phase 0. Mexiletine decreased the effective refractory period (ERP) in Purkinje fibers. The decrease in ERP was of lesser magnitude than the decrease in action potential duration (APD), with a resulting increase in the ERP/APD ratio.
- Electrophysiology in Man
- Mexiletine is a Class 1B antiarrhythmic compound with electrophysiologic properties in man similar to those of lidocaine, but dissimilar from quinidine, procainamide, and disopyramide.
- In patients with normal conduction systems, mexiletine has a minimal effect on cardiac impulse generation and propagation. In clinical trials, no development of second-degree or third degree AV block was observed. Mexiletine did not prolong ventricular depolarization (QRS duration) or repolarization (QT intervals) as measured by electrocardiography. Theoretically, therefore, mexiletine may be useful in the treatment of ventricular arrhythmias associated with a prolonged QT interval.
- In patients with pre-existing conduction defects, depression of the sinus rate, prolongation of sinus node recovery time, decreased conduction velocity and increased effective refractory period of the intraventricular conduction system have occasionally been observed.
- The antiarrhythmic effect of mexiletine has been established in controlled comparative trials against placebo, quinidine, procainamide and disopyramide. Mexiletine hydrochloride, at doses of 200 to 400 mg q8h, produced a significant reduction of ventricular premature beats, paired beats, and episodes of non-sustained ventricular tachycardia compared to placebo and was similar in effectiveness to the active agents. Among all patients entered into the studies, about 30% in each treatment group had a 70% or greater reduction in PVC count and about 40% failed to complete the 3 month studies because of adverse effects. Follow-up of patients from the controlled trials has demonstrated continued effectiveness of mexiletine in long-term use.
- Hemodynamics
- Hemodynamic studies in a limited number of patients, with normal or abnormal myocardial function, following oral administration of mexiletine hydrochloride, have shown small, usually not statistically significant, decreases in cardiac output and increases in systemic vascular resistance, but no significant negative inotropic effect. Blood pressure and pulse rate remain essentially unchanged. Mild depression of myocardial function, similar to that produced by lidocaine, has occasionally been observed following intravenous mexiletine therapy in patients with cardiac disease.
## Structure
- Mexiletine hydrochloride is an orally active antiarrhythmic agent. It is a white to off-white crystalline powder with slightly bitter taste, freely soluble in water and in alcohol. Mexiletine hydrochloride has a pKa of 9.2. The chemical name of mexiletine hydrochloride is 1-methyl-2-(2,6-xylyloxy)ethylamine hydrochloride and its structural formula is:
- Each capsule for oral administration, contains 150 mg, 200 mg, or 250 mg of mexiletine hydrochloride. 100 mg of mexiletine hydrochloride is equivalent to 83.31 mg of mexiletine base. In addition, each capsule contains the following excipients: colloidal silicon dioxide, magnesium stearate and pregelatinized starch. The capsule shell contains: FD&C Yellow #6, gelatin and titanium dioxide. The 150 mg capsule also contains: D&C Red #28 and FD&C Blue #1 and the 250 mg capsule also contains: D&C Yellow #10 and FD&C Blue #1. The imprinting ink contains: ammonium hydroxide, black iron oxide, D&C Yellow #10, ethyl alcohol, FD&C Blue #1, FD&C Blue #2, FD&C Red #40, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Mexiletine in the drug label.
## Pharmacokinetics
- Mexiletine is well absorbed (~90%) from the gastrointestinal tract. Unlike lidocaine, its first-pass metabolism is low. Peak blood levels are reached in two to three hours. In normal subjects, the plasma elimination half-life of mexiletine is approximately 10 to 12 hours. It is 50 to 60% bound to plasma protein, with a volume of distribution of 5 to 7 liters/kg. Mexiletine is mainly metabolized in the liver, the primary pathway being CYP2D6 metabolism, although it is also a substrate for CYP1A2. With involvement of CYP2D6, there can be either poor or extensive metabolizer phenotypes. Since approximately 90% of mexiletine hydrochloride is metabolized in the liver into inactive metabolites, pathological changes in the liver can restrict hepatic clearance of mexiletine hydrochloride and its metabolites. The metabolic degradation proceeds via various pathways including aromatic and aliphatic hydroxylation, dealkylation, deamination and N-oxidation. Several of the resulting metabolites are submitted to further conjugation with glucuronic acid (phase II metabolism); among these are the major metabolites p-hydroxymexiletine, hydroxy-methylmexiletine and N-hydroxy-mexiletine. Approximately 10% is excreted unchanged by the kidney. While urinary pH does not normally have much influence on elimination, marked changes in urinary pH influence the rate of excretion: acidification accelerates excretion, while alkalinization retards it.
- Several metabolites of mexiletine have shown minimal antiarrhythmics activity in animal models. The most active is the minor metabolite N-methylmexiletine, which is less than 20% as potent as mexiletine. The urinary excretion of N-methylmexiletine in man is less than 0.5%. Thus the therapeutic activity of mexiletine is due to the parent compound.
- Hepatic impairment prolongs the elimination half-life of mexiletine. In eight patients with moderate to severe liver disease, the mean half-life was approximately 25 hours.
- Consistent with the limited renal elimination of mexiletine, little change in the half-life has been detected in patients with reduced renal function. In eight patients with creatinine clearance less than 10 mL/min, the mean plasma elimination half-life was 15.7 hours; in seven patients with creatinine clearance between 11 to 40 mL/min, the mean half-life was 13.4 hours.
- The absorption rate of mexiletine is reduced in clinical situations such as acute myocardial infarction in which gastric emptying time is increased. Narcotics, atropine and magnesium-aluminum hydroxide have also been reported to slow the absorption of mexiletine. Metoclopramide has been reported to accelerate absorption.
- Mexiletine plasma levels of at least 0.5 mcg/mL are generally required for therapeutic response. An increase in the frequency of central nervous system adverse effects has been observed when plasma levels exceed 2.0 mcg/mL. Thus the therapeutic range is approximately 0.5 to 2.0 mcg/mL. Plasma levels within the therapeutic range can be attained with either three times daily or twice daily dosing but peak to trough differences are greater with the latter regimen, creating the possibility of adverse effects at peak and arrhythmic escape at trough. Nevertheless, some patients may be transferred successfully to the twice daily regimen.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Studies of carcinogenesis in rats (24 months) and mice (18 months) did not demonstrate any tumorigenic potential. Mexiletine was found to be non-mutagenic in the Ames test. Mexiletine did not impair fertility in the rat.
# Clinical Studies
There is limited information regarding Clinical Studies of Mexiletine in the drug label.
# How Supplied
- Mexiletine hydrochloride capsules USP, 150 mg are white granular powder in a hard gelatin capsule with an opaque tan cap and an opaque orange body, imprinted with N on one side and 739 and 150 on the other in black ink. They are supplied as follows: NDC 42291-624-01 bottles of 100.
- Mexiletine hydrochloride capsules USP, 200 mg are white granular powder in a hard gelatin capsule with an opaque orange cap and an opaque orange body, imprinted with N on& one side and 740 and 200 on the other in black ink. They are supplied as follows: NDC 42291-625-01 bottles of 100.
- Mexiletine hydrochloride capsules USP, 250 mg are white granular powder in a hard gelatin capsule with an opaque green cap and an opaque orange body, imprinted with N on one side and 741 and 250 on the other in black ink. They are supplied as follows: NDC 42291-626-01 bottles of 100.
- Store at 20° to 25°C (68° to 77°F).
- Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
## Storage
There is limited information regarding Mexiletine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Mexiletine in the drug label.
# Precautions with Alcohol
- Alcohol-Mexiletine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Mexitil®
# Look-Alike Drug Names
- N/A
# Drug Shortage Status
# Price | Mexiletine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi
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# Black Box Warning
# Overview
Mexiletine is an antiarrhythmic that is FDA approved for the {{{indicationType}}} of ventricular arrhythmias, such as sustained ventricular tachycardia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include heartburn, nausea, vomiting, coordination problem, dizziness, lightheadedness, tremor, blurred vision, visual disturbance, and anxiety.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Loading Dose
- When rapid control of ventricular arrhythmia is essential, an initial loading dose of 400 mg of mexiletine hydrochloride may be administered, followed by a 200 mg dose in eight hours. Onset of therapeutic effect is usually observed within 30 minutes to two hours.
- Q12H Dosage Schedule
- Some patients responding to mexiletine may be transferred to a 12 hour dosage schedule to improve convenience and compliance. If adequate suppression is achieved on a mexiletine hydrochloride dose of 300 mg or less every eight hours, the same total daily dose may be given in divided doses every 12 hours while carefully monitoring the degree of suppression of ventricular ectopy. This dose may be adjusted up to a maximum of 450 mg every 12 hours to achieve the desired response.
- Transferring to Mexiletine Hydrochloride
- The following dosage schedule, based on theoretical considerations rather than experimental data, is suggested for transferring patients from other Class I oral antiarrhythmic agents to mexiletine: mexiletine hydrochloride treatment may be initiated with a 200 mg dose, and titrated to response as described above, 6 to 12 hours after the last dose of quinidine sulfate, 3 to 6 hours after the last dose of procainamide, 6 to 12 hours after the last dose of disopryramide or 8 to 12 hours after the last dose of tocainide.
- In patients in whom withdrawal of the previous antiarrhythmic agent is likely to produce life-threatening arrhythmias, hospitalization of the patient is recommended.
- When transferring from lidocaine to mexiletine, the lidocaine infusion should be stopped when the first oral dose of mexiletine hydrochloride is administered. The infusion line should be left open until suppression of the arrhythmia appears to be satisfactorily maintained. Consideration should be given to the similarity of the adverse effects of lidocaine and mexiletine and the possibility that they may be additive.
- Dosing Information
- The dosage of mexiletine hydrochloride must be individualized on the basis of response and tolerance, both of which are dose-related. Administration with food or antacid is recommended. Initiate mexiletine therapy with 200 mg every eight hours when rapid control of arrhythmia is not essential. A minimum of two to three days between dose adjustments is recommended. Dose may be adjusted in 50 or 100 mg increments up or down.
- As with any antiarrhythmic drug, clinical and electrocardiographic evaluation (including Holter monitoring if necessary for evaluation) are needed to determine whether the desired antiarrhythmic effect has been obtained and to guide titration and dose adjustment.
- Satisfactory control can be achieved in most patients by 200 to 300 mg given every eight hours with food or antacid. If satisfactory response has not been achieved at 300 mg q8h, and the patient tolerates mexiletine well, a dose of 400 mg q8h may be tried. As the severity of CNS side effects increases with total daily dose, the dose should not exceed 1200 mg/day.
- In general, patients with renal failure will require the usual doses of mexiletine hydrochloride. Patients with severe liver disease, however, may require lower doses and must be monitored closely. Similarly, marked right-sided congestive heart failure can reduce hepatic metabolism and reduce the needed dose. Plasma level may also be affected by certain concomitant drugs
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mexiletine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mexiletine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mexiletine in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- 1.4 to 5 mg/kg (mean 3.3 mg/kg) every 8 hours[1]
# Contraindications
- Mexiletine hydrochloride capsules are contraindicated in the presence of cardiogenic shock or pre-existing second-or third-degree AV block (if no pacemaker is present).
# Warnings
### Precautions
- General
- If a ventricular pacemaker is operative, patients with second or third degree heart block may be treated with mexiletine hydrochloride if continuously monitored. A limited number of patients (45 of 475 in controlled clinical trials) with pre-existing first degree AV block were treated with mexiletine; none of these patients developed second or third degree AV block. Caution should be exercised when it is used in such patients or in patients with pre-existing sinus node dysfunction or intraventricular conduction abnormalities.
- Like other antiarrhythmics mexiletine hydrochloride can cause worsening of arrhythmias. This has been uncommon in patients with less serious arrhythmias (frequent premature beats or nonsustained ventricular tachycardia), but is of greater concern in patients with life-threatening arrhythmias such as sustained ventricular tachycardia. In patients with such arrhythmias subjected to programmed electrical stimulation or to exercise provocation, 10 to 15% of patients had exacerbation of the arrhythmia, a rate not greater than that of other agents.
- Mexiletine should be used with caution in patients with hypotension and severe congestive heart failure because of the potential for aggravating these conditions.
- Since mexiletine is metabolized in the liver, and hepatic impairment has been reported to prolong the elimination half-life of mexiletine, patients with liver disease should be followed carefully while receiving mexiletine. The same caution should be observed in patients with hepatic dysfunction secondary to congestive heart failure.
- Concurrent drug therapy or dietary regimens which may markedly alter urinary pH should be avoided during mexiletine hydrochloride therapy. The minor fluctuations in urinary pH associated with normal diet do not affect the excretion of mexiletine.
- SGOT Elevation and Liver Injury
- In three month controlled trials, elevations of SGOT greater than three times the upper limit of normal occurred in about 1% of both mexiletine-treated and control patients. Approximately 2% of patients in the mexiletine compassionate use program had elevations of SGOT greater than or equal to three times the upper limit of normal. These elevations frequently occurred in association with identifiable clinical events and therapeutic measures such as congestive heart failure, acute myocardial infarction, blood transfusions and other medications. These elevations were often asymptomatic and transient, usually not associated with elevated bilirubin levels and usually did not require discontinuation of therapy. Marked elevations of SGOT (> 1000 U/L) were seen before death in four patients with end-stage cardiac disease (severe congestive heart failure, cardiogenic shock).
- Rare instances of severe liver injury, including hepatic necrosis, have been reported in association with mexiletine treatment. It is recommended that patients in whom an abnormal liver test has occurred, or who have signs of symptoms suggesting liver dysfunction, be carefully evaluated. If persistent or worsening elevation of hepatic enzymes is detected, consideration should be given to discontinuing therapy.
- Blood Dyscrasias
- Among 10,867 patients treated with mexiletine in the compassionate use program, marked leukopenia (neutrophils less than 1000/mm3) or agranulocytosis were seen in 0.06% and milder depressions of leukocytes were seen in 0.08%, and thrombocytopenia was observed in 0.16%. Many of these patients were seriously ill and receiving concomitant medications with known hematologic adverse effects. Rechallenge with mexiletine in several cases was negative. Marked leukopenia or agranulocytosis did not occur in any patient receiving mexiletine alone; five of the six cases of agranulocytosis were associated with procainamide (sustained release preparations in four) and one with vinblastine. If significant hematologic changes are observed, the patient should be carefully evaluated, and, if warranted, mexiletine should be discontinued. Blood counts usually return to normal within a month of discontinuation.
- Convulsions (seizures) did not occur in mexiletine controlled clinical trials. In the compassionate use program, convulsions were reported in about 2 of 1000 patients. Twenty-eight percent of these patients discontinued therapy. Convulsions were reported in patients with and without a prior history of seizures. Mexiletine should be used with caution in patients with known seizure disorder.
# Adverse Reactions
## Clinical Trials Experience
- Mexiletine hydrochloride commonly produces reversible gastrointestinal and nervous system adverse reactions but is otherwise well tolerated. Mexiletine has been evaluated in 483 patients in one month and three month controlled studies and in over 10,000 patients in a large compassionate use program. Dosages in the controlled studies ranged from 600 to 1200 mg/day; some patients (8%) in the compassionate use program were treated with higher daily doses (1600 to 3200 mg/day). In the three month controlled trials comparing mexiletine to quinidine, procainamide and disopyramide, the most frequent adverse reactions were upper gastrointestinal distress (41%), lightheadedness (10.5%), tremor (12.6%) and coordination difficulties (10.2%). Similar frequency and incidence were observed in the one month placebo-controlled trial. Although these reactions were generally not serious, and were dose-related and reversible with a reduction in dosage, by taking the drug with food or antacid or by therapy discontinuation, they led to therapy discontinuation in 40% of patients in the controlled trials. Table 1 presents the adverse events reported in the one-month placebo-controlled trial.
- Table 2 presents the adverse reactions occurring in one percent or more of patients in the three month controlled studies.
- Less than 1%: Syncope, edema, hot flashes, hypertension, short-term memory loss, loss of consciousness, other psychological changes, diaphoresis, urinary hesitancy/retention, malaise, impotence/decreased libido, pharyngitis, and congestive heart failure.
- An additional group of over 10,000 patients has been treated in a program allowing administration of mexiletine hydrochloride under compassionate use circumstances. These patients were seriously ill with the large majority on multiple drug therapy. Twenty-four percent of the patients continued in the program for one year or longer. Adverse reactions leading to therapy discontinuation occurred in 15 percent of patients (usually upper gastrointestinal system or nervous system effects). In general, the more common adverse reactions were similar to those in the controlled trials. Less common adverse events possibly related to mexiletine use include:
Syncope and hypotension, each about 6 in 1000; bradycardia, about 4 in 1000; angina/angina-like pain, about 3 in 1000; edema, atrioventricular block/conduction disturbances and hot flashes, each about 2 in 1000; atrial arrhythmias, hypertension and cardiogenic shock, each about 1 in 1000.
Dysphagia, about 2 in 1000; peptic ulcer, about 8 in 10,000; upper gastrointestinal bleeding, about 7 in 10,000; esophageal ulceration, about 1 in 10,000. Rare cases of severe hepatitis/acute hepatic necrosis.
Blood dyscrasias were not seen in the controlled trials but did occur among 10,867 patients treated with mexiletine in the compassionate use program.
Myelofibrosis was reported in two patients in the compassionate use program; one was receiving long-term thiotepa therapy and the other had pretreatment myeloid abnormalities.
In postmarketing experience, there have been isolated, spontaneous reports of pulmonary changes including pulmonary infiltration and pulmonary fibrosis during mexiletine therapy with or without other drugs or diseases that are known to produce pulmonary toxicity. A causal relationship to mexiletine therapy has not been established. In addition, there have been isolated reports of drowsiness, nystagmus, ataxia, dyspepsia, hypersensitivity reaction, and exacerbation of congestive heart failure in patients with pre-existing compromised ventricular function. There have been rare reports of pancreatitis associated with mexiletine treatment.
Short-term memory loss, about 9 in 1000 patients; hallucinations and other psychological changes, each about 3 in 1000; psychosis and convulsions/seizures, each about 2 in 1000; loss of consciousness, about 6 in 10,000.
Rare cases of exfoliative dermatitis and Stevens-Johnson syndrome with mexiletine treatment have been reported.
Abnormal liver function tests, about 5 in 1000; positive ANA and thrombocytopenia, each about 2 in 1000; leukopenia (including neutropenia and agranulocytosis), about 1 in 1000; myelofibrosis, about 2 in 10,000 patients.
Diaphoresis, about 6 in 1000; altered taste, about 5 in 1000; salivary changes, hair loss and impotence/decreased libido, each about 4 in 1000; malaise, about 3 in 1000; urinary hesitancy/retention, each about 2 in 1000; hiccups, dry skin, laryngeal and pharyngeal changes and changes in oral mucous membranes, each about 1 in 1000; SLE syndrome, about 4 in 10,000.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Mexiletine in the drug label.
# Drug Interactions
- Since mexiletine hydrochloride is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs is initiated, the dose of mexiletine should be slowly titrated to desired effect.
- In a large compassionate use program mexiletine has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with mexiletine, lowered mexiletine plasma levels have been reported. Monitoring of mexiletine plasma levels is recommended during such concurrent use to avoid ineffective therapy.
- In a formal study, benzodiazepines were shown not to affect mexiletine plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent mexiletine and digoxin, diuretics, or propranolol.
- Concurrent administration of cimetidine and mexiletine has been reported to increase, decrease, or leave unchanged mexiletine plasma levels; therefore patients should be followed carefully during concurrent therapy.
- Mexiletine does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to mexiletine, has been reported to lower serum digoxin levels.
- Concurrent use of mexiletine and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35 to 136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting mexiletine. Theophylline plasma levels returned to pre-mexiletine values within 48 hours after discontinuing mexiletine. If mexiletine and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the mexiletine dose is changed. An appropriate adjustment in theophylline dose should be considered.
- Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of mexiletine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Reproduction studies performed with mexiletine in rats, mice and rabbits at doses up to four times the maximum human oral dose (24 mg/kg in a 50 kg patient) revealed no evidence of teratogenicity or impaired fertility but did show an increase in fetal resorption. There are no adequate and well-controlled studies in pregnant women; this drug should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mexiletine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Mexiletine during labor and delivery.
### Nursing Mothers
- Mexiletine appears in human milk in concentrations similar to those observed in plasma. Therefore, if the use of mexiletine hydrochloride is deemed essential, an alternative method of infant feeding should be considered.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
There is no FDA guidance on the use of Mexiletine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Mexiletine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Mexiletine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Mexiletine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Mexiletine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Mexiletine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Mexiletine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- As with any antiarrhythmic drug, clinical and electrocardiographic evaluation (including Holter monitoring if necessary for evaluation) are needed to determine whether the desired antiarrhythmic effect has been obtained and to guide titration and dose adjustment.
# IV Compatibility
There is limited information regarding IV Compatibility of Mexiletine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Clinical findings associated with mexiletine overdosage have included drowsiness, confusion, nausea, hypotension, sinus bradycardia, paresthesia, seizures, bundle branch block, AV heart block, asystole, ventricular tachyarrythmia, including ventricular fibrillation, cardiovascular collapse and coma. The lowest known dose in a fatality case was 4.4 g with postmortem serum mexiletine level of 34 to 37 mcg/mL (Jequier P. et. al., Lancet 1976: 1 (7956): 429). Patients have recovered from ingestion of 4 g to 18 g of mexiletine (Frank S. E. et. al., Am J Emerg Med 1991: 9:43-48).
### Management
- In postmarketing experience, there have been isolated, spontaneous reports of pulmonary changes including pulmonary infiltration and pulmonary fibrosis during mexiletine therapy with or without other drugs or diseases that are known to produce pulmonary toxicity. A causal relationship to mexiletine therapy has not been established. In addition, there have been isolated reports of drowsiness, nystagmus, ataxia, dyspepsia, hypersensitivity reaction, and exacerbation of congestive heart failure in patients with pre-existing compromised ventricular function. There have been rare reports of pancreatitis associated with mexiletine treatment.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Mexiletine in the drug label.
# Pharmacology
## Mechanism of Action
- Mexiletine hydrochloride is a local anesthetic, antiarrhythmic agent, structurally similar to lidocaine, but orally active. In animal studies, mexiletine has been shown to be effective in the suppression of induced ventricular arrhythmias, including those induced by glycoside toxicity and coronary artery ligation. Mexiletine, like lidocaine, inhibits the inward sodium current, thus reducing the rate of rise of the action potential, Phase 0. Mexiletine decreased the effective refractory period (ERP) in Purkinje fibers. The decrease in ERP was of lesser magnitude than the decrease in action potential duration (APD), with a resulting increase in the ERP/APD ratio.
- Electrophysiology in Man
- Mexiletine is a Class 1B antiarrhythmic compound with electrophysiologic properties in man similar to those of lidocaine, but dissimilar from quinidine, procainamide, and disopyramide.
- In patients with normal conduction systems, mexiletine has a minimal effect on cardiac impulse generation and propagation. In clinical trials, no development of second-degree or third degree AV block was observed. Mexiletine did not prolong ventricular depolarization (QRS duration) or repolarization (QT intervals) as measured by electrocardiography. Theoretically, therefore, mexiletine may be useful in the treatment of ventricular arrhythmias associated with a prolonged QT interval.
- In patients with pre-existing conduction defects, depression of the sinus rate, prolongation of sinus node recovery time, decreased conduction velocity and increased effective refractory period of the intraventricular conduction system have occasionally been observed.
- The antiarrhythmic effect of mexiletine has been established in controlled comparative trials against placebo, quinidine, procainamide and disopyramide. Mexiletine hydrochloride, at doses of 200 to 400 mg q8h, produced a significant reduction of ventricular premature beats, paired beats, and episodes of non-sustained ventricular tachycardia compared to placebo and was similar in effectiveness to the active agents. Among all patients entered into the studies, about 30% in each treatment group had a 70% or greater reduction in PVC count and about 40% failed to complete the 3 month studies because of adverse effects. Follow-up of patients from the controlled trials has demonstrated continued effectiveness of mexiletine in long-term use.
- Hemodynamics
- Hemodynamic studies in a limited number of patients, with normal or abnormal myocardial function, following oral administration of mexiletine hydrochloride, have shown small, usually not statistically significant, decreases in cardiac output and increases in systemic vascular resistance, but no significant negative inotropic effect. Blood pressure and pulse rate remain essentially unchanged. Mild depression of myocardial function, similar to that produced by lidocaine, has occasionally been observed following intravenous mexiletine therapy in patients with cardiac disease.
## Structure
- Mexiletine hydrochloride is an orally active antiarrhythmic agent. It is a white to off-white crystalline powder with slightly bitter taste, freely soluble in water and in alcohol. Mexiletine hydrochloride has a pKa of 9.2. The chemical name of mexiletine hydrochloride is 1-methyl-2-(2,6-xylyloxy)ethylamine hydrochloride and its structural formula is:
- Each capsule for oral administration, contains 150 mg, 200 mg, or 250 mg of mexiletine hydrochloride. 100 mg of mexiletine hydrochloride is equivalent to 83.31 mg of mexiletine base. In addition, each capsule contains the following excipients: colloidal silicon dioxide, magnesium stearate and pregelatinized starch. The capsule shell contains: FD&C Yellow #6, gelatin and titanium dioxide. The 150 mg capsule also contains: D&C Red #28 and FD&C Blue #1 and the 250 mg capsule also contains: D&C Yellow #10 and FD&C Blue #1. The imprinting ink contains: ammonium hydroxide, black iron oxide, D&C Yellow #10, ethyl alcohol, FD&C Blue #1, FD&C Blue #2, FD&C Red #40, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Mexiletine in the drug label.
## Pharmacokinetics
- Mexiletine is well absorbed (~90%) from the gastrointestinal tract. Unlike lidocaine, its first-pass metabolism is low. Peak blood levels are reached in two to three hours. In normal subjects, the plasma elimination half-life of mexiletine is approximately 10 to 12 hours. It is 50 to 60% bound to plasma protein, with a volume of distribution of 5 to 7 liters/kg. Mexiletine is mainly metabolized in the liver, the primary pathway being CYP2D6 metabolism, although it is also a substrate for CYP1A2. With involvement of CYP2D6, there can be either poor or extensive metabolizer phenotypes. Since approximately 90% of mexiletine hydrochloride is metabolized in the liver into inactive metabolites, pathological changes in the liver can restrict hepatic clearance of mexiletine hydrochloride and its metabolites. The metabolic degradation proceeds via various pathways including aromatic and aliphatic hydroxylation, dealkylation, deamination and N-oxidation. Several of the resulting metabolites are submitted to further conjugation with glucuronic acid (phase II metabolism); among these are the major metabolites p-hydroxymexiletine, hydroxy-methylmexiletine and N-hydroxy-mexiletine. Approximately 10% is excreted unchanged by the kidney. While urinary pH does not normally have much influence on elimination, marked changes in urinary pH influence the rate of excretion: acidification accelerates excretion, while alkalinization retards it.
- Several metabolites of mexiletine have shown minimal antiarrhythmics activity in animal models. The most active is the minor metabolite N-methylmexiletine, which is less than 20% as potent as mexiletine. The urinary excretion of N-methylmexiletine in man is less than 0.5%. Thus the therapeutic activity of mexiletine is due to the parent compound.
- Hepatic impairment prolongs the elimination half-life of mexiletine. In eight patients with moderate to severe liver disease, the mean half-life was approximately 25 hours.
- Consistent with the limited renal elimination of mexiletine, little change in the half-life has been detected in patients with reduced renal function. In eight patients with creatinine clearance less than 10 mL/min, the mean plasma elimination half-life was 15.7 hours; in seven patients with creatinine clearance between 11 to 40 mL/min, the mean half-life was 13.4 hours.
- The absorption rate of mexiletine is reduced in clinical situations such as acute myocardial infarction in which gastric emptying time is increased. Narcotics, atropine and magnesium-aluminum hydroxide have also been reported to slow the absorption of mexiletine. Metoclopramide has been reported to accelerate absorption.
- Mexiletine plasma levels of at least 0.5 mcg/mL are generally required for therapeutic response. An increase in the frequency of central nervous system adverse effects has been observed when plasma levels exceed 2.0 mcg/mL. Thus the therapeutic range is approximately 0.5 to 2.0 mcg/mL. Plasma levels within the therapeutic range can be attained with either three times daily or twice daily dosing but peak to trough differences are greater with the latter regimen, creating the possibility of adverse effects at peak and arrhythmic escape at trough. Nevertheless, some patients may be transferred successfully to the twice daily regimen.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Studies of carcinogenesis in rats (24 months) and mice (18 months) did not demonstrate any tumorigenic potential. Mexiletine was found to be non-mutagenic in the Ames test. Mexiletine did not impair fertility in the rat.
# Clinical Studies
There is limited information regarding Clinical Studies of Mexiletine in the drug label.
# How Supplied
- Mexiletine hydrochloride capsules USP, 150 mg are white granular powder in a hard gelatin capsule with an opaque tan cap and an opaque orange body, imprinted with N on one side and 739 and 150 on the other in black ink. They are supplied as follows: NDC 42291-624-01 bottles of 100.
- Mexiletine hydrochloride capsules USP, 200 mg are white granular powder in a hard gelatin capsule with an opaque orange cap and an opaque orange body, imprinted with N on& one side and 740 and 200 on the other in black ink. They are supplied as follows: NDC 42291-625-01 bottles of 100.
- Mexiletine hydrochloride capsules USP, 250 mg are white granular powder in a hard gelatin capsule with an opaque green cap and an opaque orange body, imprinted with N on one side and 741 and 250 on the other in black ink. They are supplied as follows: NDC 42291-626-01 bottles of 100.
- Store at 20° to 25°C (68° to 77°F).
- Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
## Storage
There is limited information regarding Mexiletine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Mexiletine in the drug label.
# Precautions with Alcohol
- Alcohol-Mexiletine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Mexitil®[2]
# Look-Alike Drug Names
- N/A[3]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Mexiletine | |
d6249d2b580767581a4a454db017c83e97b233ea | wikidoc | Microbiome | Microbiome
Synonyms and keywords: microbiota
# Overview
A microbiota is "the ecological community of commensal, symbiotic and pathogenic microorganisms that literally share our body space." Joshua Lederberg coined the term, arguing the importance of microorganisms inhabiting the human body in health and disease. Many scientific articles distinguish microbiome and microbiota to describe either the collective genomes of the microorganisms that reside in an environmental niche or the microorganisms themselves, respectively. However by the original definitions these terms are largely synonymous.
The human body contains over 10 times more microbial cells than human cells, although the entire microbiome only weighs about 200 grams. Because bacteria are 10-100 times smaller than human cells, the entire microbiome weighs about 200 grams, with some weight estimates ranging as high as 3 pounds (approximately 48 ounces or 1,400 grams). Some regard it as a "newly discovered organ" since its existence was not generally recognized until the late 1990s and it is understood to have potentially overwhelming impact on human health. Modern techniques for sequencing DNA have enabled researchers to find the majority of these microbes, since the majority of them cannot be cultured in a lab using current techniques. The human microbiome may have a role in auto-immune diseases like diabetes, rheumatoid arthritis, muscular dystrophy, multiple sclerosis, fibromyalgia, and perhaps some cancers. A poor mix of microbes in the gut may also aggravate common obesity. Since some of the microbes in our body can modify the production of neurotransmitters known to be found in the brain, it may also relieve schizophrenia, depression, bipolar disorder and other neuro-chemical imbalances.
The microbes being discussed are generally non-pathogenic (they do not cause disease unless they grow abnormally); they exist in harmony and symbiotically with their hosts.
# Introduction
All plants and animals, from protists to humans, live in close association with microbial organisms (see for example the human microbiome). Up until relatively recently, however, biologists have defined the interactions of plants and animals with the microbial world mostly in the context of disease states and of a relatively small number of symbiotic case studies. Organisms do not live in isolation, but have evolved in the context of complex communities. A number of advances have driven a change in the perception of microbiomes, including:
- the ability to perform genomic and gene expression analyses of single cells and even of entire microbial communities in the new disciplines of metagenomics and metatranscriptonomics
- massive databases making this information accessible to researchers across multiple disciplines
- methods of mathematical analysis that help researchers to make sense of complex data sets
Increasingly, biologists have come to appreciate that microbes make up an important part of an organism's phenotype, far beyond the occasional symbiotic case study.
Pierre-Joseph van Beneden (1809-1894), a Belgian professor at the University of Louvain, developed the concept of commensalism during the nineteenth century. In his 1875 publication Animal Parasites and Messmates, Van Beneden presented 264 examples of commensalism. His conception was widely accepted by his contemporaries and commensalism has continued to be used as a concept right up to the present day: microbiome is clearly linked to commensalism.
# Case studies
There is a strengthening consensus among evolutionary biologists that one should not separate an organism's genes from the context of its resident microbes.
## Studies in humans
- Community sequencing of total gut microbiota taken from obese and lean twins show substantial differences in their compositions. Total population sequences were analyzed to determine the levels of enzymes involved in carbohydrate, lipid, and amino acid metabolism. Obesity is associated with phylum-level differences in the microbiota, a significantly reduced bacterial diversity, and an increase in the population expression of enzymes which result in an increased efficiency of calorie harvest in the diets of the obese twins.
- Type I diabetes is an autoimmune disease that is correlated with a multiplicity of predisposing factors, including an aberrant intestinal microbiota, a leaky intestinal mucosal barrier, and intrinsic differences in immune responsiveness. Various animal models for diabetes have shown a role for bacteria in the onset of the disease. Community DNA sequencing of intestinal flora comparing healthy and autoimmune children showed that autoimmune children had relatively unstable gut biomes with significantly decreased levels of species diversity, and the populations showed large scale replacement of Firmicutes species with Bacteroidetes species.
- Human skin represents the most extensive organ of the human body, whose functions include protecting the body from pathogens, preventing loss of moisture, and participating in the regulation of body temperature. Considered as an ecosystem, the skin supports a range of microbial communities that live in distinct niches. Hair-covered scalp lies but a few inches from exposed neck, which in turn lies inches away from moist hairy underarms, but these niches are, at a microbial level, as distinct as a temperate forest would be compared with savanna and tropical rain forest. Studies characterizing the microbiota that inhabit these different niches are providing insights into the balance between skin health and disease.
- Prevention of urogenital diseases in women depends on healthy vaginal microbiomes, but what is meant by "healthy" has not been understood. Community population studies using advanced sequencing methodologies (including pyrosequencing) are yielding insights into the range of microbial diversity in the human vagina. An unexpected finding was the prevalence of Prevotella species, which are known to positively affect the growth of Gardnerella vaginalis and Peptostreptococcus anaerobius, two species linked to bacterial vaginosis, by providing these disease-associated bacteria with key nutrients.
- A proposal has been made to classify people by enterotype, based on the composition of the gut microbiome. By combining 22 newly sequenced fecal metagenomes of individuals from four countries with previously published data sets, three robust clusters were identified that are not nation or continent specific.
- The traditional view of the immune system is that it is a complex assembly of organs, tissues, cells and molecules that work together to eliminate pathogens. Modifications to this traditional view, that the immune system has evolved to control microbes, have come from the discovery that microbes coevolve with and exert control upon the immune system. It is known that germ-free animals possess an underdeveloped immune system. The biology of the T helper 17 cells (Th17) has generated interest due to their key role in inflammatory processes. Excessive amounts of the cell are thought to play a key role in autoimmune diseases such as multiple sclerosis, psoriasis, juvenile diabetes, rheumatoid arthritis, Crohn's disease, and autoimmune uveitis. It has been discovered that specific microbiota direct the differentiation of Th17 cells in the mucosa of the small intestine.
## Animal studies
- A massive, worldwide decline in amphibian populations has been well-publicised. Habitat loss and over-exploitation account for part of the problem, but many other processes seem to be at work. The spread of the virulent fungal disease chytridiomycosis represents an enigma. The ability of some species to coexist with the causative agent Batrachochytrium dendrobatidis appears to be due to the expression of antimicrobial skin peptides along with the presence of symbiotic microbes that benefit the host by resisting pathogen colonization or inhibiting their growth while being themselves resistant to high concentrations of antimicrobial skin peptides.
- The bovine rumen harbors a complex microbiome that converts plant cell wall biomass into proteins, short chain fatty acids, and gases. Multiple species are involved in this conversion. Traditional methods of characterizing the microbial population, based on culture analysis, missed many of the participants in this process. Comparative metagenomic studies yielded the surprising result that individual steer had markedly different community structures, predicted phenotype, and metabolic potentials, even though they were fed identical diets, were housed together, and were apparently functionally identical in their utilization of plant cell wall resources.
- Leaf-cutter ants form huge underground colonies with millions of workers, each colony harvesting hundreds of kilograms of leaves each year. Unable to digest the cellulose in the leaves directly, they maintain fungus gardens that are the colony's primary food source. The fungus itself does not digest cellulose. Instead, a microbial community containing a diversity of bacteria is responsible for cellulose digestion. Analysis of the microbial population's genomic content by community metagenome sequencing methods revealed the presence of many genes with a role in cellulose digestion. This microbiome's predicted carbohydrate-degrading enzyme profile is similar to that of the bovine rumen, but the species composition is almost entirely different.
- Mice are the most used models for human disease. As more and more diseases are linked to dysfunctional microbiomes, mice have become the most studied organism in this regard. Mostly it is the gut microbiota that have been studied in relation to allergic airway disease, obesity, gastointesinal diseses and diabetes. Intriguingly, recent work has shown that perinatal shifting of microbiota through administration of low dose antibiotics can have long lasting effects on future susceptibility to allergic airway disease. These studies showed a remarkable link between the frequency of certain subsets of microbes and disease severity. In aggregate these studies suggest that the presence of specific microbes, early in postnatal life, play an instructive role in the development of future immune responses. Mechanistically, a recent study done on gnotobiotic mice described a method in which certain strains of gut bacteria were found to transmit a particular phenotype to recipient germ-free mice, identifying an unanticipated range of bacterial strains that promoted accumulation of colonic regulatory T cells, as well as strains that modulated mouse adiposity and cecal metabolite concentrations. This combinatorial approach enables a systems-level understanding of microbial contributions to human biology. But also other mucoide tissues as lung and vagina have been studies in relation to diseses such as asthma, allergy and vaginosis
## Plant studies
- Plants exhibit a broad range of relationships with symbiotic microorganisms, ranging from parasitism, in which the association is disadvantageous to the host organism, to mutualism, in which the association is beneficial to both, to commensalism, in which the symbiont benefits while the host is not affected. Exchange of nutrients between symbiotic partners is an important part of the relationship: it may be bidirectional or unidirectional, and it may be context dependent. The strategies for nutrient exchange are highly diverse. Oomycetes and fungi have, through convergent evolution, developed similar morphology and occupy similar ecological niches. They develop hyphae, filamentous structures that penetrate the host cell. In those cases where the association is mutualistic, the plant often exchanges hexose sugars for inorganic phosphate from the fungal symbiont. It is speculated that such associations, which are very ancient, may have aided plants when they first colonized land.
- A huge range of bacterial symbionts colonize plants. Many of these are pathogenic, but others known as plant-growth promoting bacteria (PGPB) provide the host with essential services such as nitrogen fixation, solubilization of minerals such as phosphorus, synthesis of plant hormones, direct enhancement of mineral uptake, and protection from pathogens. PGPBs may protect plants from pathogens by competing with the pathogen for an ecological niche or a substrate, producing inhibitory allelochemicals, or inducing systemic resistance in host plants to the pathogen
# Effects on pathogenesis of various diseases
### Depression
Microbes are also implicated in depression. The pathogenic bacteria Borrelia burgdorferi causes Lyme disease which causes depression in up to 2/3 of all cases. Non-pathogenic bacteria are also implicated in depression in which bacterial populations are suppressed. One model of depression is periodic separation of infant mice from their mothers. These mice show reductions in Lactobacillus and Bifidobacterium species, functional gut abnormalities, increased corticosterone (stress hormone) levels, weight loss, and causes them to not swim as much in a forced swim test as control mice, indicating behavioural despair. Treating the mice with Lactobacillus lowered corticosterone levels and gut abnormalities. Another experiment has replicated the effect that germ free mice have an exaggerated stress response and also found reduced expression of brain-derived neurotrophic factor in the cortex and hippocampus. Another experiment showed that treating the maternally separated mice with a probiotic culture of Bifodobacterium infantis minimizes weight loss, causes mice to swim longer and causes an increase in the amount of the serotonin precursor tryptophan produced. Increasing serotonin levels through selective serotonin reuptake inhibitors is the primary treatment of depression in humans. Human patients with depression are less able to properly digest fructose, which is also associated with a reduction in tryptophan production. Eliminating fructose from their diet improved their depression.
### Anxiety
Gut microbes are also implicated in anxiety disorders. In humans anxiety disorders are common in patients with disturbed gut flora. The bacteria Campylobacter jejuni has been shown to cause anxious behaviour in mice. Germ free mice show less anxious behaviour and also less NR2B mRNA expression selectively in the central amygdala which might be responsible for the anxiolytic behaviour since NR2B antagonists have an anxiolytic effect on behaviour. The behavioural change might also be caused by increased brain derived neurotrophic factor (BDNF) mRNA expression possibly inducing plasticity in the dentate granular layer of the hippocampus. BDNF and the hippocampus are implicated in memory. Increased gut bacterial diversity has been shown to improve both working and reference memory as well as reducing anxiety-like behaviour.
### Autism
Autistic populations have a unique microbiome consisting of more clostridial species. Half of all autistic children with gastrointestinal dysfunction were found to have the bacteria Sutterella which was completely absent in non-autistic children with gastrointestinal dysfunction. There is evidence that for some children with late-onset autism antibiotics can alleviate symptoms temporarily.
### Endometriosis
Recent research has shown that endometriosis can be caused by Fusobacterium, a bacteria that is part of the normal flora of the oral, gastrointestinal, and genital tracts. This bacterium may play a role in the pathogenesis of endometriosis. Studies indicate that Fusobacterium activates transforming growth factor-β, which, in turn, triggers the transition of quiescent fibroblasts to active myofibroblasts expressing transgelin (TAGLN). These myofibroblasts have the ability to migrate and are believed to be responsible for the fibrosis and adhesions seen in endometriosis. Although not all women with endometriosis have Fusobacterium Infiltration in their endometrium and may not benefit from antibiotic therapy, this research is promising and suggests that Fusobacterium may be an infectious contributor to endometriosis and warrants further study.
### Irritable Bowel Syndrome (IBS)
The precise origin of IBS remains uncertain, but it is believed to be influenced by multiple factors. One significant factor under consideration is the role of gut microbiota.In a healthy gut, the intestinal microbiota actively prevent the proliferation and adherence of harmful bacteria to the gastrointestinal (GI) wall. However, an imbalance in the gut microbiota, known as dysbiosis, can result in the attachment of enteric pathogens, potentially contributing to the development of IBS.
### Metabolic Syndrome
Metabolic syndrome is a group of metabolic disease characterized by abdominal obesity, hypertension, insulin resistance and hyperlipidemia according to World Health Organization (WHO).In recent years research have suggested that metabolic syndrome can associated with disturbance the internal microbiota. Internal microbiota is involved in the regulation of immune system, mediation of inflammation, digestion and utilization of nutrients. Alteration in the normal internal microbiota cause disturbance of these function which result in metabolic syndrome. Regulating gut micro biome may be a potential therapy for metabolic syndrome.
# Immune system
The symbiotic relationship between animal host and microbiota has a significant impact on shaping the immune system. The immune system is able to recognize the types of bacteria that are harmful to the host and combats them, while allowing the helpful bacteria to carry out their functions. After an infant is born completely sterile, their gut is quickly populated by commensal bacteria that affect the immune response, resulting in future tolerance to that bacteria. This early colonization helps to establish the symbiotic microbiome inside the host early in its life. The bacteria are also able to stimulate lymphoid tissue associated with the gut mucosa. This enables the tissue to produce antibodies for pathogens that may enter the gut. It has been found that bacteria may also play a role in the activation of TLRs (toll-like receptors) in the intestines. TLRs are a type of PRR (pattern recognition receptor) used by host cells to help repair damage and recognize dangers to the host. This could be important in immune tolerance and autoimmune diseases. Pathogens could influence this symbiotic coexistence leading to immune dysregulation and susceptibility to diseases. This could provide new direction for managing immunological and metabolic diseases.
# Human microbiome
The human microbiome consists of about 100 trillion microbial cells, outnumbering human cells 10 to 1. It can significantly affect human physiology. For example, in healthy individuals the microbiota provide a wide range of metabolic functions that humans lack. In diseased individuals altered microbiota are associated with diseases such as neonatal necrotizing enterocolitis, inflammatory bowel disease and vaginosis. Thus studying the human microbiome is an important task that has been undertaken by initiatives such as the Human Microbiome Project and MetaHIT.
## Studying the human microbiome
The problem of elucidating the human microbiome is essentially identifying the members of a microbial community which includes bacteria, eukaryotes, and viruses. This is done primarily using DNA-based studies, though RNA, protein and metabolite based studies are also performed. DNA-based microbiome studies typically can be categorized as either targeted amplicon studies or more recently shotgun metagenomic studies. The former focuses on specific known marker genes and is primarily informative taxonomically, while the latter is an entire metagenomic approach which can also be used to study the functional potential of the community. One of the challenges that is present in human microbiome studies but not in other metagenomic studies is to avoid including the host DNA in the study.
## Presence of a core microbiome
Aside from simply elucidating the composition of the human microbiome, one of the major questions involving the human microbiome is whether there is a "core", that is, whether there is a subset of the community that is shared between most humans. If there is a core, then it would be possible to associate certain community compositions with disease states, which is one of the goals of the Human Microbiome Project. It is known that the human microbiome is highly variable both within a single subject and between different individuals. For example, the gut microbiota of humans is markedly dissimilar between individuals, a phenomenon which is also observed in mice. Hamady and Knight show that one can rule out the possibility that any species is shared among all humans at more than 0.9% abundance in the gut or at more than 2% abundance on hands. Although there is very little species level conservation between individuals, it has been shown that this may be a result of functional redundancy as different communities tend to converge on the same functional state.
On 13 June 2012, a major milestone of the Human Microbiome Project (HMP) was announced by the NIH director Francis Collins. The announcement was accompanied with a series of coordinated articles published in Nature and several journals in the Public Library of Science (PLoS) on the same day. By mapping the normal microbial make-up of healthy humans using genome sequencing techniques, the researchers of the HMP have created a reference database and the boundaries of normal microbial variation in humans. From 242 healthy U.S. volunteers, more than 5,000 samples were collected from tissues from 15 (men) to 18 (women) body sites such as mouth, nose, skin, lower intestine (stool), and vagina. All the DNA, human and microbial, were analyzed with DNA sequencing machines. The microbial genome data were extracted by identifying the bacterial specific ribosomal RNA, 16S rRNA. The researchers calculated that more than 10,000 microbial species occupy the human ecosystem and they have identified 81 – 99% of the genera.
# Hologenome theory of evolution
The hologenome theory proposes that the object of natural selection is not the individual organism, but the organism together with its associated microbial communities.
The hologenome theory originated in studies on coral reefs. Coral reefs are the largest structures created by living organisms, and contain abundant and highly complex microbial communities. Over the past several decades, major declines in coral populations have occurred. Climate change, water pollution and over-fishing are three stress factors that have been described as leading to disease susceptibility. Over twenty different coral diseases have been described, but of these, only a handful have had their causative agents isolated and characterized. Coral bleaching is the most serious of these diseases. In the Mediterranean Sea, the bleaching of Oculina patagonica was first described in 1994 and shortly determined to be due to infection by Vibrio shiloi. From 1994 to 2002, bacterial bleaching of O. patagonica occurred every summer in the eastern Mediterranean. Surprisingly, however, after 2003, O. patagonica in the eastern Mediterranean has been resistant to V. shiloi infection, although other diseases still cause bleaching. The surprise stems from the knowledge that corals are long lived, with lifespans on the order of decades, and do not have adaptive immune systems. Their innate immune systems do not produce antibodies, and they should seemingly not be able to respond to new challenges except over evolutionary time scales. The puzzle of how corals managed to acquire resistance to a specific pathogen led Eugene Rosenberg and Ilana Zilber-Rosenberg to propose the Coral Probiotic Hypothesis. This hypothesis proposes that a dynamic relationship exists between corals and their symbiotic microbial communities. By altering its composition, this "holobiont" can adapt to changing environmental conditions far more rapidly than by genetic mutation and selection alone. Extrapolating this hypothesis of adaptation and evolution to other organisms, including higher plants and animals, led to the proposal of the Hologenome Theory of Evolution.
The hologenome theory is still being debated. A major criticism has been the claim that V. shiloi was misidentified as the causative agent of coral bleaching, and that its presence in bleached O. patagonica was simply that of opportunistic colonization. If this is true, the basic observation leading to the theory would be invalid. Nevertheless, the theory has gained significant popularity as a way of explaining rapid changes in adaptation that cannot otherwise be explained by traditional mechanisms of natural selection. For those who accept the hologenome theory, the holobiont has become the principal unit of natural selection.
# Research methods
## Targeted amplicon sequencing
Targeted amplicon sequencing relies on having some expectations about the composition of the community that is being studied. In target amplicon sequencing a phylogenetically informative marker is targeted for sequencing. Such a marker should be present in ideally all the expected organisms. It should also evolve in such a way that it is conserved enough that primers can target genes from a wide range of organisms while evolving quickly enough to allow for finer resolution at the taxonomic level. A common marker for human microbiome studies is the gene for bacterial 16S rRNA (i.e. "16S rDNA", the sequence of DNA which encodes the ribosomal RNA molecule). Since ribosomes are present in all living organisms, using 16S rDNA allows for DNA to be amplified from many more organisms than if another marker were used. The 16S rDNA gene contains both slowly evolving regions and fast evolving regions; the former can be used to design broad primers while the latter allow for finer taxonomic distinction. However, species-level resolution is not typically possible using the 16S rDNA. Primer selection is an important step, as anything that cannot be targeted by the primer will not be amplified and thus will not be detected. Different sets of primers have been shown to amplify different taxonomic groups due to sequence variation.
Targeted studies of eukaryotic and viral communities are limited and subject to the challenge of excluding host DNA from amplification and the reduced eukaryotic and viral biomass in the human microbiome.
After the amplicons are sequenced, molecular phylogenetic methods are used to infer the composition of the microbial community. This is done by clustering the amplicons into operational taxonomic units (OTUs) and inferring phylogenetic relationships between the sequences. Due to the complexity of the data, distance measures such as UniFrac distances are usually defined between microbiome samples, and downstream multivariate methods are carried out on the distance matrices. An important point is that the scale of data is extensive, and further approaches must be taken to identify patterns from the available information. Tools used to analyze the data include VAMPS, QIIME and mothur.
## Metagenomic sequencing
Metagenomics is also used extensively for studying microbial communities. In metagenomic sequencing, DNA is recovered directly from environmental samples in an untargeted manner with the goal of obtaining an unbiased sample from all genes of all members of the community. Recent studies use shotgun Sanger sequencing or pyrosequencing to recover the sequences of the reads. The reads can then be assembled into contigs. To determine the phylogenetic identity of a sequence, it is compared to available full genome sequences using methods such as BLAST. One drawback of this approach is that many members of microbial communities do not have a representative sequenced genome.
Despite the fact that metagenomics is limited by the availability of reference sequences, one significant advantage of metagenomics over targeted amplicon sequencing is that metagenomics data can elucidate the functional potential of the community DNA. Targeted gene surveys cannot do this as they only reveal the phylogenetic relationship between the same gene from different organisms. Functional analysis is done by comparing the recovered sequences to databases of metagenomic annotations such as KEGG. The metabolic pathways that these genes are involved in can then be predicted with tools such as MG-RAST, CAMERA and IMG/M.
## RNA and protein-based approaches
Metatranscriptomics studies have been performed to study the gene expression of microbial communities through methods such as the pyrosequencing of extracted RNA. Structure based studies have also identified non-coding RNAs (ncRNAs) such as ribozymes from microbiota. Metaproteomics is a new approach that studies the proteins expressed by microbiota, giving insight into its functional potential.
# Projects
The Human Microbiome Project (HMP) is a United States National Institutes of Health initiative with the goal of identifying and characterizing the microorganisms which are found in association with both healthy and diseased humans (their microbial flora). Launched in 2008, it is a five-year project, best characterized as a feasibility study, and has a total budget of $115 million. The ultimate goal of this and similar NIH-sponsored microbiome projects is to test how changes in the human microbiome are associated with human health or disease.
The Earth Microbiome Project (EMP) is an initiative to collect natural samples and analyze the microbial community around the globe. Microbes are highly abundant, diverse and have an important role in the ecological system. Yet as of 2010, it was estimated that the total global environmental DNA sequencing effort had produced less than 1 percent of the total DNA found in a liter of seawater or a gram of soil, and the specific interactions between microbes are largely unknown. The EMP aims to process as many as 200,000 samples in different biomes, generating a complete database of microbes on earth to characterize environments and ecosystems by microbial composition and interaction. Using these data, new ecological and evolutionary theories can be proposed and tested.
The Brazilian Microbiome Project (BMP) aims to assemble a Brazilian Microbiome Consortium/Database. At present, many metagenomic projects underway in Brazil are widely known. Our goal is to co-ordinate and standardize these, together with future projects. This is the first attempt to collect and collate information about Brazilian microbial genetic and functional diversity in a systematic and holistic manner. New sequence data have been generated from samples collected in all Brazilian regions, however the success of the BMP depends on a massive collaborative effort of both the Brazilian and international scientific communities. Therefore, we invite all colleagues to participate in this project. There is no prioritization of specific taxonomic groups, studies could include any ecosystem, and all proposals and any help will be very welcome.
A philosophical approach to the impacts of microbiomes in human behavior plays a part in Mookie Tenembaum's system of Disillusionism.
# Conclusion
Many more case studies exist than the few presented in this article, which illustrate the diverse interactions that have been shown to exist between macro organisms and their microbial inhabitants. Elucidation of these interactions has required new technologies and an interdisciplinary approach. Genomics and ecology, once separate disciplines, are showing rapid convergence, and may together allow us to understand the molecular basis underlying the adaptations and interactions of the communities of life. | Microbiome
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: microbiota
# Overview
A microbiota is "the ecological community of commensal, symbiotic and pathogenic microorganisms that literally share our body space."[1][2] Joshua Lederberg coined the term, arguing the importance of microorganisms inhabiting the human body in health and disease. Many scientific articles distinguish microbiome and microbiota to describe either the collective genomes of the microorganisms that reside in an environmental niche or the microorganisms themselves, respectively.[3][4][5] However by the original definitions these terms are largely synonymous.
The human body contains over 10 times more microbial cells than human cells, although the entire microbiome only weighs about 200 grams. Because bacteria are 10-100 times smaller than human cells, the entire microbiome weighs about 200 grams, with some weight estimates ranging as high as 3 pounds (approximately 48 ounces or 1,400 grams). Some regard it as a "newly discovered organ" since its existence was not generally recognized until the late 1990s and it is understood to have potentially overwhelming impact on human health.[6] Modern techniques for sequencing DNA have enabled researchers to find the majority of these microbes, since the majority of them cannot be cultured in a lab using current techniques. The human microbiome may have a role in auto-immune diseases like diabetes, rheumatoid arthritis, muscular dystrophy, multiple sclerosis, fibromyalgia, and perhaps some cancers. A poor mix of microbes in the gut may also aggravate common obesity. Since some of the microbes in our body can modify the production of neurotransmitters known to be found in the brain, it may also relieve schizophrenia, depression, bipolar disorder and other neuro-chemical imbalances.
The microbes being discussed are generally non-pathogenic (they do not cause disease unless they grow abnormally); they exist in harmony and symbiotically with their hosts.[7]
# Introduction
All plants and animals, from protists to humans, live in close association with microbial organisms (see for example the human microbiome). Up until relatively recently, however, biologists have defined the interactions of plants and animals with the microbial world mostly in the context of disease states and of a relatively small number of symbiotic case studies. Organisms do not live in isolation, but have evolved in the context of complex communities. A number of advances have driven a change in the perception of microbiomes, including:
- the ability to perform genomic and gene expression analyses of single cells and even of entire microbial communities in the new disciplines of metagenomics and metatranscriptonomics
- massive databases making this information accessible to researchers across multiple disciplines
- methods of mathematical analysis that help researchers to make sense of complex data sets
Increasingly, biologists have come to appreciate that microbes make up an important part of an organism's phenotype, far beyond the occasional symbiotic case study.[8]
Pierre-Joseph van Beneden (1809-1894), a Belgian professor at the University of Louvain, developed the concept of commensalism during the nineteenth century. In his 1875 publication Animal Parasites and Messmates, Van Beneden presented 264 examples of commensalism. His conception was widely accepted by his contemporaries and commensalism has continued to be used as a concept right up to the present day: microbiome is clearly linked to commensalism.[9]
# Case studies
There is a strengthening consensus among evolutionary biologists that one should not separate an organism's genes from the context of its resident microbes.
## Studies in humans
- Community sequencing of total gut microbiota taken from obese and lean twins show substantial differences in their compositions. Total population sequences were analyzed to determine the levels of enzymes involved in carbohydrate, lipid, and amino acid metabolism. Obesity is associated with phylum-level differences in the microbiota, a significantly reduced bacterial diversity, and an increase in the population expression of enzymes which result in an increased efficiency of calorie harvest in the diets of the obese twins.[10]
- Type I diabetes is an autoimmune disease that is correlated with a multiplicity of predisposing factors, including an aberrant intestinal microbiota, a leaky intestinal mucosal barrier, and intrinsic differences in immune responsiveness. Various animal models for diabetes have shown a role for bacteria in the onset of the disease. Community DNA sequencing of intestinal flora comparing healthy and autoimmune children showed that autoimmune children had relatively unstable gut biomes with significantly decreased levels of species diversity, and the populations showed large scale replacement of Firmicutes species with Bacteroidetes species.[11]
- Human skin represents the most extensive organ of the human body, whose functions include protecting the body from pathogens, preventing loss of moisture, and participating in the regulation of body temperature. Considered as an ecosystem, the skin supports a range of microbial communities that live in distinct niches. Hair-covered scalp lies but a few inches from exposed neck, which in turn lies inches away from moist hairy underarms, but these niches are, at a microbial level, as distinct as a temperate forest would be compared with savanna and tropical rain forest. Studies characterizing the microbiota that inhabit these different niches are providing insights into the balance between skin health and disease.[12]
- Prevention of urogenital diseases in women depends on healthy vaginal microbiomes, but what is meant by "healthy" has not been understood. Community population studies using advanced sequencing methodologies (including pyrosequencing) are yielding insights into the range of microbial diversity in the human vagina. An unexpected finding was the prevalence of Prevotella species, which are known to positively affect the growth of Gardnerella vaginalis and Peptostreptococcus anaerobius, two species linked to bacterial vaginosis, by providing these disease-associated bacteria with key nutrients.[13]
- A proposal has been made to classify people by enterotype, based on the composition of the gut microbiome. By combining 22 newly sequenced fecal metagenomes of individuals from four countries with previously published data sets, three robust clusters were identified that are not nation or continent specific.[14][15]
- The traditional view of the immune system is that it is a complex assembly of organs, tissues, cells and molecules that work together to eliminate pathogens. Modifications to this traditional view, that the immune system has evolved to control microbes, have come from the discovery that microbes coevolve with and exert control upon the immune system. It is known that germ-free animals possess an underdeveloped immune system. The biology of the T helper 17 cells (Th17) has generated interest due to their key role in inflammatory processes. Excessive amounts of the cell are thought to play a key role in autoimmune diseases such as multiple sclerosis, psoriasis, juvenile diabetes, rheumatoid arthritis, Crohn's disease, and autoimmune uveitis. It has been discovered that specific microbiota direct the differentiation of Th17 cells in the mucosa of the small intestine.[16]
## Animal studies
- A massive, worldwide decline in amphibian populations has been well-publicised. Habitat loss and over-exploitation account for part of the problem, but many other processes seem to be at work. The spread of the virulent fungal disease chytridiomycosis represents an enigma.[17] The ability of some species to coexist with the causative agent Batrachochytrium dendrobatidis appears to be due to the expression of antimicrobial skin peptides along with the presence of symbiotic microbes that benefit the host by resisting pathogen colonization or inhibiting their growth while being themselves resistant to high concentrations of antimicrobial skin peptides.[18]
- The bovine rumen harbors a complex microbiome that converts plant cell wall biomass into proteins, short chain fatty acids, and gases. Multiple species are involved in this conversion. Traditional methods of characterizing the microbial population, based on culture analysis, missed many of the participants in this process. Comparative metagenomic studies yielded the surprising result that individual steer had markedly different community structures, predicted phenotype, and metabolic potentials,[19] even though they were fed identical diets, were housed together, and were apparently functionally identical in their utilization of plant cell wall resources.
- Leaf-cutter ants form huge underground colonies with millions of workers, each colony harvesting hundreds of kilograms of leaves each year. Unable to digest the cellulose in the leaves directly, they maintain fungus gardens that are the colony's primary food source. The fungus itself does not digest cellulose. Instead, a microbial community containing a diversity of bacteria is responsible for cellulose digestion. Analysis of the microbial population's genomic content by community metagenome sequencing methods revealed the presence of many genes with a role in cellulose digestion. This microbiome's predicted carbohydrate-degrading enzyme profile is similar to that of the bovine rumen, but the species composition is almost entirely different.[20]
- Mice are the most used models for human disease. As more and more diseases are linked to dysfunctional microbiomes, mice have become the most studied organism in this regard. Mostly it is the gut microbiota that have been studied in relation to allergic airway disease, obesity, gastointesinal diseses and diabetes. Intriguingly, recent work has shown that perinatal shifting of microbiota through administration of low dose antibiotics can have long lasting effects on future susceptibility to allergic airway disease.[21][22] These studies showed a remarkable link between the frequency of certain subsets of microbes and disease severity. In aggregate these studies suggest that the presence of specific microbes, early in postnatal life, play an instructive role in the development of future immune responses. Mechanistically, a recent study done on gnotobiotic mice described a method in which certain strains of gut bacteria were found to transmit a particular phenotype to recipient germ-free mice, identifying an unanticipated range of bacterial strains that promoted accumulation of colonic regulatory T cells, as well as strains that modulated mouse adiposity and cecal metabolite concentrations. This combinatorial approach enables a systems-level understanding of microbial contributions to human biology.[23] But also other mucoide tissues as lung and vagina have been studies in relation to diseses such as asthma, allergy and vaginosis [24]
## Plant studies
- Plants exhibit a broad range of relationships with symbiotic microorganisms, ranging from parasitism, in which the association is disadvantageous to the host organism, to mutualism, in which the association is beneficial to both, to commensalism, in which the symbiont benefits while the host is not affected. Exchange of nutrients between symbiotic partners is an important part of the relationship: it may be bidirectional or unidirectional, and it may be context dependent. The strategies for nutrient exchange are highly diverse. Oomycetes and fungi have, through convergent evolution, developed similar morphology and occupy similar ecological niches. They develop hyphae, filamentous structures that penetrate the host cell. In those cases where the association is mutualistic, the plant often exchanges hexose sugars for inorganic phosphate from the fungal symbiont. It is speculated that such associations, which are very ancient, may have aided plants when they first colonized land.[25][26]
- A huge range of bacterial symbionts colonize plants. Many of these are pathogenic, but others known as plant-growth promoting bacteria (PGPB) provide the host with essential services such as nitrogen fixation, solubilization of minerals such as phosphorus, synthesis of plant hormones, direct enhancement of mineral uptake, and protection from pathogens.[27][28] PGPBs may protect plants from pathogens by competing with the pathogen for an ecological niche or a substrate, producing inhibitory allelochemicals, or inducing systemic resistance in host plants to the pathogen[29]
# Effects on pathogenesis of various diseases
### Depression
Microbes are also implicated in depression. The pathogenic bacteria Borrelia burgdorferi causes Lyme disease which causes depression in up to 2/3 of all cases.[30] Non-pathogenic bacteria are also implicated in depression in which bacterial populations are suppressed. One model of depression is periodic separation of infant mice from their mothers. These mice show reductions in Lactobacillus and Bifidobacterium species, functional gut abnormalities, increased corticosterone (stress hormone) levels, weight loss, and causes them to not swim as much in a forced swim test as control mice, indicating behavioural despair. Treating the mice with Lactobacillus lowered corticosterone levels and gut abnormalities.[31] Another experiment has replicated the effect that germ free mice have an exaggerated stress response and also found reduced expression of brain-derived neurotrophic factor in the cortex and hippocampus.[32] Another experiment showed that treating the maternally separated mice with a probiotic culture of Bifodobacterium infantis minimizes weight loss, causes mice to swim longer and causes an increase in the amount of the serotonin precursor tryptophan produced.[33] Increasing serotonin levels through selective serotonin reuptake inhibitors is the primary treatment of depression in humans. Human patients with depression are less able to properly digest fructose,[34] which is also associated with a reduction in tryptophan production.[35] Eliminating fructose from their diet improved their depression.[36]
### Anxiety
Gut microbes are also implicated in anxiety disorders. In humans anxiety disorders are common in patients with disturbed gut flora.[37] The bacteria Campylobacter jejuni has been shown to cause anxious behaviour in mice.[38] Germ free mice show less anxious behaviour and also less NR2B mRNA expression selectively in the central amygdala which might be responsible for the anxiolytic behaviour since NR2B antagonists have an anxiolytic effect on behaviour.[39] The behavioural change might also be caused by increased brain derived neurotrophic factor (BDNF) mRNA expression possibly inducing plasticity in the dentate granular layer of the hippocampus.[40] BDNF and the hippocampus are implicated in memory. Increased gut bacterial diversity has been shown to improve both working and reference memory as well as reducing anxiety-like behaviour.[41]
### Autism
Autistic populations have a unique microbiome consisting of more clostridial species.[42] Half of all autistic children with gastrointestinal dysfunction were found to have the bacteria Sutterella which was completely absent in non-autistic children with gastrointestinal dysfunction.[43] There is evidence that for some children with late-onset autism antibiotics can alleviate symptoms temporarily.[44]
### Endometriosis
Recent research has shown that endometriosis can be caused by Fusobacterium, a bacteria that is part of the normal flora of the oral, gastrointestinal, and genital tracts. This bacterium may play a role in the pathogenesis of endometriosis. Studies indicate that Fusobacterium activates transforming growth factor-β, which, in turn, triggers the transition of quiescent fibroblasts to active myofibroblasts expressing transgelin (TAGLN). These myofibroblasts have the ability to migrate and are believed to be responsible for the fibrosis and adhesions seen in endometriosis. Although not all women with endometriosis have Fusobacterium Infiltration in their endometrium and may not benefit from antibiotic therapy, this research is promising and suggests that Fusobacterium may be an infectious contributor to endometriosis and warrants further study.[45]
### Irritable Bowel Syndrome (IBS)
The precise origin of IBS remains uncertain, but it is believed to be influenced by multiple factors. One significant factor under consideration is the role of gut microbiota[46].In a healthy gut, the intestinal microbiota actively prevent the proliferation and adherence of harmful bacteria to the gastrointestinal (GI) wall.[47] However, an imbalance in the gut microbiota, known as dysbiosis, can result in the attachment of enteric pathogens, potentially contributing to the development of IBS.[48]
### Metabolic Syndrome
Metabolic syndrome is a group of metabolic disease characterized by abdominal obesity, hypertension, insulin resistance and hyperlipidemia according to World Health Organization (WHO).In recent years research have suggested that metabolic syndrome can associated with disturbance the internal microbiota. Internal microbiota is involved in the regulation of immune system, mediation of inflammation, digestion and utilization of nutrients. Alteration in the normal internal microbiota cause disturbance of these function which result in metabolic syndrome. Regulating gut micro biome may be a potential therapy for metabolic syndrome.[49]
# Immune system
The symbiotic relationship between animal host and microbiota has a significant impact on shaping the immune system. The immune system is able to recognize the types of bacteria that are harmful to the host and combats them, while allowing the helpful bacteria to carry out their functions. After an infant is born completely sterile, their gut is quickly populated by commensal bacteria that affect the immune response, resulting in future tolerance to that bacteria. This early colonization helps to establish the symbiotic microbiome inside the host early in its life. The bacteria are also able to stimulate lymphoid tissue associated with the gut mucosa. This enables the tissue to produce antibodies for pathogens that may enter the gut. It has been found that bacteria may also play a role in the activation of TLRs (toll-like receptors) in the intestines. TLRs are a type of PRR (pattern recognition receptor) used by host cells to help repair damage and recognize dangers to the host. This could be important in immune tolerance and autoimmune diseases. Pathogens could influence this symbiotic coexistence leading to immune dysregulation and susceptibility to diseases. This could provide new direction for managing immunological and metabolic diseases.[50]
# Human microbiome
The human microbiome consists of about 100 trillion microbial cells, outnumbering human cells 10 to 1.[51] It can significantly affect human physiology. For example, in healthy individuals the microbiota provide a wide range of metabolic functions that humans lack.[52] In diseased individuals altered microbiota are associated with diseases such as neonatal necrotizing enterocolitis,[53] inflammatory bowel disease[54] and vaginosis.[13] Thus studying the human microbiome is an important task that has been undertaken by initiatives such as the Human Microbiome Project[55] and MetaHIT.[56]
## Studying the human microbiome
The problem of elucidating the human microbiome is essentially identifying the members of a microbial community which includes bacteria, eukaryotes, and viruses. This is done primarily using DNA-based studies, though RNA, protein and metabolite based studies are also performed.[57] DNA-based microbiome studies typically can be categorized as either targeted amplicon studies or more recently shotgun metagenomic studies. The former focuses on specific known marker genes and is primarily informative taxonomically, while the latter is an entire metagenomic approach which can also be used to study the functional potential of the community. One of the challenges that is present in human microbiome studies but not in other metagenomic studies is to avoid including the host DNA in the study.[58]
## Presence of a core microbiome
Aside from simply elucidating the composition of the human microbiome, one of the major questions involving the human microbiome is whether there is a "core", that is, whether there is a subset of the community that is shared between most humans.[59][60] If there is a core, then it would be possible to associate certain community compositions with disease states, which is one of the goals of the Human Microbiome Project. It is known that the human microbiome is highly variable both within a single subject and between different individuals. For example, the gut microbiota of humans is markedly dissimilar between individuals, a phenomenon which is also observed in mice.[61] Hamady and Knight show that one can rule out the possibility that any species is shared among all humans at more than 0.9% abundance in the gut or at more than 2% abundance on hands.[60] Although there is very little species level conservation between individuals, it has been shown that this may be a result of functional redundancy as different communities tend to converge on the same functional state.[10]
On 13 June 2012, a major milestone of the Human Microbiome Project (HMP) was announced by the NIH director Francis Collins.[62] The announcement was accompanied with a series of coordinated articles published in Nature[63][64] and several journals in the Public Library of Science (PLoS) on the same day. By mapping the normal microbial make-up of healthy humans using genome sequencing techniques, the researchers of the HMP have created a reference database and the boundaries of normal microbial variation in humans. From 242 healthy U.S. volunteers, more than 5,000 samples were collected from tissues from 15 (men) to 18 (women) body sites such as mouth, nose, skin, lower intestine (stool), and vagina. All the DNA, human and microbial, were analyzed with DNA sequencing machines. The microbial genome data were extracted by identifying the bacterial specific ribosomal RNA, 16S rRNA. The researchers calculated that more than 10,000 microbial species occupy the human ecosystem and they have identified 81 – 99% of the genera.
# Hologenome theory of evolution
The hologenome theory proposes that the object of natural selection is not the individual organism, but the organism together with its associated microbial communities.
The hologenome theory originated in studies on coral reefs. Coral reefs are the largest structures created by living organisms, and contain abundant and highly complex microbial communities. Over the past several decades, major declines in coral populations have occurred. Climate change, water pollution and over-fishing are three stress factors that have been described as leading to disease susceptibility. Over twenty different coral diseases have been described, but of these, only a handful have had their causative agents isolated and characterized. Coral bleaching is the most serious of these diseases. In the Mediterranean Sea, the bleaching of Oculina patagonica was first described in 1994 and shortly determined to be due to infection by Vibrio shiloi. From 1994 to 2002, bacterial bleaching of O. patagonica occurred every summer in the eastern Mediterranean. Surprisingly, however, after 2003, O. patagonica in the eastern Mediterranean has been resistant to V. shiloi infection, although other diseases still cause bleaching. The surprise stems from the knowledge that corals are long lived, with lifespans on the order of decades,[65] and do not have adaptive immune systems. Their innate immune systems do not produce antibodies, and they should seemingly not be able to respond to new challenges except over evolutionary time scales. The puzzle of how corals managed to acquire resistance to a specific pathogen led Eugene Rosenberg and Ilana Zilber-Rosenberg to propose the Coral Probiotic Hypothesis. This hypothesis proposes that a dynamic relationship exists between corals and their symbiotic microbial communities. By altering its composition, this "holobiont" can adapt to changing environmental conditions far more rapidly than by genetic mutation and selection alone. Extrapolating this hypothesis of adaptation and evolution to other organisms, including higher plants and animals, led to the proposal of the Hologenome Theory of Evolution.[66]
The hologenome theory is still being debated.[67] A major criticism has been the claim that V. shiloi was misidentified as the causative agent of coral bleaching, and that its presence in bleached O. patagonica was simply that of opportunistic colonization.[68] If this is true, the basic observation leading to the theory would be invalid. Nevertheless, the theory has gained significant popularity as a way of explaining rapid changes in adaptation that cannot otherwise be explained by traditional mechanisms of natural selection. For those who accept the hologenome theory, the holobiont has become the principal unit of natural selection.
# Research methods
## Targeted amplicon sequencing
Targeted amplicon sequencing relies on having some expectations about the composition of the community that is being studied. In target amplicon sequencing a phylogenetically informative marker is targeted for sequencing. Such a marker should be present in ideally all the expected organisms. It should also evolve in such a way that it is conserved enough that primers can target genes from a wide range of organisms while evolving quickly enough to allow for finer resolution at the taxonomic level. A common marker for human microbiome studies is the gene for bacterial 16S rRNA (i.e. "16S rDNA", the sequence of DNA which encodes the ribosomal RNA molecule).[57] Since ribosomes are present in all living organisms, using 16S rDNA allows for DNA to be amplified from many more organisms than if another marker were used. The 16S rDNA gene contains both slowly evolving regions and fast evolving regions; the former can be used to design broad primers while the latter allow for finer taxonomic distinction. However, species-level resolution is not typically possible using the 16S rDNA. Primer selection is an important step, as anything that cannot be targeted by the primer will not be amplified and thus will not be detected. Different sets of primers have been shown to amplify different taxonomic groups due to sequence variation.
Targeted studies of eukaryotic and viral communities are limited[69] and subject to the challenge of excluding host DNA from amplification and the reduced eukaryotic and viral biomass in the human microbiome.[58]
After the amplicons are sequenced, molecular phylogenetic methods are used to infer the composition of the microbial community. This is done by clustering the amplicons into operational taxonomic units (OTUs) and inferring phylogenetic relationships between the sequences. Due to the complexity of the data, distance measures such as UniFrac distances are usually defined between microbiome samples, and downstream multivariate methods are carried out on the distance matrices. An important point is that the scale of data is extensive, and further approaches must be taken to identify patterns from the available information. Tools used to analyze the data include VAMPS,[70] QIIME[71] and mothur.[72]
## Metagenomic sequencing
Metagenomics is also used extensively for studying microbial communities.[10][56][73] In metagenomic sequencing, DNA is recovered directly from environmental samples in an untargeted manner with the goal of obtaining an unbiased sample from all genes of all members of the community. Recent studies use shotgun Sanger sequencing or pyrosequencing to recover the sequences of the reads.[74] The reads can then be assembled into contigs. To determine the phylogenetic identity of a sequence, it is compared to available full genome sequences using methods such as BLAST. One drawback of this approach is that many members of microbial communities do not have a representative sequenced genome.[57]
Despite the fact that metagenomics is limited by the availability of reference sequences, one significant advantage of metagenomics over targeted amplicon sequencing is that metagenomics data can elucidate the functional potential of the community DNA.[75][76] Targeted gene surveys cannot do this as they only reveal the phylogenetic relationship between the same gene from different organisms. Functional analysis is done by comparing the recovered sequences to databases of metagenomic annotations such as KEGG. The metabolic pathways that these genes are involved in can then be predicted with tools such as MG-RAST,[77] CAMERA[78] and IMG/M.[79]
## RNA and protein-based approaches
Metatranscriptomics studies have been performed to study the gene expression of microbial communities through methods such as the pyrosequencing of extracted RNA.[80] Structure based studies have also identified non-coding RNAs (ncRNAs) such as ribozymes from microbiota.[81] Metaproteomics is a new approach that studies the proteins expressed by microbiota, giving insight into its functional potential.[82]
# Projects
The Human Microbiome Project (HMP) is a United States National Institutes of Health initiative with the goal of identifying and characterizing the microorganisms which are found in association with both healthy and diseased humans (their microbial flora). Launched in 2008, it is a five-year project, best characterized as a feasibility study, and has a total budget of $115 million. The ultimate goal of this and similar NIH-sponsored microbiome projects is to test how changes in the human microbiome are associated with human health or disease.
The Earth Microbiome Project (EMP) is an initiative to collect natural samples and analyze the microbial community around the globe. Microbes are highly abundant, diverse and have an important role in the ecological system. Yet as of 2010[update], it was estimated that the total global environmental DNA sequencing effort had produced less than 1 percent of the total DNA found in a liter of seawater or a gram of soil, and the specific interactions between microbes are largely unknown. The EMP aims to process as many as 200,000 samples in different biomes, generating a complete database of microbes on earth to characterize environments and ecosystems by microbial composition and interaction. Using these data, new ecological and evolutionary theories can be proposed and tested.
The Brazilian Microbiome Project (BMP) aims to assemble a Brazilian Microbiome Consortium/Database. At present, many metagenomic projects underway in Brazil are widely known. Our goal is to co-ordinate and standardize these, together with future projects. This is the first attempt to collect and collate information about Brazilian microbial genetic and functional diversity in a systematic and holistic manner. New sequence data have been generated from samples collected in all Brazilian regions, however the success of the BMP depends on a massive collaborative effort of both the Brazilian and international scientific communities. Therefore, we invite all colleagues to participate in this project. There is no prioritization of specific taxonomic groups, studies could include any ecosystem, and all proposals and any help will be very welcome.
A philosophical approach to the impacts of microbiomes in human behavior plays a part in Mookie Tenembaum's system of Disillusionism.
# Conclusion
Many more case studies exist than the few presented in this article, which illustrate the diverse interactions that have been shown to exist between macro organisms and their microbial inhabitants. Elucidation of these interactions has required new technologies and an interdisciplinary approach. Genomics and ecology, once separate disciplines, are showing rapid convergence, and may together allow us to understand the molecular basis underlying the adaptations and interactions of the communities of life.[8] | https://www.wikidoc.org/index.php/Microbiome | |
1b3d927d33bcbe53c35fa060347e4289fc3cfdeb | wikidoc | Microgyrus | Microgyrus
A microgyrus is an area of the cerebral cortex that includes only four cortical layers instead of six.
Microgyria are believed by some to be the cause of, or one of the causes of, dyslexia.
Albert Galaburda of Harvard Medical School noticed that language centers in dyslexic brains showed microscopic flaws known as ectopias and microgyria. Both affect the normal six-layer structure of the cortex. These flaws affect connectivity and functionality of the cortex in critical areas related to sound and visual processing. These and similar structural abnormalities may be the basis of the inevitable and hard to overcome difficulty in reading. | Microgyrus
A microgyrus is an area of the cerebral cortex that includes only four cortical layers instead of six.
Microgyria are believed by some to be the cause of, or one of the causes of, dyslexia.
Albert Galaburda of Harvard Medical School noticed that language centers in dyslexic brains showed microscopic flaws known as ectopias and microgyria. Both affect the normal six-layer structure of the cortex. These flaws affect connectivity and functionality of the cortex in critical areas related to sound and visual processing. These and similar structural abnormalities may be the basis of the inevitable and hard to overcome difficulty in reading.
Template:Health-stub
# External links
- [Cerebral microgyria, thalamic cell size and auditory temporal processing in male and female rats]http://www.ncbi.nlm.nih.gov/pubmed/9261574
- The neurological basis of developmental dyslexia
- Another article on the subject
- Birthdates of neurons in induced microgyria
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Microgyria | |
d5f99f4dc961c8898f134600f2de4d9afeffbbe4 | wikidoc | Micropenis | Micropenis
Micropenis is a medical term that describes an unusually small penis in a human male.
A common criterion is a dorsal (measured on top) erect penile length at least 2.5 standard deviations smaller than the mean penis size. The condition is usually recognized shortly after birth. The term is most often used medically when the rest of the penis, scrotum, and perineum is without ambiguity such as hypospadias.
# Causes
Of the abnormal conditions associated with micropenis, most are conditions of reduced prenatal androgen production or effect. Examples include abnormal testicular development (testicular dysgenesis, Klinefelter syndrome, Leydig cell hypoplasia), specific defects of testosterone or dihydrotestosterone synthesis (17,20-lyase deficiency, 5α-reductase deficiency), androgen insensitivity syndromes, inadequate pituitary stimulation (gonadotropin deficiency) or other forms of congenital hypogonadism. Micropenis can also occur as part of many genetic malformation syndromes not involving the sex chromosomes. It sometimes is a sign of congenital growth hormone deficiency or congenital hypopituitarism. Finally, several Homeobox genes have been identified which affects penis and digit size without detectable hormone abnormalities.
After evaluation to detect any of the conditions described above, micropenis can often be treated in infancy with injections of various hormones, such as human chorionic gonadotropin or testosterone.
Most eight to fourteen year old boys referred for micropenis do not have the micropenis condition. Such concerns are usually explained by one of the following:
- a penis concealed in suprapubic fat (extra fat around the mons pubis).
- a large body and frame for which a prepubertal penis simply appears too small.
- delayed puberty with every reason to expect good future growth.
# Treatment
## Hormone treatment
Growth of the penis both before birth and during childhood and puberty is strongly influenced by testosterone and, to a lesser degree, growth hormone, but their value in the treatment of micropenis is mainly limited to conditions of hormone deficiency such as hypopituitarism or hypogonadism.
Regardless of the cause of a micropenis, if it is recognized in infancy, a brief course of testosterone is often prescribed (usually no more than 3 months). This will usually induce a small amount of growth, confirming the likelihood of further growth at puberty, but rarely achieves normal size. No additional testosterone is given during childhood to avoid unwanted virilization and bone maturation. (There is also some evidence that premature administration of testosterone can lead to reduced penis size in the adult.)
Testosterone treatment is resumed in adolescence only for boys with hypogonadism. Penile growth is completed at the end of puberty, similarly to the completion of height growth, and provision of extra testosterone to post-pubertal adults will produce little or no further growth.
## Surgery
Because hormone treatment rarely achieves average size, a number of surgical techniques like phalloplasty for penis enlargement have been devised and performed but are not generally considered successful enough to be widely adopted and are rarely performed in childhood.
In extreme cases of micropenis, there is barely any shaft, and the glans appears to sit almost on the pubic skin. From the 1960s until the late 1970s, it was not unusual for sex reassignment and surgery to be recommended. This was especially likely if evidence suggested that response to additional testosterone and pubertal testosterone would be poor. If parents accepted, the boy would be reassigned and renamed as a girl, and surgery performed to remove the testes and construct an artificial vagina. This was based on three now questioned assumptions:
- gender identity and sex differences were solely a matter of social learning rather than biology.
- a male with a penis too small to put into a vagina could not find a satisfactory social and sexual place in society.
- a functionally acceptable vagina could be constructed surgically.
The center most known for this approach (Johns Hopkins Hospital) performed twelve such reassignments between 1960 and 1980, most notably, that of David Reimer, overseen by Dr. John Money. By the mid-1990s reassignment was less often offered, and all three premises had been challenged. Former subjects of such surgery, vocally dissatisfied with adult outcome, played a large part in discouraging this practice. As a result, sexual reassignment is rarely performed today for severe micropenis (although the issue of raising the child as a girl is sometimes still discussed.) Much inaccurate or exaggerated folklore on this topic is available on the internet. (See History of intersex surgery for a more complete discussion of this issue.)
# Micropenis in studies
A relatively high incidence of alleles believed to cause the micropenis condition have been found in a Japanese study of patients with micropenis, consisting of 81 Japanese patients. The presence of a micropenis in these subjects is considered to be due to a higher mutation rate for the SRD5A2 gene, which encodes for the enzyme 5{alpha}-reductase-2 and plays a role in male sex differentiation. The mutation led to decreased expression of the enzyme, which in turn results in penises with erect lengths of -2.5 standard deviations. In the case of the Japanese sample, hormone treatments were also studied and found to be effective, resulting in penis lengths at nearly the average of age-matched Japanese controls (2-3 cm). After extended study of various micropenises, it can be concluded that this condition has severe effects both mentally and physically for the patient. | Micropenis
Editor-in-Chief: Joel Gelman, M.D. [1], Director of the Center for Reconstructive Urology and Associate Clinical Professor in the Department of Urology at the University of California, Irvine
Micropenis is a medical term that describes an unusually small penis in a human male.
A common criterion is a dorsal (measured on top) erect penile length at least 2.5 standard deviations smaller than the mean penis size.[1] The condition is usually recognized shortly after birth. The term is most often used medically when the rest of the penis, scrotum, and perineum is without ambiguity such as hypospadias.
# Causes
Of the abnormal conditions associated with micropenis, most are conditions of reduced prenatal androgen production or effect. Examples include abnormal testicular development (testicular dysgenesis, Klinefelter syndrome, Leydig cell hypoplasia), specific defects of testosterone or dihydrotestosterone synthesis (17,20-lyase deficiency, 5α-reductase deficiency), androgen insensitivity syndromes, inadequate pituitary stimulation (gonadotropin deficiency) or other forms of congenital hypogonadism. Micropenis can also occur as part of many genetic malformation syndromes not involving the sex chromosomes. It sometimes is a sign of congenital growth hormone deficiency or congenital hypopituitarism. Finally, several Homeobox genes have been identified which affects penis and digit size without detectable hormone abnormalities.
After evaluation to detect any of the conditions described above, micropenis can often be treated in infancy with injections of various hormones, such as human chorionic gonadotropin or testosterone.
Most eight to fourteen year old boys referred for micropenis do not have the micropenis condition. Such concerns are usually explained by one of the following:
- a penis concealed in suprapubic fat (extra fat around the mons pubis).
- a large body and frame for which a prepubertal penis simply appears too small.
- delayed puberty with every reason to expect good future growth.
# Treatment
## Hormone treatment
Growth of the penis both before birth and during childhood and puberty is strongly influenced by testosterone and, to a lesser degree, growth hormone, but their value in the treatment of micropenis is mainly limited to conditions of hormone deficiency such as hypopituitarism or hypogonadism.
Regardless of the cause of a micropenis, if it is recognized in infancy, a brief course of testosterone is often prescribed[2] (usually no more than 3 months). This will usually induce a small amount of growth, confirming the likelihood of further growth at puberty, but rarely achieves normal size. No additional testosterone is given during childhood to avoid unwanted virilization and bone maturation. (There is also some evidence that premature administration of testosterone can lead to reduced penis size in the adult.)[3]
Testosterone treatment is resumed in adolescence only for boys with hypogonadism. Penile growth is completed at the end of puberty, similarly to the completion of height growth, and provision of extra testosterone to post-pubertal adults will produce little or no further growth.
## Surgery
Because hormone treatment rarely achieves average size, a number of surgical techniques like phalloplasty for penis enlargement have been devised and performed but are not generally considered successful enough to be widely adopted and are rarely performed in childhood.
In extreme cases of micropenis, there is barely any shaft, and the glans appears to sit almost on the pubic skin. From the 1960s until the late 1970s, it was not unusual for sex reassignment and surgery to be recommended. This was especially likely if evidence suggested that response to additional testosterone and pubertal testosterone would be poor. If parents accepted, the boy would be reassigned and renamed as a girl, and surgery performed to remove the testes and construct an artificial vagina. This was based on three now questioned assumptions:
- gender identity and sex differences were solely a matter of social learning rather than biology.
- a male with a penis too small to put into a vagina could not find a satisfactory social and sexual place in society.
- a functionally acceptable vagina could be constructed surgically.
The center most known for this approach (Johns Hopkins Hospital) performed twelve such reassignments between 1960 and 1980, most notably, that of David Reimer, overseen by Dr. John Money. By the mid-1990s reassignment was less often offered, and all three premises had been challenged. Former subjects of such surgery, vocally dissatisfied with adult outcome, played a large part in discouraging this practice. As a result, sexual reassignment is rarely performed today for severe micropenis (although the issue of raising the child as a girl is sometimes still discussed.)[4] Much inaccurate or exaggerated folklore on this topic is available on the internet. (See History of intersex surgery for a more complete discussion of this issue.)
# Micropenis in studies
A relatively high incidence of alleles believed to cause the micropenis condition have been found in a Japanese study of patients with micropenis, consisting of 81 Japanese patients. The presence of a micropenis in these subjects is considered to be due to a higher mutation rate for the SRD5A2 gene, which encodes for the enzyme 5{alpha}-reductase-2 and plays a role in male sex differentiation.[5] The mutation led to decreased expression of the enzyme, which in turn results in penises with erect lengths of -2.5 standard deviations. In the case of the Japanese sample, hormone treatments were also studied and found to be effective, resulting in penis lengths at nearly the average of age-matched Japanese controls (2-3 cm). After extended study of various micropenises, it can be concluded that this condition has severe effects both mentally and physically for the patient. | https://www.wikidoc.org/index.php/Micropenis | |
a8a1d4ac5138e1a7ba08a6f8967dd3c075dfdc7f | wikidoc | Microscope | Microscope
# Overview
A microscope (Greek: Template:Polytonic (micron) = small + Template:Polytonic (skopein) = to look at) is an instrument for viewing objects that are too small to be seen by the naked or unaided eye. The science of investigating small objects using such an instrument is called microscopy. The term microscopic means minute or very small, not visible with the eye unless aided by a microscope. The microscopes used in schools and homes trace their history back almost 400 years.
The first useful microscope was developed in the Netherlands in the early 1600s. Three different eyeglass makers have been given credit for the invention: Hans Lippershey (who also developed the first real telescope); Hans Janssen; and his son, Zacharias. The coining of the name "microscope" has been credited to Giovanni Faber, who gave that name to Galileo Galilei's compound microscope in 1625. (Galileo had called it the "occhiolino" or "little eye".)
The most common type of microscope—and the first to be invented—is the optical microscope. This is an optical instrument containing one or more lenses that produce an enlarged image of an object placed in the focal plane of the lens(es). There are, however, many other microscope designs.
# Types
"Microscopes" can largely be separated into three classes, optical theory microscopes, electron microscopes and scanning probe microscopes.
Optical theory microscopes are microscopes which function through the optical theory of lenses in order to magnify the image generated by the passage of a wave through the sample. The waves used are either electromagnetic in optical microscopes or electron beams in electron microscopes. The types are the Compound Light, Stereo, and the electron microscope.
## Optical microscopes
Optical microscopes, through their use of visible wavelengths of light, are the simplest and hence most widely used type of microscope.
Optical microscopes use refractive lenses, typically of glass and occasionally of plastic, to focus light into the eye or another light detector. Typical magnification of a light microscope is up to 1500x with a theoretical resolution of around 0.2 micrometres or 200 nanometers. Specialised techniques (e.g., scanning confocal microscopy) may exceed this magnification but the resolution is an insurmountable diffraction limit.
Various wavelengths of light are sometimes used for special purposes, for example, in the study of biological tissue. Ultraviolet light is used to illuminate the object being viewed in order to excite a fluorescent dye which then emits visible light. Infrared light is used to study thick slices of biological tissue because infrared light's low diffraction coefficient permits viewing deeper into tissue.
Other microscopes which use electromagnetic wavelengths not visible to the human eye are often called optical microscopes. The most common of these, due to its high resolution yet no requirement for a vacuum like electron microscopes, is the x-ray microscope.
## Electron microscopes
Electron microscopes, which use beams of electrons instead of light, are designed for very high magnification usage. Electrons, which can be accelerated to produce a much smaller wavelength than visible light, allow a much higher resolution. The main limitation of the electron beam is that it must pass through a vacuum as air molecules would otherwise scatter the beam.
Instead of relying on refraction, lenses for electron microscopes are specially designed electromagnets which generate magnetic fields that are approximately parallel to the direction that electrons travel. The electrons are typically detected by a phosphor screen, photographic film or a charged-coupled device (CCD).
Two major variants of electron microscopes exist:
- Scanning electron microscope: looks at the surface of bulk objects by scanning the surface with a fine electron beam and measuring reflection. May also be used for spectroscopy.
- Transmission electron microscope: passes electrons completely through the sample, analogous to basic optical microscopy. This requires careful sample preparation, since electrons are scattered so strongly by most materials. It can also obtain detailed information on the sample's crystallography through selected area diffraction
## Scanning probe microscope
In scanning probe microscopy (SPM), a physical probe is used either in close contact to the sample or nearly touching it. By rastering the probe across the sample, and by measuring the interactions between the sharp tip of the probe and the sample, a micrograph is generated. The exact nature of the interactions between the probe and the sample determines exactly what kind of SPM is being used. Because this kind of microscopy relies on the interactions between the tip and the sample, it generally only measures information about the surface of the sample.
A variation of the SPM is the SECM (Scanning ElectroChemical Microscope). A SECM images a sample in a similar manner as a SPM but the sample is in an electrolyte solution with the SECM using electrochemically active tip.
## Other microscopes
Scanning acoustic microscopes use sound waves to measure variations in acoustic impedance. Similar to Sonar in principle, they are used for such jobs as detecting defects in the subsurfaces of materials including those found in integrated circuits. | Microscope
Template:Infobox Laboratory equipment
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A microscope (Greek: Template:Polytonic (micron) = small + Template:Polytonic (skopein) = to look at) is an instrument for viewing objects that are too small to be seen by the naked or unaided eye. The science of investigating small objects using such an instrument is called microscopy. The term microscopic means minute or very small, not visible with the eye unless aided by a microscope. The microscopes used in schools and homes trace their history back almost 400 years.
The first useful microscope was developed in the Netherlands in the early 1600s.[1] Three different eyeglass makers have been given credit for the invention: Hans Lippershey (who also developed the first real telescope); Hans Janssen; and his son, Zacharias. The coining of the name "microscope" has been credited to Giovanni Faber, who gave that name to Galileo Galilei's compound microscope in 1625. (Galileo had called it the "occhiolino" or "little eye".)
The most common type of microscope—and the first to be invented—is the optical microscope. This is an optical instrument containing one or more lenses that produce an enlarged image of an object placed in the focal plane of the lens(es). There are, however, many other microscope designs.
# Types
"Microscopes" can largely be separated into three classes, optical theory microscopes, electron microscopes and scanning probe microscopes.
Optical theory microscopes are microscopes which function through the optical theory of lenses in order to magnify the image generated by the passage of a wave through the sample. The waves used are either electromagnetic in optical microscopes or electron beams in electron microscopes. The types are the Compound Light, Stereo, and the electron microscope.
## Optical microscopes
Optical microscopes, through their use of visible wavelengths of light, are the simplest and hence most widely used type of microscope.
Optical microscopes use refractive lenses, typically of glass and occasionally of plastic, to focus light into the eye or another light detector. Typical magnification of a light microscope is up to 1500x with a theoretical resolution of around 0.2 micrometres or 200 nanometers. Specialised techniques (e.g., scanning confocal microscopy) may exceed this magnification but the resolution is an insurmountable diffraction limit.
Various wavelengths of light are sometimes used for special purposes, for example, in the study of biological tissue.[2] Ultraviolet light is used to illuminate the object being viewed in order to excite a fluorescent dye which then emits visible light. Infrared light is used to study thick slices of biological tissue because infrared light's low diffraction coefficient permits viewing deeper into tissue.
Other microscopes which use electromagnetic wavelengths not visible to the human eye are often called optical microscopes. The most common of these, due to its high resolution yet no requirement for a vacuum like electron microscopes, is the x-ray microscope.
## Electron microscopes
Electron microscopes, which use beams of electrons instead of light, are designed for very high magnification usage. Electrons, which can be accelerated to produce a much smaller wavelength than visible light, allow a much higher resolution. The main limitation of the electron beam is that it must pass through a vacuum as air molecules would otherwise scatter the beam.
Instead of relying on refraction, lenses for electron microscopes are specially designed electromagnets which generate magnetic fields that are approximately parallel to the direction that electrons travel. The electrons are typically detected by a phosphor screen, photographic film or a charged-coupled device (CCD).
Two major variants of electron microscopes exist:
- Scanning electron microscope: looks at the surface of bulk objects by scanning the surface with a fine electron beam and measuring reflection. May also be used for spectroscopy.
- Transmission electron microscope: passes electrons completely through the sample, analogous to basic optical microscopy. This requires careful sample preparation, since electrons are scattered so strongly by most materials. It can also obtain detailed information on the sample's crystallography through selected area diffraction
## Scanning probe microscope
In scanning probe microscopy (SPM), a physical probe is used either in close contact to the sample or nearly touching it. By rastering the probe across the sample, and by measuring the interactions between the sharp tip of the probe and the sample, a micrograph is generated. The exact nature of the interactions between the probe and the sample determines exactly what kind of SPM is being used. Because this kind of microscopy relies on the interactions between the tip and the sample, it generally only measures information about the surface of the sample.
A variation of the SPM is the SECM (Scanning ElectroChemical Microscope). A SECM images a sample in a similar manner as a SPM but the sample is in an electrolyte solution with the SECM using electrochemically active tip[3].
## Other microscopes
Scanning acoustic microscopes use sound waves to measure variations in acoustic impedance. Similar to Sonar in principle, they are used for such jobs as detecting defects in the subsurfaces of materials including those found in integrated circuits.
# External links
- Nikon MicroscopyU, tutorials from Nikon
- Molecular Expressions : Exploring the World of Optics and Microscopy, Florida State University.
- "Microscopes made from bamboo" nature.com | https://www.wikidoc.org/index.php/Microscope | |
b699e2da739ea009f237b9663165d4b8005025c9 | wikidoc | Middle age | Middle age
Middle age is the period of life beyond young adulthood but before the onset of old age. Various attempts have been made to define this age, which is around the third quarter of the average life span of human beings.
According to Collins Dictionary, this is "... usually considered to occur approximately between the ages of 40 and 60".
The OED gives a similar definition but with a later start point "... the period between youth and old age, about 45 to 60".
The US Census lists middle age as including both the age categories 35 to 44 and 45 to 54, whilst Erik Erikson sees it ending a little later and defines middle adulthood as between 40 and 65.
In many Western societies, this is seen to be the period of life in which a person is expected to have settled down in terms of their sense of identity and place in the world, be raising a family, and have established career stability. It is also a period often associated with the potential onset of mid-life crisis.
# Health
Middle-aged adults often show visible signs of aging such as loss of skin elasticity and graying of the hair. Physical fitness usually wanes, with a 5-10 kg (10-20 lb) accumulation of body fat, reduction in aerobic performance and a decrease in maximal heart rate. Strength and flexibility also decrease throughout middle age. However, people age at different rates and there can be large differences between individuals of the same age.
Female fertility declines significantly after age 40, and an advanced maternal age increases the risk of a child being born with some disorders such as Down’s Syndrome. Some conditions are also correlated with advanced paternal age. Most women go through the menopause, which ends natural fertility, in their late 40s or 50s.
In developed countries, yearly mortality begins to increase from age 40 onwards, mainly due to age-related health problems such as heart disease and cancer. However, the majority of middle-aged people in industrialized nations can expect to live into old age. Life expectancy in developing countries is much lower and the risk of death at all ages is higher.
# The prime of life
Some people challenge the concept that middle age is something to dread. They assert that with the right attitude and careful planning, middle age can be truly a person's best years. Those age-positive groups range from advocacy groups such as the American Association of Retired Persons (AARP) to purely social clubs like the Red Hat Society.
# Further listening
- Does Age Quash Our Spirit of Adventure?, a segment on NPR's "All Things Considered" on an aging study done by middle-age neuroscientist Robert Sapolsky
- Ali Khan, Living Fully at Forty and Beyond | Middle age
Middle age is the period of life beyond young adulthood but before the onset of old age. Various attempts have been made to define this age, which is around the third quarter of the average life span of human beings.
According to Collins Dictionary, this is "... usually considered to occur approximately between the ages of 40 and 60".
The OED gives a similar definition but with a later start point "... the period between youth and old age, about 45 to 60".
The US Census lists middle age as including both the age categories 35 to 44 and 45 to 54, whilst Erik Erikson sees it ending a little later and defines middle adulthood as between 40 and 65.
In many Western societies, this is seen to be the period of life in which a person is expected to have settled down in terms of their sense of identity and place in the world, be raising a family, and have established career stability. It is also a period often associated with the potential onset of mid-life crisis.
# Health
Middle-aged adults often show visible signs of aging such as loss of skin elasticity and graying of the hair. Physical fitness usually wanes, with a 5-10 kg (10-20 lb) accumulation of body fat, reduction in aerobic performance and a decrease in maximal heart rate. Strength and flexibility also decrease throughout middle age. However, people age at different rates and there can be large differences between individuals of the same age. [1]
Female fertility declines significantly after age 40, and an advanced maternal age increases the risk of a child being born with some disorders such as Down’s Syndrome. Some conditions are also correlated with advanced paternal age. Most women go through the menopause, which ends natural fertility, in their late 40s or 50s. [2]
In developed countries, yearly mortality begins to increase from age 40 onwards, mainly due to age-related health problems such as heart disease and cancer. [3] [4] However, the majority of middle-aged people in industrialized nations can expect to live into old age. Life expectancy in developing countries is much lower and the risk of death at all ages is higher. [3]
# The prime of life
Some people [5] challenge the concept that middle age is something to dread. They assert that with the right attitude and careful planning, middle age can be truly a person's best years. Those age-positive groups range from advocacy groups such as the American Association of Retired Persons (AARP) to purely social clubs like the Red Hat Society.
# Further listening
- Does Age Quash Our Spirit of Adventure?, a segment on NPR's "All Things Considered" on an aging study done by middle-age neuroscientist Robert Sapolsky
- Ali Khan, Living Fully at Forty and Beyond | https://www.wikidoc.org/index.php/Middle_age | |
0b55ef27f305789be15f18dde190b46fbd018110 | wikidoc | Right lung | Right lung
# Overview
The Right lung is divided into three lobes, superior, middle, and inferior, by two interlobular fissures:
# Fissures
- One of these, the oblique fissure, separates the inferior from the middle and superior lobes, and corresponds closely with the fissure in the left lung. Its direction is, however, more vertical, and it cuts the lower border about 7.5 cm. behind its anterior extremity.
- The other fissure, the horizontal fissure, separates the superior from the middle lobe. It begins in the previous fissure near the posterior border of the lung, and, running horizontally forward, cuts the anterior border on a level with the sternal end of the fourth costal cartilage; on the mediastinal surface it may be traced backward to the hilus.
# Lobes
The middle lobe, the smallest lobe of the right lung, is wedge-shaped, and includes the lower part of the anterior border and the anterior part of the base of the lung. (There is no middle lobe on the left lung, though there is a lingula.)
The superior and inferior lobes are similar to their counterparts on the left lung.
# Difference in size
The right lung, although shorter by 2.5 cm. than the left, in consequence of the diaphragm rising higher on the right side to accommodate the liver, is broader, owing to the inclination of the heart to the left side; its total capacity is greater and it weighs more than the left lung.
# Impressions
On the mediastinal surface, immediately above the hilus, is an arched furrow which accommodates the azygos vein; while running upward, and then arching lateralward some little distance below the apex, is a wide groove for the superior vena cava and right innominate vein; behind this, and nearer the apex, is a furrow for the innominate artery.
Behind the hilus and the attachment of the pulmonary ligament is a vertical groove for the esophagus; this groove becomes less distinct below, owing to the inclination of the lower part of the esophagus to the left of the middle line.
In front and to the right of the lower part of the esophageal groove is a deep concavity for the extrapericardiac portion of the thoracic part of the inferior vena cava.
# Additional images
- Anatomy of lungs.
- Front view of heart and lungs.
- Transverse section of thorax, showing relations of pulmonary artery.
- The position and relation of the esophagus in the cervical region and in the posterior mediastinum. Seen from behind.
- The thymus of a full-time fetus, exposed in situ. | Right lung
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The Right lung is divided into three lobes, superior, middle, and inferior, by two interlobular fissures:
# Fissures
- One of these, the oblique fissure, separates the inferior from the middle and superior lobes, and corresponds closely with the fissure in the left lung. Its direction is, however, more vertical, and it cuts the lower border about 7.5 cm. behind its anterior extremity.
- The other fissure, the horizontal fissure, separates the superior from the middle lobe. It begins in the previous fissure near the posterior border of the lung, and, running horizontally forward, cuts the anterior border on a level with the sternal end of the fourth costal cartilage; on the mediastinal surface it may be traced backward to the hilus.
# Lobes
The middle lobe, the smallest lobe of the right lung, is wedge-shaped, and includes the lower part of the anterior border and the anterior part of the base of the lung. (There is no middle lobe on the left lung, though there is a lingula.)
The superior and inferior lobes are similar to their counterparts on the left lung.
# Difference in size
The right lung, although shorter by 2.5 cm. than the left, in consequence of the diaphragm rising higher on the right side to accommodate the liver, is broader, owing to the inclination of the heart to the left side; its total capacity is greater and it weighs more than the left lung.
# Impressions
On the mediastinal surface, immediately above the hilus, is an arched furrow which accommodates the azygos vein; while running upward, and then arching lateralward some little distance below the apex, is a wide groove for the superior vena cava and right innominate vein; behind this, and nearer the apex, is a furrow for the innominate artery.
Behind the hilus and the attachment of the pulmonary ligament is a vertical groove for the esophagus; this groove becomes less distinct below, owing to the inclination of the lower part of the esophagus to the left of the middle line.
In front and to the right of the lower part of the esophageal groove is a deep concavity for the extrapericardiac portion of the thoracic part of the inferior vena cava.
# Additional images
- Anatomy of lungs.
- Front view of heart and lungs.
- Transverse section of thorax, showing relations of pulmonary artery.
- The position and relation of the esophagus in the cervical region and in the posterior mediastinum. Seen from behind.
- The thymus of a full-time fetus, exposed in situ. | https://www.wikidoc.org/index.php/Middle_lobe | |
4abb5c1c6ce67ee047e4f4500277b2d378093f94 | wikidoc | Mind's eye | Mind's eye
# Overview
The phrase "mind's eye" refers to the human ability for visual perception, imagination, visualization, and memory, or, in other words, one's ability to "see" things with the mind.
# Physical basis
The biological foundation of the mind's eye is not fully understood. fMRI studies have shown that the lateral geniculate nucleus and the V1 area of the visual cortex are activated during mental imagery tasks. Ratey writes:
The visual pathway is not a one-way street. Higher areas of the brain can also send visual input back to neurons in lower areas of the visual cortex... As humans, we have the ability to see with the mind's eye -to have a perceptual experience in the absence of visual input. For example, PET scans have shown that when subjects, seated in a room, imagine they are at their front door starting to walk either to the left or right, activation begins in the visual association cortex, the parietal cortex, and the prefrontal cortex - all higher cognitive processing centers of the brain.
Not all humans have this ability. With eyes closed, some humans report that they can visualize, or imagine, detailed scenery that is not just a memory. Others however, cannot. These humans report that while details of visual memories can be recalled (with eyes open), the images themselves cannot be brought up, even with eyes closed.
Users of hallucinogenic drugs report seeing images with eyes closed, however the images are random and hard to control, and may interfere with normal consciousness.
# Philosophy
The use of the phrase mind's eye does not imply that there is a single or unitary place in the mind or brain where visual consciousness occurs. Various philosophers have criticized this view, Daniel Dennett being one of the best-known. However, others, such as Johnjoe McFadden of the University of Surrey in the UK and the New Zealand-based neurobiologist Susan Pockett, have proposed that the brain's electromagnetic field is consciousness itself, thus causing the perception of a unitary location. | Mind's eye
Template:Otheruses1
# Overview
The phrase "mind's eye" refers to the human ability for visual perception, imagination, visualization, and memory, or, in other words, one's ability to "see" things with the mind.
# Physical basis
The biological foundation of the mind's eye is not fully understood. fMRI studies have shown that the lateral geniculate nucleus and the V1 area of the visual cortex are activated during mental imagery tasks.[1] Ratey writes:
The visual pathway is not a one-way street. Higher areas of the brain can also send visual input back to neurons in lower areas of the visual cortex... As humans, we have the ability to see with the mind's eye -to have a perceptual experience in the absence of visual input. For example, PET scans have shown that when subjects, seated in a room, imagine they are at their front door starting to walk either to the left or right, activation begins in the visual association cortex, the parietal cortex, and the prefrontal cortex - all higher cognitive processing centers of the brain.[2]
Not all humans have this ability. With eyes closed, some humans report that they can visualize, or imagine, detailed scenery that is not just a memory. Others however, cannot. These humans report that while details of visual memories can be recalled (with eyes open), the images themselves cannot be brought up, even with eyes closed[citation needed].
Users of hallucinogenic drugs report seeing images with eyes closed, however the images are random and hard to control, and may interfere with normal consciousness.
# Philosophy
The use of the phrase mind's eye does not imply that there is a single or unitary place in the mind or brain where visual consciousness occurs. Various philosophers have criticized this view, Daniel Dennett being one of the best-known.[3] However, others, such as Johnjoe McFadden of the University of Surrey in the UK and the New Zealand-based neurobiologist Susan Pockett, have proposed that the brain's electromagnetic field is consciousness itself, thus causing the perception of a unitary location.[4][5] | https://www.wikidoc.org/index.php/Mind%27s_eye | |
ccfac74795580388244ce10012fe42d2d9d5d2bf | wikidoc | Mipomersen | Mipomersen
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# Black Box Warning
# Overview
Mipomersen is a lipid-lowering medication that is FDA approved for the {{{indicationType}}} of hypercholesterolemia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include injection site reactions, flu-like symptoms, nausea, headache, and elevations in serum transaminases, specifically ALT.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- KynamroTM is indicated as an adjunct to lipid-lowering medications and diet to reduce low density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apo B), total cholesterol (TC), and non-high density lipoprotein-cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH).
- Limitations of Use
- The safety and effectiveness of Kynamro have not been established in patients with hypercholesterolemia who do not have HoFH.
- The effect of Kynamro on cardiovascular morbidity and mortality has not been determined.
- The safety and effectiveness of Kynamro as an adjunct to LDL apheresis have not been established; therefore, the use of Kynamro as an adjunct to LDL apheresis is not recommended.
- Dosing Information
- Before beginning treatment with Kynamro, measure transaminases (ALT, AST), alkaline phosphatase, and total bilirubin.
- The recommended dose of Kynamro is 200 milligrams (mg) once weekly as a subcutaneous injection.
- Kynamro is intended for subcutaneous use only. Do not administer intramuscularly or intravenously.
- The injection should be given on the same day every week, but if a dose is missed, the injection should be given at least 3 days from the next weekly dose.
- After initiation of Kynamro therapy lipid levels should be monitored at least every 3 months for the first year. Maximal reduction of LDL-C may be seen with Kynamro therapy after approximately 6 months (based on the time to steady state seen in clinical studies). Health care providers should assess the patient’s LDL-C level after 6 months to determine if the LDL-C reduction achieved with Kynamro is sufficiently robust to warrant the potential risk of liver toxicity.
- Administration
- Each vial or pre-filled syringe of Kynamro provides 200 mg of mipomersen sodium in a deliverable volume of 1 milliliter (mL) of solution and is intended for single-use only.
- The Kynamro vial or pre-filled syringe should be removed from 2-8°C (36-46°F) refrigerated storage and allowed to reach room temperature for at least 30 minutes prior to administration.
- Parenteral drug products should be inspected visually prior to administration. If the solution is cloudy or contains visible particulate matter, the contents must not be injected and the product should be returned to the pharmacy.
- The first injection administered by the patient or caregiver should be performed under the guidance and supervision of an appropriately qualified health care professional.
- Kynamro should be injected into the abdomen, thigh region, or outer area of the upper arm. Kynamro should not be injected in areas of active skin disease or injury such as sunburns, skin rashes, inflammation, skin infections, active areas of psoriasis, etc. Areas of tattooed skin and scarring should also be avoided.
- Adjustments for Patients Developing transaminase Elevations
- Table 1 summarizes recommendations for monitoring for patients who develop elevated transaminases during therapy with Kynamro.
- If transaminase elevations are accompanied by clinical symptoms of liver injury (e.g., nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin ≥ 2x ULN, or active liver disease, discontinue treatment with Kynamro and investigate to identify the probable cause.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mipomersen in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Mipomersen 200 mg subQ once weekly.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness have not been established in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mipomersen in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mipomersen in pediatric patients.
# Contraindications
- Moderate or severe hepatic impairment (Child-Pugh B or C) or active liver disease, including unexplained persistent elevations of serum transaminases.
- Patients with a known hypersensitivity to any component of this product.
# Warnings
- Kynamro can cause elevations in transaminases and hepatic steatosis, as described below. To what extent Kynamro-associated hepatic steatosis promotes the elevations in transaminases is unknown. There is concern that Kynamro could induce steatohepatitis, which can progress to cirrhosis over several years. The clinical studies supporting the safety and efficacy of Kynamro in HoFH would have been unlikely to detect this adverse outcome given their size and duration.
- Kynamro can cause increases in serum transaminases (alanine aminotransferase and/or aspartate aminotransferase ). In the clinical trial, 4 (12%) of the 34 subjects with HoFH treated with Kynamro compared to 0% of the 17 subjects treated with placebo had an elevation in ALT ≥ 3x ULN, and 3 (9%) of those treated with Kynamro compared to 0% treated with placebo had at least one elevation in ALT ≥ 5x ULN.
- Measure a full liver panel to include ALT, AST, total bilirubin, and alkaline phosphatase before initiation of treatment with Kynamro. Kynamro is contraindicated in patients with moderate or severe hepatic impairment, or active liver disease, including unexplained persistent elevations of serum transaminases. If the baseline liver-related tests are abnormal, consider initiating Kynamro after an appropriate work-up and the baseline abnormalities are explained or resolved. During the first year, conduct liver-related tests monthly (ALT and AST, at a minimum). After the first year, conduct these tests at least every 3 months. Discontinue Kynamro for persistent or clinically significant elevations.
- If transaminase elevations are accompanied by clinical symptoms of liver injury (e.g., nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin ≥ 2x ULN, or active liver disease, discontinue treatment with Kynamro and identify the probable cause.
- Kynamro increases hepatic fat (steatosis) with or without concomitant increases in transaminases. Hepatic steatosis is a risk factor for advanced liver disease, including steatohepatitis and cirrhosis. The long-term consequences of hepatic steatosis associated with Kynamro therapy are unknown. During the clinical trials in patients with heterozygous familial hypercholesterolemia (HeFH) and hyperlipidemia, the median absolute increase in hepatic fat was 10% after 26 weeks of treatment, from 0% at baseline, measured by magnetic resonance imaging (MRI).
- Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury. It is recommended that patients taking Kynamro should consume no more than one alcoholic drink per day.
- Caution should be exercised when Kynamro is used with other medications known to have potential for hepatotoxicity, for example isotretinoin, amiodarone, acetaminophen (>4 g/day for ≥ 3 days/week), methotrexate, tetracyclines, and tamoxifen. The effect of concomitant administration of Kynamro with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
- Mipomersen has not been studied concomitantly with other LDL-lowering agents that can also increase hepatic fat. Therefore, the combined use of such agents is not recommended.
- Because of the risk of hepatotoxicity, Kynamro is available only through a limited program under the REMS. Under the Kynamro REMS, only certified healthcare providers and pharmacies may prescribe and distribute Kynamro. Further information is available at www.KynamroREMS.com or by telephone at 1-877-Kynamro (1-877-596-2676).
- Injection site reactions have been reported in 84% of patients receiving Kynamro therapy. These local reactions typically consist of one or more of the following: erythema, pain, tenderness, pruritus and local swelling. Injection site reactions do not occur with all injections but resulted in discontinuation of therapy in 5% of patients in pooled Phase 3 trials. To minimize the potential for injection site reactions, proper technique for subcutaneous administration should be followed.
- Flu-like symptoms have been reported in 30% of patients receiving Kynamro therapy and include one or more of the following: influenza-like illness, pyrexia, chills, myalgia, arthralgia, malaise or fatigue. Flu-like symptoms, which typically occur within 2 days after an injection, do not occur with all injections but resulted in discontinuation of therapy in 3% of patients in pooled Phase 3 trials.
# 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 trial of another drug and may not reflect the rates observed in patients in clinical practice.
- Safety data are based on pooled results from four Phase 3, randomized, double-blind, placebo-controlled trials with a total of 390 patients of which 261 patients received weekly subcutaneous injections of 200 mg of Kynamro and 129 patients received placebo for a median treatment duration of 25 weeks (age range 12-81 years, 47% women, 84% Caucasian, 10% Blacks, 3% Asian, 3% other). For the 141 participants who subsequently enrolled in the open-label extension trial, the mean length of study treatment, including exposure to Kynamro in the index study, was 19.8 months and the median was 18.2 months. A total of 41 individuals with HoFH were exposed to Kynamro for at least 6 months and 25 were exposed for at least 12 months.
- Eighteen percent of patients on Kynamro and 2% of patients on placebo discontinued treatment due to adverse reactions. The five most common adverse reactions in patients treated with Kynamro that led to treatment discontinuation and occurred at a rate greater than placebo were: injection site reactions (5.0%), alanine aminotransferase increased (3.4%), flu-like symptoms (2.7%), aspartate aminotransferase increased (2.3%), and liver function test abnormal (1.5%).
- Table 2 enumerates adverse reactions that occurred among pooled Phase 3 patients treated with Kynamro at an incidence that was at least 2% more than that observed in the placebo-treated patients, listed by system organ class and frequency (MedDRA v.13.0). Similar types and severities of adverse reactions were observed across all populations in this pooled table including the subset of patients with HoFH.
- In the pooled Phase 3 trials, neoplasms (benign and malignant) were reported in 4% of patients receiving Kynamro and 0% of patients receiving placebo. In addition, 9% of patients receiving Kynamro and 3% of patients receiving placebo developed 1+ or greater proteinuria by dipstick measurement by the end of the trial.
- In the open-label extension trial, one case of hypersensitivity reaction with angioedema and one case of glomerular nephritis were reported.
- In the pooled, placebo-controlled clinical trials with Kynamro, elevated serum transaminase levels, mainly ALT, have been observed as presented in Table 3. Elevated ALT levels ≥ 3x ULN have been reported on two consecutive occasions at least 7 days apart in 8.4% of patients receiving Kynamro therapy (versus 0% of placebo patients) with 16.5% of patients receiving Kynamro therapy having at least 1 result that was ≥ 3x ULN (versus 0.8% for placebo patients). The ALT elevations observed in the pooled, placebo-controlled trials were generally accompanied by lesser AST elevations and were not associated with increased total bilirubin, changes in INR or PTT, nor by decreased albumin levels. After stopping therapy, in the patients in whom an elevation was observed, transaminase elevations trended toward baseline over a period of weeks to months.
- Increases in liver fat as measured by MRI were greater in patients receiving Kynamro therapy than in patients receiving placebo. Data from Phase 3 supportive trials in patients with heterozygous familial hypercholesterolemia and coronary artery disease and in patients with high risk hypercholesterolemia demonstrated after 26 weeks of treatment, a median nominal increase in fat fraction of 9.6% relative to baseline following Kynamro therapy versus a nominal 0.02% change in the placebo group (mean increases were 12.2% mipomersen vs 0.4% placebo). The maximum change in fat fraction was 46% for the Kynamro group and 28% for the placebo group. Sixty-two percent of patients receiving Kynamro developed a 5% or greater increase in hepatic fat versus 8% of patients receiving placebo. In general, these elevations in fat fraction decreased when assessed by MRI performed 24 weeks after cessation of Kynamro in the Phase 3 trial of patients with high-risk hypercholesterolemia. In the open-label extension trial, among individuals with a measurement at baseline and at 12 months or longer on Kynamro, 25% had an average liver fat fraction > 20% on at least one occasion.
- The most commonly-reported adverse reactions were injection site reactions occurring in 84% of patients receiving Kynamro versus 33% of placebo treated patients. The most common injection site reactions were erythema (59%), pain (56%), hematoma (32%), pruritus (29%), swelling (18%) and discoloration (17%). Injection site reactions did not occur with every injection. Injection site reactions resulted in discontinuation of Kynamro in 5% of patients. Recall reactions, consisting of local erythema, tenderness and/or pruritus at previous injection sites when subsequent injections were administered, were observed in 8% of patients, all of whom were receiving Kynamro.
- Flu-like symptoms, defined as any one of the following: influenza-like illness, pyrexia, chills, myalgia, arthralgia, malaise or fatigue and occurring within 2 days of injection, have been reported more frequently in patients receiving Kynamro (29.9%) versus placebo (16.3%) in the pooled Phase 3 studies. Flu-like symptoms did not occur with all injections. Flu-like symptoms resulted in discontinuation of Kynamro in 2.7% of patients. In the open-label extension trial, in which all patients received Kynamro therapy, 66% reported flu-like symptoms, 25% discontinued treatment due to flu-like symptoms and 9% experienced severe flu-like symptoms.
- In the pooled Phase 3 trials, 38% of Kynamro-treated patients tested positive for anti-Kynamro antibodies during the 6-month trials. Efficacy results in the Phase 3 trials in patients who tested positive for anti-Kynamro antibodies were similar to patients who remained negative for antibodies (mean LDL-C percent change from baseline was -32% for antibody-positive and -34% for antibody-negative participants). In the open-label extension trial, approximately 72% of patients receiving Kynamro therapy tested positive for anti-Kynamro antibodies (35% with titers >3200). The incidence of flu-like symptoms and the incidence of discontinuation of Kynamro were higher in antibody-positive patients. Antibodies to Kynamro were associated with higher trough levels for the drug. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Kynamro with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Mipomersen in the drug label.
# Drug Interactions
- No clinically relevant pharmacokinetic interactions were reported between Kynamro and warfarin, or between Kynamro and simvastatin or ezetimibe. Additionally, coadministration of Kynamro with warfarin did not result in a pharmacodynamic interaction as determined by INR, aPTT and PT.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- There are no adequate and well-controlled studies in pregnant women. Reproduction and embryofetal development studies performed in mice at doses up to 87.5 mg/kg/wk given by subcutaneous administration from mating through organogenesis and in pregnant rabbits given 52.5 mg/kg/wk, show no evidence of impaired fertility or harm to the fetus at 2 (mice) to 5 (rabbits) times clinical exposure at a 200 mg/wk therapeutic dose. Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed.
- Pregnant rats given subcutaneous doses of 7, 35, 70 mg/kg/wk mipomersen sodium from gestation day 6 through weaning on lactation day 20, resulted in decreased rat pup survival at 70 mg/kg/wk, 3-times clinical exposure at a 200 mg/wk therapeutic dose based on body surface area comparisons across species. Dose related decreases in pup body weights, impaired reflexes and grip strength were observed at 35 mg/kg/wk (2-times the anticipated human dose). Levels of mipomersen in rat milk were very low (≤ 0.92 µg/mL at subcutaneous doses up to 70 mg/kg/wk). Due to the poor oral bioavailability of mipomersen sodium, it was considered unlikely that these low milk exposure levels adversely affected the pups during lactation.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mipomersen in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Mipomersen during labor and delivery.
### Nursing Mothers
- It is not known whether Kynamro is excreted in human milk. Because many drugs are excreted in human milk a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
- Levels of mipomersen present in rat milk were low (≤ 0.92 µg/mL) given subcutaneous doses up to 70 mg/kg/wk. Oral bioavailability is expected to be less than 10%. However a risk to newborns/infants cannot be excluded, therefore caution should be used when Kynamro is administered to a nursing woman.
- Lactating rats administered mipomersen sodium at doses up to 70 mg/kg/wk (3-times the anticipated systemic exposure from a 200 mg/wk dose, based on body surface area comparison) consumed less food while nursing. This correlated with reduced weight gain in the rat pups, and decreased pup survival in litters of dams given 70 mg/kg/wk.
### Pediatric Use
- Safety and effectiveness have not been established in pediatric patients.
- A juvenile toxicity study was conducted in rats at doses up to 50 mg/kg/wk (2-times the systemic exposure from a 200 mg/wk clinical dose based on body surface area comparisons). Doses > 10 mg/kg/wk were associated with reduced body weight gain in young rats, but had no effect on long bone growth or sexual development.
### Geriatic Use
- Clinical studies of Kynamro did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of the 51 patients enrolled in the Phase 3 trial in HoFH, the mean age was 31 years and the oldest patient in the trial was 53 years. Of the 261 patients who received Kynamro in the pooled Phase 3 trials, 59 (22.6%) were ≥ 65 years old and 10 (3.8%) were ≥ 75 years old. In the pooled Phase 3 trials, patients ≥ 65 years of age treated with Kynamro had a higher incidence of hypertension and peripheral edema compared to placebo patients in this age group, as well as compared to the younger Kynamro-treated age group. Hepatic steatosis was also reported with greater frequency in the ≥ 65 group (13.6%) compared to the <65 group (10.4%).
### Gender
There is no FDA guidance on the use of Mipomersen with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Mipomersen with respect to specific racial populations.
### Renal Impairment
- The safety and efficacy of Kynamro treatment in patients with known renal impairment or in patients undergoing renal dialysis have not been established. Due to the lack of clinical data and Kynamro’s renal safety profile, Kynamro is not recommended in patients with severe renal impairment, clinically significant proteinuria, or on renal dialysis.
### Hepatic Impairment
- The safety and efficacy of Kynamro treatment in patients with known hepatic impairment have not been established. Kynamro is contraindicated in patients with clinically significant hepatic dysfunction, which may include persistent elevations of transaminases.
### Females of Reproductive Potential and Males
- Kynamro may cause fetal harm. Females who become pregnant during Kynamro therapy should notify their healthcare provider.
- Contraception
- Females of reproductive potential should use effective contraception during Kynamro therapy.
### Immunocompromised Patients
There is no FDA guidance one the use of Mipomersen in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Mipomersen in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Mipomersen in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- There have been no reports of overdose with Kynamro treatment. In clinical trials, patients receiving higher doses of Kynamro (300 mg and 400 mg once weekly for 13 weeks) experienced adverse reactions similar to the adverse reactions experienced by patients receiving treatment with 200 mg once weekly but at slightly higher rates and greater severity. Liver-related tests should be monitored.
### Management
- Although there is no information on the effect of hemodialysis in treating an overdose with mipomersen, hemodialysis is unlikely to be useful in overdose management since mipomersen is highly bound to plasma proteins.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Mipomersen in the drug label.
# Pharmacology
## Mechanism of Action
- Mipomersen is an antisense oligonucleotide targeted to human messenger ribonucleic acid (mRNA) for apo B-100, the principal apolipoprotein of LDL and its metabolic precursor, VLDL. Mipomersen is complementary to the coding region of the mRNA for apo B-100, and binds by Watson and Crick base pairing. The hybridization of mipomersen to the cognate mRNA results in RNase H-mediated degradation of the cognate mRNA thus inhibiting translation of the apo B-100 protein.
- The in vitro pharmacologic activity of mipomersen was characterized in human hepatoma cell lines (HepG2, Hep3B) and in human and cynomolgus monkey primary hepatocytes. In these experiments, mipomersen selectively reduced apo B mRNA, protein and secreted protein in a concentration- and time-dependent manner. The effects of mipomersen were shown to be highly sequence-specific. The binding site for mipomersen lies within the coding region of the apo B mRNA at the position 3249-3268 relative to the published sequence GenBank accession number NM_000384.1.
## Structure
- Kynamro (mipomersen sodium) Injection is a sterile, preservative-free, clear, colorless to slightly yellow, aqueous solution for subcutaneous injection. Kynamro is supplied in single-use, 2 mL, clear glass vials or single-use, 1 mL, clear glass pre-filled syringes filled to deliver 1 mL of solution containing 200 mg of mipomersen sodium (200 mg per 1 mL). Kynamro is formulated in water for injection and may include hydrochloric acid and/or sodium hydroxide for pH adjustment to 7.5 – 8.5.
- Mipomersen sodium is an oligonucleotide inhibitor of apo B-100 synthesis. ApoB is the principal apolipoprotein of LDL and its metabolic precursor, very low density lipoprotein (VLDL). Mipomersen inhibits synthesis of apoB by sequence-specific binding to its messenger ribonucleic acid (mRNA) resulting in degradation of the mRNA through enzyme-mediated pathways or disruption of mRNA function through binding alone.
- Mipomersen sodium is a synthetic phosphorothioate oligonucleotide sodium salt, 20 nucleotides in length, with the following sequence:
- Mipomersen sodium is represented by the following structural formula:
## Pharmacodynamics
- At a concentration of 3.8 times the Cmax of the maximum recommended dose (200 mg subcutaneous injection), mipomersen does not prolong the QTc interval to any clinically relevant extent.
## Pharmacokinetics
- Single- and multiple-dose pharmacokinetics of mipomersen in healthy volunteers and in patients with FH and non-FH has shown that mipomersen plasma exposure increases with increasing dose in the range of 30 mg to 400 mg.
- Following subcutaneous injection, peak concentrations of mipomersen are typically reached in 3 to 4 hours. The estimated plasma bioavailability of mipomersen following subcutaneous administration over a dose range of 50 mg to 400 mg, relative to intravenous administration, ranged from 54% to 78%.
- Mipomersen is highly bound to human plasma proteins (≥ 90%) at clinically relevant concentrations (1-8 µg/mL). Mipomersen has a distribution plasma half-life of approximately 2 to 5 hours.
- With once weekly dosing, plasma trough levels increase over time and approach steady-state, typically within 6 months.
- Mipomersen is not a substrate for CYP450 metabolism, and is metabolized in tissues by endonucleases to form shorter oligonucleotides that are then substrates for additional metabolism by exonucleases.
- The elimination of mipomersen involves both metabolism in tissues and excretion, primarily in urine. Both mipomersen and putative shorter oligonucleotide metabolites were identified in human urine. Urinary recovery was limited in humans with less than 4% within the 24 hours post dose. Following subcutaneous administration, elimination half-life for mipomersen is approximately 1 to 2 months.
- No clinically relevant pharmacokinetic interactions were reported between mipomersen and warfarin, or between mipomersen and simvastatin or ezetimibe. The results of these studies are summarized in Figures 1 and 2.
## Nonclinical Toxicology
- In a subcutaneous carcinogenicity study in mice, mipomersen sodium was administered for up to 104 weeks at doses of 5, 20, 60 mg/kg/week. There were statistically significant increases in the incidences of hepatocellular adenoma and combined adenoma and carcinoma in female mice at 60 mg/kg/wk (2-times the systemic clinical exposure at 200 mg/wk, based on a body surface area comparison) for both mipomersen sodium and the mouse-specific analog. This dose also resulted in statistically significant increases in the incidence of hemangiosarcomas in female mice and fibrosarcomas of the skin/subcutis in male mice.
- In a subcutaneous carcinogenicity study in rats, mipomersen sodium was administered for up to 104 weeks at doses of 3, 10, 20 mg/kg/wk. The incidence of fibrosarcomas of the skin/subcutis and the combination of fibroma, fibrosarcomas and malignant fibrous histiocytoma of the skin/subcutis was statistically significantly increased in female rats at 10 mg/kg/wk, at less than clinical exposure at the 200 mg/wk dose based on body surface area comparisons. Both sexes of rats also had statistically significant increases in the incidence of malignant fibrous histiocytoma of the skin/subcutis at 20 mg/kg/wk (at clinical exposure at the 200 mg/wk dose based on body surface area comparisons.
- Mipomersen did not exhibit genotoxic potential in a battery of studies, including the in vitro Bacterial Reverse Mutation (Ames) assay, an in vitro cytogenetics assay using a mouse lymphoma cell line, and an in vivo micronucleus assay in mice.
- Mipomersen sodium had no effect on fertility in mice at doses up to 87.5 mg/kg/wk (2-times clinical exposure at the 200 mg/wk dose based on body surface area comparisons).
- The principal target organs for mipomersen pathology are the kidneys and liver. These organs represent the highest distribution of compound, and exhibit microscopic changes reflective of cellular uptake in macrophages. The most widespread toxicological effect of mipomersen was a spectrum of inflammatory changes in numerous organs, including lymphohistiocytic cell infiltrates and increases in lymphoid organ weights, associated with increases in plasma cytokines, chemokines and total serum IgG. In a chronic monkey study, multi-focal intimal hyperplasia with mixed inflammatory infiltrates was evident in vascular beds in 2 of 6 monkeys treated for 12 months with 30 mg/kg/week with a no-observed-adverse-effect-level (NOAEL) of 10 mg/kg/week (approximately equal to clinical exposures anticipated from a 200 mg/wk dose based on body surface area comparisons across species).
# Clinical Studies
- The safety and effectiveness of Kynamro, given as 200 mg weekly subcutaneous injections, as an adjunct to lipid-lowering medications in individuals with HoFH were evaluated in a multinational, randomized (34 Kynamro; 17 placebo), placebo-controlled, 26-week trial in 51 patients with HoFH. A diagnosis of functional HoFH was defined by the presence of at least one of the following clinical or laboratory criteria: (1) history of genetic testing confirming 2 mutated alleles at the LDLr gene locus, or (2) documented history of untreated LDL-C > 500 mg/dL and at least one of the criteria (a) tendinous and/or cutaneous xanthoma prior to age 10 years or (b) documentation of elevated LDL-C > 190 mg/dL prior to lipid-lowering therapy consistent with HeFH in both parents. In case a parent was not available, a history of coronary artery disease in a first degree male relative of the parent younger than 55 years or first degree female relative of the parent younger than 60 years was acceptable.
- The baseline demographic characteristics were well-matched between the Kynamro and placebo patients. The mean age was 32 years (range, 12 to 53 years), the mean body mass index (BMI) was 26 kg/m2, 43% were men, and the majority (75%) were Caucasian. In 50 of 51 (98%) patients, the background therapy of maximally tolerated lipid-lowering medication included statins. In total, 44 of the 50 (88%) patients were on maximum-dose statin therapy with or without other lipid-lowering medications. Thirty-eight of the 50 (76%) patients were also taking at least one other lipid-lowering medication, most commonly ezetimibe in 37 of 50 (74%) patients; patients were not on LDL apheresis. Eighty-two percent of the Kynamro group and 100% of the placebo group completed the efficacy endpoint at week 28. Adverse events contributed to premature discontinuation for four patients, all in the Kynamro group .
- The primary efficacy endpoint was percent change in LDL-C from baseline to Week 28. At Week 28, the mean and median percent changes in LDL-C from baseline were -25% (p<0.001) and -19%, respectively, for the Kynamro group. The mean and median treatment difference from placebo was -21% (95% confidence interval : -33, -10) and -19%, respectively. Changes in lipids and lipoproteins through the efficacy endpoint at Week 28 are presented in Table 4.
- LDL-C percent changes from baseline with Kynamro were variable among individuals with HoFH ranging from a 2% increase to an 82% reduction. The LDL-C percent changes from baseline in the placebo group range from a 43% increase to a 33% reduction. Mean LDL-C percent changes over time are presented in Figure 3.
# How Supplied
- Kynamro is supplied in single-use, 2 mL, clear glass vials or single-use, 1 mL, clear pre-filled syringes with staked needles. Each single-use vial or single-use pre-filled syringe of Kynamro is filled to deliver 1 mL of 200 mg/mL solution containing 200 mg of mipomersen sodium.
- Kynamro is available in cartons containing 1 or 4 vials and 1 or 4 pre-filled syringes.
- Store refrigerated Kynamro at 2-8 °C (36-46 °F). Kynamro should be protected from light and kept in the original carton until time of use. When refrigeration is not available Kynamro may be stored at or below 30 °C (86 °F), away from heat sources, for up to 14 days. Do not use Kynamro after the expiration date on the label. This product contains no preservatives; any unused drug remaining in vial after extracting 1 mL for injection must be safely discarded.
## Storage
There is limited information regarding Mipomersen Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Mipomersen interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Kynamro®
# Look-Alike Drug Names
- N/A
# Drug Shortage Status
# Price | Mipomersen
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi
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# Black Box Warning
# Overview
Mipomersen is a lipid-lowering medication that is FDA approved for the {{{indicationType}}} of hypercholesterolemia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include injection site reactions, flu-like symptoms, nausea, headache, and elevations in serum transaminases, specifically ALT.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- KynamroTM is indicated as an adjunct to lipid-lowering medications and diet to reduce low density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apo B), total cholesterol (TC), and non-high density lipoprotein-cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH).
- Limitations of Use
- The safety and effectiveness of Kynamro have not been established in patients with hypercholesterolemia who do not have HoFH.
- The effect of Kynamro on cardiovascular morbidity and mortality has not been determined.
- The safety and effectiveness of Kynamro as an adjunct to LDL apheresis have not been established; therefore, the use of Kynamro as an adjunct to LDL apheresis is not recommended.
- Dosing Information
- Before beginning treatment with Kynamro, measure transaminases (ALT, AST), alkaline phosphatase, and total bilirubin.
- The recommended dose of Kynamro is 200 milligrams (mg) once weekly as a subcutaneous injection.
- Kynamro is intended for subcutaneous use only. Do not administer intramuscularly or intravenously.
- The injection should be given on the same day every week, but if a dose is missed, the injection should be given at least 3 days from the next weekly dose.
- After initiation of Kynamro therapy lipid levels should be monitored at least every 3 months for the first year. Maximal reduction of LDL-C may be seen with Kynamro therapy after approximately 6 months (based on the time to steady state seen in clinical studies). Health care providers should assess the patient’s LDL-C level after 6 months to determine if the LDL-C reduction achieved with Kynamro is sufficiently robust to warrant the potential risk of liver toxicity.
- Administration
- Each vial or pre-filled syringe of Kynamro provides 200 mg of mipomersen sodium in a deliverable volume of 1 milliliter (mL) of solution and is intended for single-use only.
- The Kynamro vial or pre-filled syringe should be removed from 2-8°C (36-46°F) refrigerated storage and allowed to reach room temperature for at least 30 minutes prior to administration.
- Parenteral drug products should be inspected visually prior to administration. If the solution is cloudy or contains visible particulate matter, the contents must not be injected and the product should be returned to the pharmacy.
- The first injection administered by the patient or caregiver should be performed under the guidance and supervision of an appropriately qualified health care professional.
- Kynamro should be injected into the abdomen, thigh region, or outer area of the upper arm. Kynamro should not be injected in areas of active skin disease or injury such as sunburns, skin rashes, inflammation, skin infections, active areas of psoriasis, etc. Areas of tattooed skin and scarring should also be avoided.
- Adjustments for Patients Developing transaminase Elevations
- Table 1 summarizes recommendations for monitoring for patients who develop elevated transaminases during therapy with Kynamro.
- If transaminase elevations are accompanied by clinical symptoms of liver injury (e.g., nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin ≥ 2x ULN, or active liver disease, discontinue treatment with Kynamro and investigate to identify the probable cause.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mipomersen in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Mipomersen 200 mg subQ once weekly.[1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness have not been established in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mipomersen in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mipomersen in pediatric patients.
# Contraindications
- Moderate or severe hepatic impairment (Child-Pugh B or C) or active liver disease, including unexplained persistent elevations of serum transaminases.
- Patients with a known hypersensitivity to any component of this product.
# Warnings
- Kynamro can cause elevations in transaminases and hepatic steatosis, as described below. To what extent Kynamro-associated hepatic steatosis promotes the elevations in transaminases is unknown. There is concern that Kynamro could induce steatohepatitis, which can progress to cirrhosis over several years. The clinical studies supporting the safety and efficacy of Kynamro in HoFH would have been unlikely to detect this adverse outcome given their size and duration.
- Kynamro can cause increases in serum transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]). In the clinical trial, 4 (12%) of the 34 subjects with HoFH treated with Kynamro compared to 0% of the 17 subjects treated with placebo had an elevation in ALT ≥ 3x ULN, and 3 (9%) of those treated with Kynamro compared to 0% treated with placebo had at least one elevation in ALT ≥ 5x ULN.
- Measure a full liver panel to include ALT, AST, total bilirubin, and alkaline phosphatase before initiation of treatment with Kynamro. Kynamro is contraindicated in patients with moderate or severe hepatic impairment, or active liver disease, including unexplained persistent elevations of serum transaminases. If the baseline liver-related tests are abnormal, consider initiating Kynamro after an appropriate work-up and the baseline abnormalities are explained or resolved. During the first year, conduct liver-related tests monthly (ALT and AST, at a minimum). After the first year, conduct these tests at least every 3 months. Discontinue Kynamro for persistent or clinically significant elevations.
- If transaminase elevations are accompanied by clinical symptoms of liver injury (e.g., nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin ≥ 2x ULN, or active liver disease, discontinue treatment with Kynamro and identify the probable cause.
- Kynamro increases hepatic fat (steatosis) with or without concomitant increases in transaminases. Hepatic steatosis is a risk factor for advanced liver disease, including steatohepatitis and cirrhosis. The long-term consequences of hepatic steatosis associated with Kynamro therapy are unknown. During the clinical trials in patients with heterozygous familial hypercholesterolemia (HeFH) and hyperlipidemia, the median absolute increase in hepatic fat was 10% after 26 weeks of treatment, from 0% at baseline, measured by magnetic resonance imaging (MRI).
- Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury. It is recommended that patients taking Kynamro should consume no more than one alcoholic drink per day.
- Caution should be exercised when Kynamro is used with other medications known to have potential for hepatotoxicity, for example isotretinoin, amiodarone, acetaminophen (>4 g/day for ≥ 3 days/week), methotrexate, tetracyclines, and tamoxifen. The effect of concomitant administration of Kynamro with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
- Mipomersen has not been studied concomitantly with other LDL-lowering agents that can also increase hepatic fat. Therefore, the combined use of such agents is not recommended.
- Because of the risk of hepatotoxicity, Kynamro is available only through a limited program under the REMS. Under the Kynamro REMS, only certified healthcare providers and pharmacies may prescribe and distribute Kynamro. Further information is available at www.KynamroREMS.com or by telephone at 1-877-Kynamro (1-877-596-2676).
- Injection site reactions have been reported in 84% of patients receiving Kynamro therapy. These local reactions typically consist of one or more of the following: erythema, pain, tenderness, pruritus and local swelling. Injection site reactions do not occur with all injections but resulted in discontinuation of therapy in 5% of patients in pooled Phase 3 trials. To minimize the potential for injection site reactions, proper technique for subcutaneous administration should be followed.
- Flu-like symptoms have been reported in 30% of patients receiving Kynamro therapy and include one or more of the following: influenza-like illness, pyrexia, chills, myalgia, arthralgia, malaise or fatigue. Flu-like symptoms, which typically occur within 2 days after an injection, do not occur with all injections but resulted in discontinuation of therapy in 3% of patients in pooled Phase 3 trials.
# 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 trial of another drug and may not reflect the rates observed in patients in clinical practice.
- Safety data are based on pooled results from four Phase 3, randomized, double-blind, placebo-controlled trials with a total of 390 patients of which 261 patients received weekly subcutaneous injections of 200 mg of Kynamro and 129 patients received placebo for a median treatment duration of 25 weeks (age range 12-81 years, 47% women, 84% Caucasian, 10% Blacks, 3% Asian, 3% other). For the 141 participants who subsequently enrolled in the open-label extension trial, the mean length of study treatment, including exposure to Kynamro in the index study, was 19.8 months and the median was 18.2 months. A total of 41 individuals with HoFH were exposed to Kynamro for at least 6 months and 25 were exposed for at least 12 months.
- Eighteen percent of patients on Kynamro and 2% of patients on placebo discontinued treatment due to adverse reactions. The five most common adverse reactions in patients treated with Kynamro that led to treatment discontinuation and occurred at a rate greater than placebo were: injection site reactions (5.0%), alanine aminotransferase increased (3.4%), flu-like symptoms (2.7%), aspartate aminotransferase increased (2.3%), and liver function test abnormal (1.5%).
- Table 2 enumerates adverse reactions that occurred among pooled Phase 3 patients treated with Kynamro at an incidence that was at least 2% more than that observed in the placebo-treated patients, listed by system organ class and frequency (MedDRA v.13.0). Similar types and severities of adverse reactions were observed across all populations in this pooled table including the subset of patients with HoFH.
- In the pooled Phase 3 trials, neoplasms (benign and malignant) were reported in 4% of patients receiving Kynamro and 0% of patients receiving placebo. In addition, 9% of patients receiving Kynamro and 3% of patients receiving placebo developed 1+ or greater proteinuria by dipstick measurement by the end of the trial.
- In the open-label extension trial, one case of hypersensitivity reaction with angioedema and one case of glomerular nephritis were reported.
- In the pooled, placebo-controlled clinical trials with Kynamro, elevated serum transaminase levels, mainly ALT, have been observed as presented in Table 3. Elevated ALT levels ≥ 3x ULN have been reported on two consecutive occasions at least 7 days apart in 8.4% of patients receiving Kynamro therapy (versus 0% of placebo patients) with 16.5% of patients receiving Kynamro therapy having at least 1 result that was ≥ 3x ULN (versus 0.8% for placebo patients). The ALT elevations observed in the pooled, placebo-controlled trials were generally accompanied by lesser AST elevations and were not associated with increased total bilirubin, changes in INR or PTT, nor by decreased albumin levels. After stopping therapy, in the patients in whom an elevation was observed, transaminase elevations trended toward baseline over a period of weeks to months.
- Increases in liver fat as measured by MRI were greater in patients receiving Kynamro therapy than in patients receiving placebo. Data from Phase 3 supportive trials in patients with heterozygous familial hypercholesterolemia and coronary artery disease and in patients with high risk hypercholesterolemia demonstrated after 26 weeks of treatment, a median nominal increase in fat fraction of 9.6% relative to baseline following Kynamro therapy versus a nominal 0.02% change in the placebo group (mean increases were 12.2% mipomersen vs 0.4% placebo). The maximum change in fat fraction was 46% for the Kynamro group and 28% for the placebo group. Sixty-two percent of patients receiving Kynamro developed a 5% or greater increase in hepatic fat versus 8% of patients receiving placebo. In general, these elevations in fat fraction decreased when assessed by MRI performed 24 weeks after cessation of Kynamro in the Phase 3 trial of patients with high-risk hypercholesterolemia. In the open-label extension trial, among individuals with a measurement at baseline and at 12 months or longer on Kynamro, 25% had an average liver fat fraction > 20% on at least one occasion.
- The most commonly-reported adverse reactions were injection site reactions occurring in 84% of patients receiving Kynamro versus 33% of placebo treated patients. The most common injection site reactions were erythema (59%), pain (56%), hematoma (32%), pruritus (29%), swelling (18%) and discoloration (17%). Injection site reactions did not occur with every injection. Injection site reactions resulted in discontinuation of Kynamro in 5% of patients. Recall reactions, consisting of local erythema, tenderness and/or pruritus at previous injection sites when subsequent injections were administered, were observed in 8% of patients, all of whom were receiving Kynamro.
- Flu-like symptoms, defined as any one of the following: influenza-like illness, pyrexia, chills, myalgia, arthralgia, malaise or fatigue and occurring within 2 days of injection, have been reported more frequently in patients receiving Kynamro (29.9%) versus placebo (16.3%) in the pooled Phase 3 studies. Flu-like symptoms did not occur with all injections. Flu-like symptoms resulted in discontinuation of Kynamro in 2.7% of patients. In the open-label extension trial, in which all patients received Kynamro therapy, 66% reported flu-like symptoms, 25% discontinued treatment due to flu-like symptoms and 9% experienced severe flu-like symptoms.
- In the pooled Phase 3 trials, 38% of Kynamro-treated patients tested positive for anti-Kynamro antibodies during the 6-month trials. Efficacy results in the Phase 3 trials in patients who tested positive for anti-Kynamro antibodies were similar to patients who remained negative for antibodies (mean LDL-C percent change from baseline was -32% for antibody-positive and -34% for antibody-negative participants). In the open-label extension trial, approximately 72% of patients receiving Kynamro therapy tested positive for anti-Kynamro antibodies (35% with titers >3200). The incidence of flu-like symptoms and the incidence of discontinuation of Kynamro were higher in antibody-positive patients. Antibodies to Kynamro were associated with higher trough levels for the drug. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Kynamro with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Mipomersen in the drug label.
# Drug Interactions
- No clinically relevant pharmacokinetic interactions were reported between Kynamro and warfarin, or between Kynamro and simvastatin or ezetimibe. Additionally, coadministration of Kynamro with warfarin did not result in a pharmacodynamic interaction as determined by INR, aPTT and PT.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- There are no adequate and well-controlled studies in pregnant women. Reproduction and embryofetal development studies performed in mice at doses up to 87.5 mg/kg/wk given by subcutaneous administration from mating through organogenesis and in pregnant rabbits given 52.5 mg/kg/wk, show no evidence of impaired fertility or harm to the fetus at 2 (mice) to 5 (rabbits) times clinical exposure at a 200 mg/wk therapeutic dose. Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed.
- Pregnant rats given subcutaneous doses of 7, 35, 70 mg/kg/wk mipomersen sodium from gestation day 6 through weaning on lactation day 20, resulted in decreased rat pup survival at 70 mg/kg/wk, 3-times clinical exposure at a 200 mg/wk therapeutic dose based on body surface area comparisons across species. Dose related decreases in pup body weights, impaired reflexes and grip strength were observed at 35 mg/kg/wk (2-times the anticipated human dose). Levels of mipomersen in rat milk were very low (≤ 0.92 µg/mL at subcutaneous doses up to 70 mg/kg/wk). Due to the poor oral bioavailability of mipomersen sodium, it was considered unlikely that these low milk exposure levels adversely affected the pups during lactation.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mipomersen in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Mipomersen during labor and delivery.
### Nursing Mothers
- It is not known whether Kynamro is excreted in human milk. Because many drugs are excreted in human milk a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
- Levels of mipomersen present in rat milk were low (≤ 0.92 µg/mL) given subcutaneous doses up to 70 mg/kg/wk. Oral bioavailability is expected to be less than 10%. However a risk to newborns/infants cannot be excluded, therefore caution should be used when Kynamro is administered to a nursing woman.
- Lactating rats administered mipomersen sodium at doses up to 70 mg/kg/wk (3-times the anticipated systemic exposure from a 200 mg/wk dose, based on body surface area comparison) consumed less food while nursing. This correlated with reduced weight gain in the rat pups, and decreased pup survival in litters of dams given 70 mg/kg/wk.
### Pediatric Use
- Safety and effectiveness have not been established in pediatric patients.
- A juvenile toxicity study was conducted in rats at doses up to 50 mg/kg/wk (2-times the systemic exposure from a 200 mg/wk clinical dose based on body surface area comparisons). Doses > 10 mg/kg/wk were associated with reduced body weight gain in young rats, but had no effect on long bone growth or sexual development.
### Geriatic Use
- Clinical studies of Kynamro did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of the 51 patients enrolled in the Phase 3 trial in HoFH, the mean age was 31 years and the oldest patient in the trial was 53 years. Of the 261 patients who received Kynamro in the pooled Phase 3 trials, 59 (22.6%) were ≥ 65 years old and 10 (3.8%) were ≥ 75 years old. In the pooled Phase 3 trials, patients ≥ 65 years of age treated with Kynamro had a higher incidence of hypertension and peripheral edema compared to placebo patients in this age group, as well as compared to the younger Kynamro-treated age group. Hepatic steatosis was also reported with greater frequency in the ≥ 65 group (13.6%) compared to the <65 group (10.4%).
### Gender
There is no FDA guidance on the use of Mipomersen with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Mipomersen with respect to specific racial populations.
### Renal Impairment
- The safety and efficacy of Kynamro treatment in patients with known renal impairment or in patients undergoing renal dialysis have not been established. Due to the lack of clinical data and Kynamro’s renal safety profile, Kynamro is not recommended in patients with severe renal impairment, clinically significant proteinuria, or on renal dialysis.
### Hepatic Impairment
- The safety and efficacy of Kynamro treatment in patients with known hepatic impairment have not been established. Kynamro is contraindicated in patients with clinically significant hepatic dysfunction, which may include persistent elevations of transaminases.
### Females of Reproductive Potential and Males
- Kynamro may cause fetal harm. Females who become pregnant during Kynamro therapy should notify their healthcare provider.
- Contraception
- Females of reproductive potential should use effective contraception during Kynamro therapy.
### Immunocompromised Patients
There is no FDA guidance one the use of Mipomersen in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Mipomersen in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Mipomersen in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- There have been no reports of overdose with Kynamro treatment. In clinical trials, patients receiving higher doses of Kynamro (300 mg and 400 mg once weekly for 13 weeks) experienced adverse reactions similar to the adverse reactions experienced by patients receiving treatment with 200 mg once weekly but at slightly higher rates and greater severity. Liver-related tests should be monitored.
### Management
- Although there is no information on the effect of hemodialysis in treating an overdose with mipomersen, hemodialysis is unlikely to be useful in overdose management since mipomersen is highly bound to plasma proteins.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Mipomersen in the drug label.
# Pharmacology
## Mechanism of Action
- Mipomersen is an antisense oligonucleotide targeted to human messenger ribonucleic acid (mRNA) for apo B-100, the principal apolipoprotein of LDL and its metabolic precursor, VLDL. Mipomersen is complementary to the coding region of the mRNA for apo B-100, and binds by Watson and Crick base pairing. The hybridization of mipomersen to the cognate mRNA results in RNase H-mediated degradation of the cognate mRNA thus inhibiting translation of the apo B-100 protein.
- The in vitro pharmacologic activity of mipomersen was characterized in human hepatoma cell lines (HepG2, Hep3B) and in human and cynomolgus monkey primary hepatocytes. In these experiments, mipomersen selectively reduced apo B mRNA, protein and secreted protein in a concentration- and time-dependent manner. The effects of mipomersen were shown to be highly sequence-specific. The binding site for mipomersen lies within the coding region of the apo B mRNA at the position 3249-3268 relative to the published sequence GenBank accession number NM_000384.1.
## Structure
- Kynamro (mipomersen sodium) Injection is a sterile, preservative-free, clear, colorless to slightly yellow, aqueous solution for subcutaneous injection. Kynamro is supplied in single-use, 2 mL, clear glass vials or single-use, 1 mL, clear glass pre-filled syringes filled to deliver 1 mL of solution containing 200 mg of mipomersen sodium (200 mg per 1 mL). Kynamro is formulated in water for injection and may include hydrochloric acid and/or sodium hydroxide for pH adjustment to 7.5 – 8.5.
- Mipomersen sodium is an oligonucleotide inhibitor of apo B-100 synthesis. ApoB is the principal apolipoprotein of LDL and its metabolic precursor, very low density lipoprotein (VLDL). Mipomersen inhibits synthesis of apoB by sequence-specific binding to its messenger ribonucleic acid (mRNA) resulting in degradation of the mRNA through enzyme-mediated pathways or disruption of mRNA function through binding alone.
- Mipomersen sodium is a synthetic phosphorothioate oligonucleotide sodium salt, 20 nucleotides in length, with the following sequence:
- Mipomersen sodium is represented by the following structural formula:
## Pharmacodynamics
- At a concentration of 3.8 times the Cmax of the maximum recommended dose (200 mg subcutaneous injection), mipomersen does not prolong the QTc interval to any clinically relevant extent.
## Pharmacokinetics
- Single- and multiple-dose pharmacokinetics of mipomersen in healthy volunteers and in patients with FH and non-FH has shown that mipomersen plasma exposure increases with increasing dose in the range of 30 mg to 400 mg.
- Following subcutaneous injection, peak concentrations of mipomersen are typically reached in 3 to 4 hours. The estimated plasma bioavailability of mipomersen following subcutaneous administration over a dose range of 50 mg to 400 mg, relative to intravenous administration, ranged from 54% to 78%.
- Mipomersen is highly bound to human plasma proteins (≥ 90%) at clinically relevant concentrations (1-8 µg/mL). Mipomersen has a distribution plasma half-life of approximately 2 to 5 hours.
- With once weekly dosing, plasma trough levels increase over time and approach steady-state, typically within 6 months.
- Mipomersen is not a substrate for CYP450 metabolism, and is metabolized in tissues by endonucleases to form shorter oligonucleotides that are then substrates for additional metabolism by exonucleases.
- The elimination of mipomersen involves both metabolism in tissues and excretion, primarily in urine. Both mipomersen and putative shorter oligonucleotide metabolites were identified in human urine. Urinary recovery was limited in humans with less than 4% within the 24 hours post dose. Following subcutaneous administration, elimination half-life for mipomersen is approximately 1 to 2 months.
- No clinically relevant pharmacokinetic interactions were reported between mipomersen and warfarin, or between mipomersen and simvastatin or ezetimibe. The results of these studies are summarized in Figures 1 and 2.
## Nonclinical Toxicology
- In a subcutaneous carcinogenicity study in mice, mipomersen sodium was administered for up to 104 weeks at doses of 5, 20, 60 mg/kg/week. There were statistically significant increases in the incidences of hepatocellular adenoma and combined adenoma and carcinoma in female mice at 60 mg/kg/wk (2-times the systemic clinical exposure at 200 mg/wk, based on a body surface area comparison) for both mipomersen sodium and the mouse-specific analog. This dose also resulted in statistically significant increases in the incidence of hemangiosarcomas in female mice and fibrosarcomas of the skin/subcutis in male mice.
- In a subcutaneous carcinogenicity study in rats, mipomersen sodium was administered for up to 104 weeks at doses of 3, 10, 20 mg/kg/wk. The incidence of fibrosarcomas of the skin/subcutis and the combination of fibroma, fibrosarcomas and malignant fibrous histiocytoma of the skin/subcutis was statistically significantly increased in female rats at 10 mg/kg/wk, at less than clinical exposure at the 200 mg/wk dose based on body surface area comparisons. Both sexes of rats also had statistically significant increases in the incidence of malignant fibrous histiocytoma of the skin/subcutis at 20 mg/kg/wk (at clinical exposure at the 200 mg/wk dose based on body surface area comparisons.
- Mipomersen did not exhibit genotoxic potential in a battery of studies, including the in vitro Bacterial Reverse Mutation (Ames) assay, an in vitro cytogenetics assay using a mouse lymphoma cell line, and an in vivo micronucleus assay in mice.
- Mipomersen sodium had no effect on fertility in mice at doses up to 87.5 mg/kg/wk (2-times clinical exposure at the 200 mg/wk dose based on body surface area comparisons).
- The principal target organs for mipomersen pathology are the kidneys and liver. These organs represent the highest distribution of compound, and exhibit microscopic changes reflective of cellular uptake in macrophages. The most widespread toxicological effect of mipomersen was a spectrum of inflammatory changes in numerous organs, including lymphohistiocytic cell infiltrates and increases in lymphoid organ weights, associated with increases in plasma cytokines, chemokines and total serum IgG. In a chronic monkey study, multi-focal intimal hyperplasia with mixed inflammatory infiltrates was evident in vascular beds in 2 of 6 monkeys treated for 12 months with 30 mg/kg/week with a no-observed-adverse-effect-level (NOAEL) of 10 mg/kg/week (approximately equal to clinical exposures anticipated from a 200 mg/wk dose based on body surface area comparisons across species).
# Clinical Studies
- The safety and effectiveness of Kynamro, given as 200 mg weekly subcutaneous injections, as an adjunct to lipid-lowering medications in individuals with HoFH were evaluated in a multinational, randomized (34 Kynamro; 17 placebo), placebo-controlled, 26-week trial in 51 patients with HoFH. A diagnosis of functional HoFH was defined by the presence of at least one of the following clinical or laboratory criteria: (1) history of genetic testing confirming 2 mutated alleles at the LDLr gene locus, or (2) documented history of untreated LDL-C > 500 mg/dL and at least one of the criteria (a) tendinous and/or cutaneous xanthoma prior to age 10 years or (b) documentation of elevated LDL-C > 190 mg/dL prior to lipid-lowering therapy consistent with HeFH in both parents. In case a parent was not available, a history of coronary artery disease in a first degree male relative of the parent younger than 55 years or first degree female relative of the parent younger than 60 years was acceptable.
- The baseline demographic characteristics were well-matched between the Kynamro and placebo patients. The mean age was 32 years (range, 12 to 53 years), the mean body mass index (BMI) was 26 kg/m2, 43% were men, and the majority (75%) were Caucasian. In 50 of 51 (98%) patients, the background therapy of maximally tolerated lipid-lowering medication included statins. In total, 44 of the 50 (88%) patients were on maximum-dose statin therapy with or without other lipid-lowering medications. Thirty-eight of the 50 (76%) patients were also taking at least one other lipid-lowering medication, most commonly ezetimibe in 37 of 50 (74%) patients; patients were not on LDL apheresis. Eighty-two percent of the Kynamro group and 100% of the placebo group completed the efficacy endpoint at week 28. Adverse events contributed to premature discontinuation for four patients, all in the Kynamro group [see Adverse Reactions (6)].
- The primary efficacy endpoint was percent change in LDL-C from baseline to Week 28. At Week 28, the mean and median percent changes in LDL-C from baseline were -25% (p<0.001) and -19%, respectively, for the Kynamro group. The mean and median treatment difference from placebo was -21% (95% confidence interval [CI]: -33, -10) and -19%, respectively. Changes in lipids and lipoproteins through the efficacy endpoint at Week 28 are presented in Table 4.
- LDL-C percent changes from baseline with Kynamro were variable among individuals with HoFH ranging from a 2% increase to an 82% reduction. The LDL-C percent changes from baseline in the placebo group range from a 43% increase to a 33% reduction. Mean LDL-C percent changes over time are presented in Figure 3.
# How Supplied
- Kynamro is supplied in single-use, 2 mL, clear glass vials or single-use, 1 mL, clear pre-filled syringes with staked needles. Each single-use vial or single-use pre-filled syringe of Kynamro is filled to deliver 1 mL of 200 mg/mL solution containing 200 mg of mipomersen sodium.
- Kynamro is available in cartons containing 1 or 4 vials and 1 or 4 pre-filled syringes.
- Store refrigerated Kynamro at 2-8 °C (36-46 °F). Kynamro should be protected from light and kept in the original carton until time of use. When refrigeration is not available Kynamro may be stored at or below 30 °C (86 °F), away from heat sources, for up to 14 days. Do not use Kynamro after the expiration date on the label. This product contains no preservatives; any unused drug remaining in vial after extracting 1 mL for injection must be safely discarded.
## Storage
There is limited information regarding Mipomersen Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Mipomersen interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Kynamro®[2]
# Look-Alike Drug Names
- N/A[3]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Mipomersen | |
f6d3e172e84fc4d080fb790d072113dcd278720f | wikidoc | Mirabegron | Mirabegron
- Content
- Dosing Information
- The recommended starting dose of Myrbetriq is 25 mg once daily with or without food. Myrbetriq 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.
- Myrbetriq should be taken with water, swallowed whole and should not be chewed, divided, or crushed.
- Dose Adjustments in Specific Populations
- The daily dose of Myrbetriq should not exceed 25 mg once daily in the following populations:
- Patients with severe renal impairment (CL cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m 2).
- Patients with moderate hepatic impairment (Child-Pugh Class B).
- Myrbetriq is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C).
- Myrbetriq can increase blood pressure. Periodic blood pressure determinations are recommended, especially in hypertensive patients. Myrbetriq is not recommended for use in patients with severe uncontrolled hypertension (defined as systolic blood pressure greater than or equal to 180 mm Hg and/or diastolic blood pressure greater than or equal to 110 mm Hg).
- In two, randomized, placebo-controlled, healthy volunteer studies, Myrbetriq was associated with dose-related increases in supine blood pressure. In these studies, at the maximum recommended dose of 50 mg, the mean maximum increase in systolic/diastolic blood pressure was approximately 3.5/1.5 mm Hg greater than placebo.
- In contrast, in OAB patients in clinical trials, the mean increase in systolic and diastolic blood pressure at the maximum recommended dose of 50 mg was approximately 0.5 - 1 mm Hg greater than placebo. Worsening of pre-existing hypertension was reported infrequently in Myrbetriq patients.
Urinary Retention in Patients with Bladder Outlet Obstruction and in Patients Taking Antimuscarinic Medications for OAB
- Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medications for the treatment of OAB has been reported in postmarketing experience in patients taking mirabegron. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in Myrbetriq patients; however, Myrbetriq should be administered with caution to patients with clinically significant BOO. Myrbetriq should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB.
Patients Taking Drugs Metabolized by CYP2D6
- Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index drugs metabolized by CYP2D6, such as thioridazine, flecainide, and propafenone.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- In three, 12 week, double-blind, placebo-controlled, safety and efficacy studies in patients with overactive bladder (Studies 1, 2, and 3), Myrbetriq was evaluated for safety in 2736 patients. Study 1 also included an active control. For the combined Studies 1, 2, and 3, 432 patients received Myrbetriq 25 mg, 1375 received Myrbetriq 50 mg, and 929 received Myrbetriq 100 mg once daily. In these studies, the majority of the patients were Caucasian (94%), and female (72%) with a mean age of 59 years (range 18 to 95 years).
- Myrbetriq was also evaluated for safety in 1632 patients who received Myrbetriq 50 mg once daily (n=812 patients) or Myrbetriq 100 mg (n=820 patients) in a 1 year, randomized, fixed dose, double-blind, active controlled, safety study in patients with overactive bladder (Study 4). Of these patients, 731 received Myrbetriq in a previous 12 week study. In Study 4, 1385 patients received Myrbetriq continuously for at least 6 months, 1311 patients received Myrbetriq for at least 9 months, and 564 patients received Myrbetriq for at least 1 year.
- The most frequent adverse events (0.2%) leading to discontinuation in Studies 1, 2 and 3 for the 25 mg or 50 mg dose were nausea, headache, hypertension, diarrhea, constipation, dizziness and tachycardia.
- Atrial fibrillation (0.2%) and prostate cancer (0.1%) were reported as serious adverse events by more than 1 patient and at a rate greater than placebo.
- Table 1 lists adverse reactions, derived from all adverse events, that were reported in Studies 1, 2 and 3 at an incidence greater than placebo and in 1% or more of patients treated with Myrbetriq 25 mg or 50 mg once daily for up to 12 weeks. The most commonly reported adverse reactions (greater than 2% of Myrbetriq patients and greater than placebo) were hypertension, nasopharyngitis, urinary tract infection and headache.
- Other adverse reactions reported by less than 1% of patients treated with Myrbetriq in Studies 1, 2, or 3 included:
- Cardiac disorders: palpitations, blood pressure increased
- Eye Disorders: glaucoma
- Gastrointestinal disorders: dyspepsia, gastritis, abdominal distension
- Infections and Infestations: sinusitis, rhinitis
- Investigations: GGT increased, AST increased, ALT increased, LDH increased
- Renal and urinary disorders: nephrolithiasis, bladder pain
- Reproductive system and breast disorders: vulvovaginal pruritus, vaginal infection
- Skin and subcutaneous tissue disorders: urticaria, leukocytoclastic vasculitis, rash, pruritus, purpura, lip edema
- Table 2 lists the rates of the most commonly reported adverse reactions, derived from all adverse events in patients treated with Myrbetriq 50 mg for up to 52 weeks in Study 4. The most commonly reported adverse reactions (>3% of Myrbetriq patients) were hypertension, urinary tract infection, headache, and nasopharyngitis.
- In Study 4, in patients treated with Myrbetriq 50 mg once daily, adverse reactions leading to discontinuation reported by more than 2 patients and at a rate greater than active control included: constipation (0.9%), headache (0.6%), dizziness (0.5%), hypertension (0.5%), dry eyes (0.4%), nausea (0.4%), vision blurred (0.4%), and urinary tract infection (0.4%). Serious adverse events reported by at least 2 patients and exceeding active control included cerebrovascular accident (0.4%) and osteoarthritis (0.2%). Serum ALT/AST increased from baseline by greater than 10-fold in 2 patients (0.3%) taking Myrbetriq 50 mg, and these markers subsequently returned to baseline while both patients continued Myrbetriq.
- In Study 4, serious adverse events of neoplasm were reported by 0.1%, 1.3%, and 0.5% of patients treated with Myrbetriq 50 mg, Myrbetriq 100 mg and active control once daily, respectively. Neoplasms reported by 2 patients treated with Myrbetriq 100 mg included breast cancer, lung neoplasm malignant and prostate cancer.
- In a separate clinical study in Japan, a single case was reported as Stevens-Johnson syndrome with increased serum ALT, AST and bilirubin in a patient taking Myrbetriq 100 mg as well as an herbal medication (Kyufu Gold).
- The following events have been reported in association with mirabegron use in worldwide postmarketing experience:
- Urologic: urinary retention
- The following are drug interactions for which monitoring is recommended:
Drugs Metabolized by CYP2D6
- Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure of drugs metabolized by CYP2D6 enzyme such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary when Myrbetriq is co-administered with these drugs, especially with narrow therapeutic index CYP2D6 substrates, such as thioridazine, flecainide, and propafenone.
Digoxin
- When given in combination, mirabegron increased mean digoxin Cmax from 1.01 to 1.3 ng/mL (29%) and AUC from 16.7 to 19.3 ng.h/mL (27%). Therefore, for patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should initially be considered. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.
Warfarin
- The mean Cmax of S- and R-warfarin was increased by approximately 4% and AUC by approximately 9% when administered as a single dose of 25 mg after multiple doses of 100 mg mirabegron. Following a single dose administration of 25 mg warfarin, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as International Normalized Ratio (INR) and prothrombin time. However, the effect of mirabegron on multiple doses of warfarin and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated.
Risk Summary
- Based on animal data, mirabegron is predicted to have a low probability of increasing the risk of adverse developmental outcomes above background risk. Reversible adverse developmental findings consisting of delayed ossification and wavy ribs in rats and decreased fetal body weights in rabbits occurred at exposures greater than or equal to 22 and 14 times, respectively, the maximal recommended human dose (MRHD). At maternally toxic exposures decreased fetal weights were observed in rats and rabbits, and fetal death, dilated aorta, and cardiomegaly were reported in rabbits.
Animal Data
- In the rat embryo/fetal developmental toxicity study, pregnant rats received daily oral doses of mirabegron at 0, 10, 30, 100, or 300 mg/kg from implantation to closure of the fetal hard palate (7th to 17th day of gestation). Maternal systemic exposures were approximately 0, 1, 6, 22, or 96 times greater than exposures in women treated at the MRHD of 50 mg based on AUC. No embryo/fetal toxicities were observed in rats exposed up to 6 times the human systemic exposure at the MRHD of 50 mg. At systemic exposures equal to or greater than 22 times the human systemic exposure at the MRHD, delayed ossification and wavy ribs were observed in fetuses at an increased incidence. These findings were reversible.
- In the rabbit embryo/fetal developmental toxicity study, pregnant rabbits received daily oral doses of mirabegron at 0, 3, 10, or 30 mg/kg from implantation to closure of the fetal hard palate (6th to 20th day of gestation). Maternal systemic exposures were 0, 1, 14, or 36 times that in women treated at the MRHD of 50 mg based on AUC. The embryo/fetal No Adverse Effect Level (NOAEL) was similar to the exposure in women at the MRHD and was established in this species based on reduced fetal body weight observed at systemic exposures that were 14-fold higher than the human systemic exposure at MRHD. At higher doses, where systemic exposures were 36-fold higher than the human exposure at MRHD, maternal body weight gain and food consumption were reduced, one of 17 pregnant rabbits died, the incidence of fetal death increased, and fetal findings of dilated aorta and cardiomegaly were reported.
- The effects of mirabegron on prenatal and postnatal development was assessed in pregnant rats dosed at 0, 10, 30, or 100 mg/kg/day from the seventh day of gestation until 20 days after birth. Maternal systemic exposures were 0, 1, 6, and 22 times the exposure in women at the MRHD based on AUC. Rat pups exposed to mirabegron in utero and through 21 days of lactation had no discernable adverse effects at maternal systemic exposures 6 times the MRHD. A slight but statistically significant decrease in the survival of pups was observed 4 days after birth at exposures 22 times the MRHD (92.7% survival) compared to the control group (98.8%), however, there was no effect on survival of pups 21 days after birth. Absolute body weight of pups was not affected on the day of birth. However, at the 30 mg/kg dose (22-fold higher systemic exposure than humans at MHRD) body weight gain of pups was reduced 5% to 13% from postnatal day 4 to 7 but not throughout the remainder of the lactation period. In utero and lactational exposure did not affect behavior or fertility of offspring at exposures up to 22 times the MRHD.
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mirabegron in women who are pregnant.
eGFR <15 mL/min/1.73 m2 or patients requiring hemodialysis), and, therefore is not recommended for use in these patient populations.
- In patients with severe renal impairment (CLcr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m2), the daily dose of Myrbetriq should not exceed 25 mg. No dose adjustment is necessary in patients with mild or moderate renal impairment (CLcr 30 to 89 mL/min or eGFR 30 to 89 mL/min/1.73 m2).
- In patients with moderate hepatic impairment (Child-Pugh Class B), the daily dose of Myrbetriq should not exceed 25 mg. No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh Class A).
- The recommended starting dose of Myrbetriq is 25 mg once daily with or without food. Myrbetriq 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.
- Myrbetriq should be taken with water, swallowed whole and should not be chewed, divided, or crushed.
Dose Adjustments in Specific Populations
- The daily dose of Myrbetriq should not exceed 25 mg once daily in the following populations:
- Patients with severe renal impairment (CL cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m 2).
- Patients with moderate hepatic impairment (Child-Pugh Class B).
- Myrbetriq is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C).
DOSAGE FORMS AND STRENGTHS
- Myrbetriq extended-release tablets are supplied in two different strengths as described below:
- 25 mg oval, brown, film coated tablet, debossed with the Astellas logo (Astellas logo) and “325”
- 50 mg oval, yellow, film coated tablet, debossed with theAstellas logo (Astellas logo) and "355"
- Mirabegron is a white powder. It is practically insoluble in water (0.082 mg/mL). It is soluble in methanol and dimethyl sulfoxide.
- Each Myrbetriq extended-release tablet, for oral administration contains either 25 mg or 50 mg of mirabegron and the following inactive ingredients: polyethylene oxide, polyethylene glycol, hydroxypropyl cellulose, butylated hydroxytoluene, magnesium stearate, hypromellose, yellow ferric oxide, and red ferric oxide (25 mg tablet only).
- The effects of Myrbetriq on maximum urinary flow rate and detrusor pressure at maximum flow rate were assessed in a urodynamic study consisting of 200 male patients with lower urinary tract symptoms (LUTS) and BOO. Administration of Myrbetriq once daily for 12 weeks did not adversely affect the mean maximum flow rate or mean detrusor pressure at maximum flow rate in this study. Nonetheless, Myrbetriq should be administered with caution to patients with clinically significant BOO.
Cardiac Electrophysiology
- The effect of multiple doses of Myrbetriq 50 mg, 100 mg and 200 mg once daily on QTc interval was evaluated in a randomized, placebo- and active- controlled (moxifloxacin 400 mg) four-treatment-arm parallel crossover study in 352 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 msec. For the 50 mg Myrbetriq dose group (the maximum approved dosage), the mean difference from placebo on QTcI interval at 4-5 hours post-dose was 3.7 msec (upper bound of the 95% CI 5.1 msec).
- For the Myrbetriq 100 mg and 200 mg doses groups (dosages greater than the maximum approved dose and resulting in substantial multiples of the anticipated maximum blood levels at 50 mg), the mean differences from placebo in QTcI interval at 4-5 hours post-dose were 6.1 msec (upper bound of the 95% CI 7.6 msec) and 8.1 msec (upper bound of the 95% CI 9.8 msec), respectively. At the Myrbetriq 200 mg dose, in females, the mean effect was 10.4 msec (upper bound of the 95% CI 13.4 msec).
- In this thorough QT study, Myrbetriq increased heart rate on ECG in a dose dependent manner. Maximum mean increases from baseline in heart rate for the 50 mg, 100 mg, and 200 mg dose groups compared to placebo were 6.7 beats per minutes (bpm), 11 bpm, and 17 bpm, respectively. In the clinical efficacy and safety studies, the change from baseline in mean pulse rate for Myrbetriq 50 mg was approximately 1 bpm. In this thorough QT study, Myrbetriq also increased blood pressure in a dose dependent manner (see Effects on Blood Pressure).
Effects on Blood Pressure
- In a study of 352 healthy subjects assessing the effect of multiple daily doses of 50 mg, 100 mg, and 200 mg of Myrbetriq for 10 days on the QTc interval, the maximum mean increase in supine SBP/DBP at the maximum recommended dose of 50 mg was approximately 4.0/1.6 mm Hg greater than placebo. The 24-hour average increases in SBP compared to placebo were 3.0, 5.5, and 9.7 mm Hg at Myrbetriq doses of 50 mg, 100 mg and 200 mg, respectively. Increases in DBP were also dose-dependent, but were smaller than SBP.
- In another study in 96 healthy subjects to assess the impact of age on pharmacokinetics of multiple daily doses of 50 mg, 100 mg, 200 mg, and 300 mg of Myrbetriq for 10 days, SBP also increased in a dose-dependent manner. The mean maximum increases in SBP were approximately 2.5, 4.5, 5.5 and 6.5 mm Hg for Myrbetriq exposures associated with doses of 50 mg, 100 mg, 200 mg and 300 mg, respectively.
- In three, 12-week, double-blind, placebo-controlled, safety and efficacy studies (Studies 1, 2 and 3) in OAB patients receiving Myrbetriq 25 mg, 50 mg, or 100 mg once daily, mean increases in SBP/DBP compared to placebo of approximately 0.5 - 1 mm Hg were observed. Morning SBP increased by at least 15 mm Hg from baseline in 5.3%, 5.1%, and 6.7% of placebo, Myrbetriq 25 mg and Myrbetriq 50 mg patients, respectively. Morning DBP increased by at least 10 mm Hg in 4.6%, 4.1% and 6.6% of placebo, Myrbetriq 25 mg, and Myrbetriq 50 mg patients, respectively. Both SBP and DBP increases were reversible upon discontinuation of treatment.
Effect on Intraocular Pressure (IOP)
- Myrbetriq 100 mg once daily did not increase IOP in healthy subjects after 56 days of treatment. In a phase 1 study assessing the effect of Myrbetriq on IOP using Goldmann applanation tonometry in 310 healthy subjects, a dose of Myrbetriq 100 mg was non-inferior to placebo for the primary endpoint of the treatment difference in mean change from baseline to day 56 in subject-average IOP; upper bound of the two-sided 95% CI of the treatment difference between Myrbetriq 100 mg and placebo was 0.3 mm Hg.
- After oral administration of mirabegron in healthy volunteers, mirabegron is absorbed to reach maximum plasma concentrations (Cmax) at approximately 3.5 hours. The absolute bioavailability increases from 29% at a dose of 25 mg to 35% at a dose of 50 mg. Mean Cmax and AUC increase more than dose proportionally. This relationship is more apparent at doses above 50 mg. In the overall population of males and females, a 2-fold increase in dose from 50 mg to 100 mg mirabegron increased Cmax and AUCtau by approximately 2.9- and 2.6-fold, respectively, whereas a 4-fold increase in dose from 50 to 200 mg mirabegron increased Cmax and AUCtau by approximately 8.4- and 6.5-fold. Steady state concentrations are achieved within 7 days of once daily dosing with mirabegron. After once daily administration, plasma exposure of mirabegron at steady state is approximately double that seen after a single dose.
Effect of Food
- Co-administration of a 50 mg tablet with a high-fat meal reduced mirabegron Cmax and AUC by 45% and 17%, respectively. A low-fat meal decreased mirabegron Cmax and AUC by 75% and 51%, respectively. In the phase 3 studies, mirabegron was administered irrespective of food contents and intake (i.e., with or without food) and demonstrated both safety and efficacy. Therefore, mirabegron can be taken with or without food at the recommended dose.
Distribution
- Mirabegron is extensively distributed in the body. The volume of distribution at steady state (Vss) is approximately 1670 L following intravenous administration. Mirabegron is bound (approximately 71%) to human plasma proteins, and shows moderate affinity for albumin and alpha-1 acid glycoprotein. Mirabegron distributes to erythrocytes. Based on in vitro study erythrocyte concentrations of 14C-mirabegron were about 2-fold higher than in plasma.
Metabolism
- Mirabegron is metabolized via multiple pathways involving dealkylation, oxidation, (direct) glucuronidation, and amide hydrolysis. Mirabegron is the major circulating component following a single dose of 14C-mirabegron. Two major metabolites were observed in human plasma and are phase 2 glucuronides representing 16% and 11% of total exposure, respectively. These metabolites are not pharmacologically active toward beta-3 adrenergic receptor. Although in vitro studies suggest a role for CYP2D6 and CYP3A4 in the oxidative metabolism of mirabegron, in vivo results indicate that these isozymes play a limited role in the overall elimination. In healthy subjects who are genotypically poor metabolizers of CYP2D6, mean Cmax and AUCtau were approximately 16% and 17% higher than in extensive metabolizers of CYP2D6, respectively. In vitro and ex vivo studies have shown the involvement of butylcholinesterase, uridine diphospho-glucuronosyltransferases (UGT) and possibly alcohol dehydrogenase in the metabolism of mirabegron, in addition to CYP3A4 and CYP2D6.
Excretion
- Total body clearance (CLtot) from plasma is approximately 57 L/h following intravenous administration. The terminal elimination half-life (t1/2) is approximately 50 hours. Renal clearance (CLR) is approximately 13 L/h, which corresponds to nearly 25% of CLtot. Renal elimination of mirabegron is primarily through active tubular secretion along with glomerular filtration. The urinary elimination of unchanged mirabegron is dose-dependent and ranges from approximately 6.0% after a daily dose of 25 mg to 12.2% after a daily dose of 100 mg. Following the administration of 160 mg 14C-mirabegron solution to healthy volunteers, approximately 55% of the radioactivity dose was recovered in the urine and 34% in the feces. Approximately 25% of unchanged mirabegron was recovered in urine and 0% in feces.
Specific Populations
Geriatric Patients
- The Cmax and AUC of mirabegron following multiple oral doses in elderly volunteers (≥ 65 years) were similar to those in younger volunteers (18 to 45 years).
Pediatric Patients
- The pharmacokinetics of mirabegron in pediatric patients have not been evaluated.
Gender
- The Cmax and AUC of mirabegron were approximately 40% to 50% higher in females than in males. When corrected for differences in body weight, the mirabegron systemic exposure is 20% - 30% higher in females compared to males.
Race
- The pharmacokinetics of mirabegron were comparable between Caucasians and African American Blacks. Cross studies comparison shows that the exposure in Japanese subjects is higher than that in North American subjects. However, when the Cmax and AUC were normalized for dose and body weight, the difference is smaller.
Renal Impairment
- Following single dose administration of 100 mg mirabegron in volunteers with mild renal impairment (eGFR 60 to 89 mL/min/1.73 m2 as estimated by MDRD), mean mirabegron Cmax and AUC were increased by 6% and 31% relative to volunteers with normal renal function. In volunteers with moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2), Cmax and AUC were increased by 23% and 66%, respectively. In patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2), mean Cmax and AUC values were 92% and 118% higher compared to healthy subjects with normal renal function. Mirabegron has not been studied in patients with End Stage Renal Disease-ESRD (CLcr less than 15 mL/min or eGFR less than 15 mL/min/1.73 m2 or patients requiring hemodialysis).
Hepatic Impairment
- Following single dose administration of 100 mg mirabegron in volunteers with mild hepatic impairment (Child-Pugh Class A), mean mirabegron Cmax and AUC were increased by 9% and 19% relative to volunteers with normal hepatic function. In volunteers with moderate hepatic impairment (Child-Pugh Class B), mean Cmax and AUC values were 175% and 65% higher. Mirabegron has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).
Drug Interaction Studies
In Vitro Studies
Effect of Other Drugs on Mirabegron
- Mirabegron is transported and metabolized through multiple pathways. Mirabegron is a substrate for CYP3A4, CYP2D6, butyrylcholinesterase, UGT, the efflux transporter P-glycoprotein (P-gp) and the influx organic cation transporters (OCT) OCT1, OCT2, and OCT3. Sulfonylurea hypoglycemic agents glibenclamide (a CYP3A4 substrate), gliclazide (a CYP2C9 and CYP3A4 substrate) and tolbutamide (a CYP2C9 substrate) did not affect the in vitro metabolism of mirabegron.
Effect of Mirabegron on Other Drugs
- Studies of mirabegron using human liver microsomes and recombinant human CYP enzymes showed that mirabegron is a moderate and time-dependent inhibitor of CYP2D6 and a weak inhibitor of CYP3A. Mirabegron is unlikely to inhibit the metabolism of co-administered drugs metabolized by the following cytochrome P450 enzymes: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2E1 because mirabegron did not inhibit the activity of these enzymes at clinically relevant concentrations. Mirabegron did not induce CYP1A2 or CYP3A. Mirabegron inhibited P-gp-mediated drug transport at high concentrations. Mirabegron is predicted not to cause clinically relevant inhibition of OCT-mediated drug transport. Mirabegron did not affect the metabolism of glibenclamide or tolbutamide.
In Vivo Studies
- The effect of co-administered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of co-administered drugs was studied after single and multiple doses of mirabegron. Most drug-drug interactions (DDI) were studied using mirabegron 100 mg extended-release tablets. However, interaction studies of mirabegron with metoprolol and with metformin were studied using mirabegron 160 mg immediate release (IR) tablets.
- The effect of ketoconazole, rifampicin, solifenacin, tamsulosin, and metformin on systemic mirabegron exposure is shown in Figure 1.
- The effect of mirabegron on metoprolol, desipramine, combined oral contraceptive-COC (ethinyl estradiol-EE, levonorgestrel-LNG), solifenacin, digoxin, warfarin, tamsulosin, and metformin is shown in Figure 2.
- In these studies, the largest increase in mirabegron systemic exposure was seen in the ketoconazole DDI study. As a potent CYP3A4 inhibitor, ketoconazole increased mirabegron Cmax by 45% and mirabegron AUC by 80% after multiple dose administration of 400 mg of ketoconazole for 9 days prior to the administration of a single dose of 100 mg mirabegron in 23 male and female healthy subjects.
- As a moderate CYP2D6 inhibitor, mirabegron increased the systemic exposure to metoprolol and desipramine:
- Mirabegron increased the C max of metoprolol by 90% and metoprolol AUC by 229% after multiple doses of 160 mg mirabegron IR tablets once daily for 5 days and a single dose of 100 mg metoprolol tablet in 12 healthy male subjects administered before and concomitantly with mirabegron.
- Mirabegron increased the C max of desipramine by 79% and desipramine AUC by 241% after multiple dose administration of 100 mg mirabegron once daily for 18 days and a single dose of 50 mg desipramine before and concomitantly with mirabegron in 28 male and female healthy subjects.
- Caution is advised if Myrbetriq is co-administered with CYP2D6 substrates such as metoprolol and desipramine, and especially narrow therapeutic index drugs, such as thioridazine, flecainide, and propafenone.
Figures 1 and 2 show the magnitude of these interactions on the pharmacokinetic parameters and the recommendations for dose adjustment, if any:
- Although no dose adjustment is recommended with solifenacin or tamsulosin based on the lack of pharmacokinetic interaction, Myrbetriq should be administered with caution to patients taking antimuscarinic medications for the treatment of OAB and in patients with clinically significant BOO because of the risk of urinary retention.
- Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index CYP2D6 substrates, such as thioridazine, flecainide, and propafenone.
- For patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should initially be prescribed. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.
- Warfarin was administered as a single 25 mg dose of the racemate (a mixture of R-warfarin and S-warfarin). Based on this single dose study, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as INR and prothrombin time. However, the effect of mirabegron on multiple doses of warfarin and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated.
- Although no dose adjustment is recommended with solifenacin or tamsulosin based on the lack of pharmacokinetic interaction, Myrbetriq should be administered with caution to patients taking antimuscarinic medications for the treatment of OAB and in BOO because of the risk of urinary retention.
Carcinogenicity
- Long-term carcinogenicity studies were conducted in rats and mice dosed orally with mirabegron for two years. Male rats were dosed at 0, 12.5, 25, or 50 mg/kg/day and female rats and both sexes of mice were dosed at 0, 25, 50, or 100 mg/kg/day. Mirabegron showed no carcinogenic potential at systemic exposures (AUC) 38 to 45-fold higher in rats and 21 to 38-fold higher in mice than the human systemic exposure at the 50 mg dose.
Mutagenesis
- Mirabegron was not mutagenic in the Ames bacterial reverse mutation assay, did not induce chromosomal aberrations in human peripheral blood lymphocytes at concentrations that were not cytotoxic, and was not clastogenic in the rat micronucleus assay.
Impairment of Fertility
- Fertility studies in rats showed that mirabegron had no effect on either male or female fertility at non-lethal doses up to 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg in female rats was estimated to be 22 times the MRHD in women and 93 times the MRHD in men.
- In Study 1, patients were randomized to placebo, Myrbetriq 50 mg, Myrbetriq 100 mg, or an active control once daily. In Study 2, patients were randomized to placebo, Myrbetriq 50 mg or Myrbetriq 100 mg once daily. In Study 3, patients were randomized to placebo, Myrbetriq 25 mg or Myrbetriq 50 mg once daily.
- The co-primary efficacy endpoints in all 3 trials were (1) change from baseline to end of treatment (Week 12) in mean number of incontinence episodes per 24 hours and (2) change from baseline to end of treatment (Week 12) in mean number of micturitions per 24 hours, based on a 3-day micturition diary. An important secondary endpoint was the change from baseline to end of treatment (Week 12) in mean volume voided per micturition.
- Results for the co-primary endpoints and mean volume voided per micturition from Studies 1, 2, and 3 are shown in Table 3.
- Myrbetriq 25 mg was effective in treating the symptoms of OAB within 8 weeks, and Myrbetriq 50 mg was effective in treating the symptoms of OAB within 4 weeks. Efficacy of both 25 mg and 50 mg doses of Myrbetriq was maintained through the 12-week treatment period.
- Figures 3 through 8 show the co-primary endpoints, mean change from baseline (BL) over time in number of incontinence episodes per 24 hours and mean change from baseline over time in number of micturitions per 24 hours, in Studies 1, 2 and 3.
- Inform patients that Myrbetriq may increase blood pressure. Periodic blood pressure determinations are recommended, especially in patients with hypertension. Myrbetriq has also been associated with infrequent urinary tract infections, rapid heart beat, rash, and pruritus. Inform patients that urinary retention has been reported when taking mirabegron in combination with antimuscarinic drugs used in the treatment of overactive bladder. Instruct patients to contact their physician if they experience these effects while taking Myrbetriq.
- Patients should read the patient leaflet entitled “Patient Information” before starting therapy with Myrbetriq.
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- Content
- Dosing Information
- The recommended starting dose of Myrbetriq is 25 mg once daily with or without food. Myrbetriq 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.
- Myrbetriq should be taken with water, swallowed whole and should not be chewed, divided, or crushed.
- Dose Adjustments in Specific Populations
- The daily dose of Myrbetriq should not exceed 25 mg once daily in the following populations:
- Patients with severe renal impairment (CL cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m 2).
- Patients with moderate hepatic impairment (Child-Pugh Class B).
- Myrbetriq is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C).
- Myrbetriq can increase blood pressure. Periodic blood pressure determinations are recommended, especially in hypertensive patients. Myrbetriq is not recommended for use in patients with severe uncontrolled hypertension (defined as systolic blood pressure greater than or equal to 180 mm Hg and/or diastolic blood pressure greater than or equal to 110 mm Hg).
- In two, randomized, placebo-controlled, healthy volunteer studies, Myrbetriq was associated with dose-related increases in supine blood pressure. In these studies, at the maximum recommended dose of 50 mg, the mean maximum increase in systolic/diastolic blood pressure was approximately 3.5/1.5 mm Hg greater than placebo.
- In contrast, in OAB patients in clinical trials, the mean increase in systolic and diastolic blood pressure at the maximum recommended dose of 50 mg was approximately 0.5 - 1 mm Hg greater than placebo. Worsening of pre-existing hypertension was reported infrequently in Myrbetriq patients.
Urinary Retention in Patients with Bladder Outlet Obstruction and in Patients Taking Antimuscarinic Medications for OAB
- Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medications for the treatment of OAB has been reported in postmarketing experience in patients taking mirabegron. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in Myrbetriq patients; however, Myrbetriq should be administered with caution to patients with clinically significant BOO. Myrbetriq should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB.
Patients Taking Drugs Metabolized by CYP2D6
- Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index drugs metabolized by CYP2D6, such as thioridazine, flecainide, and propafenone.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- In three, 12 week, double-blind, placebo-controlled, safety and efficacy studies in patients with overactive bladder (Studies 1, 2, and 3), Myrbetriq was evaluated for safety in 2736 patients. Study 1 also included an active control. For the combined Studies 1, 2, and 3, 432 patients received Myrbetriq 25 mg, 1375 received Myrbetriq 50 mg, and 929 received Myrbetriq 100 mg once daily. In these studies, the majority of the patients were Caucasian (94%), and female (72%) with a mean age of 59 years (range 18 to 95 years).
- Myrbetriq was also evaluated for safety in 1632 patients who received Myrbetriq 50 mg once daily (n=812 patients) or Myrbetriq 100 mg (n=820 patients) in a 1 year, randomized, fixed dose, double-blind, active controlled, safety study in patients with overactive bladder (Study 4). Of these patients, 731 received Myrbetriq in a previous 12 week study. In Study 4, 1385 patients received Myrbetriq continuously for at least 6 months, 1311 patients received Myrbetriq for at least 9 months, and 564 patients received Myrbetriq for at least 1 year.
- The most frequent adverse events (0.2%) leading to discontinuation in Studies 1, 2 and 3 for the 25 mg or 50 mg dose were nausea, headache, hypertension, diarrhea, constipation, dizziness and tachycardia.
- Atrial fibrillation (0.2%) and prostate cancer (0.1%) were reported as serious adverse events by more than 1 patient and at a rate greater than placebo.
- Table 1 lists adverse reactions, derived from all adverse events, that were reported in Studies 1, 2 and 3 at an incidence greater than placebo and in 1% or more of patients treated with Myrbetriq 25 mg or 50 mg once daily for up to 12 weeks. The most commonly reported adverse reactions (greater than 2% of Myrbetriq patients and greater than placebo) were hypertension, nasopharyngitis, urinary tract infection and headache.
- Other adverse reactions reported by less than 1% of patients treated with Myrbetriq in Studies 1, 2, or 3 included:
- Cardiac disorders: palpitations, blood pressure increased
- Eye Disorders: glaucoma
- Gastrointestinal disorders: dyspepsia, gastritis, abdominal distension
- Infections and Infestations: sinusitis, rhinitis
- Investigations: GGT increased, AST increased, ALT increased, LDH increased
- Renal and urinary disorders: nephrolithiasis, bladder pain
- Reproductive system and breast disorders: vulvovaginal pruritus, vaginal infection
- Skin and subcutaneous tissue disorders: urticaria, leukocytoclastic vasculitis, rash, pruritus, purpura, lip edema
- Table 2 lists the rates of the most commonly reported adverse reactions, derived from all adverse events in patients treated with Myrbetriq 50 mg for up to 52 weeks in Study 4. The most commonly reported adverse reactions (>3% of Myrbetriq patients) were hypertension, urinary tract infection, headache, and nasopharyngitis.
- In Study 4, in patients treated with Myrbetriq 50 mg once daily, adverse reactions leading to discontinuation reported by more than 2 patients and at a rate greater than active control included: constipation (0.9%), headache (0.6%), dizziness (0.5%), hypertension (0.5%), dry eyes (0.4%), nausea (0.4%), vision blurred (0.4%), and urinary tract infection (0.4%). Serious adverse events reported by at least 2 patients and exceeding active control included cerebrovascular accident (0.4%) and osteoarthritis (0.2%). Serum ALT/AST increased from baseline by greater than 10-fold in 2 patients (0.3%) taking Myrbetriq 50 mg, and these markers subsequently returned to baseline while both patients continued Myrbetriq.
- In Study 4, serious adverse events of neoplasm were reported by 0.1%, 1.3%, and 0.5% of patients treated with Myrbetriq 50 mg, Myrbetriq 100 mg and active control once daily, respectively. Neoplasms reported by 2 patients treated with Myrbetriq 100 mg included breast cancer, lung neoplasm malignant and prostate cancer.
- In a separate clinical study in Japan, a single case was reported as Stevens-Johnson syndrome with increased serum ALT, AST and bilirubin in a patient taking Myrbetriq 100 mg as well as an herbal medication (Kyufu Gold).
- The following events have been reported in association with mirabegron use in worldwide postmarketing experience:
- Urologic: urinary retention
- The following are drug interactions for which monitoring is recommended:
Drugs Metabolized by CYP2D6
- Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure of drugs metabolized by CYP2D6 enzyme such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary when Myrbetriq is co-administered with these drugs, especially with narrow therapeutic index CYP2D6 substrates, such as thioridazine, flecainide, and propafenone.
Digoxin
- When given in combination, mirabegron increased mean digoxin Cmax from 1.01 to 1.3 ng/mL (29%) and AUC from 16.7 to 19.3 ng.h/mL (27%). Therefore, for patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should initially be considered. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.
Warfarin
- The mean Cmax of S- and R-warfarin was increased by approximately 4% and AUC by approximately 9% when administered as a single dose of 25 mg after multiple doses of 100 mg mirabegron. Following a single dose administration of 25 mg warfarin, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as International Normalized Ratio (INR) and prothrombin time. However, the effect of mirabegron on multiple doses of warfarin and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated.
Risk Summary
- Based on animal data, mirabegron is predicted to have a low probability of increasing the risk of adverse developmental outcomes above background risk. Reversible adverse developmental findings consisting of delayed ossification and wavy ribs in rats and decreased fetal body weights in rabbits occurred at exposures greater than or equal to 22 and 14 times, respectively, the maximal recommended human dose (MRHD). At maternally toxic exposures decreased fetal weights were observed in rats and rabbits, and fetal death, dilated aorta, and cardiomegaly were reported in rabbits.
Animal Data
- In the rat embryo/fetal developmental toxicity study, pregnant rats received daily oral doses of mirabegron at 0, 10, 30, 100, or 300 mg/kg from implantation to closure of the fetal hard palate (7th to 17th day of gestation). Maternal systemic exposures were approximately 0, 1, 6, 22, or 96 times greater than exposures in women treated at the MRHD of 50 mg based on AUC. No embryo/fetal toxicities were observed in rats exposed up to 6 times the human systemic exposure at the MRHD of 50 mg. At systemic exposures equal to or greater than 22 times the human systemic exposure at the MRHD, delayed ossification and wavy ribs were observed in fetuses at an increased incidence. These findings were reversible.
- In the rabbit embryo/fetal developmental toxicity study, pregnant rabbits received daily oral doses of mirabegron at 0, 3, 10, or 30 mg/kg from implantation to closure of the fetal hard palate (6th to 20th day of gestation). Maternal systemic exposures were 0, 1, 14, or 36 times that in women treated at the MRHD of 50 mg based on AUC. The embryo/fetal No Adverse Effect Level (NOAEL) was similar to the exposure in women at the MRHD and was established in this species based on reduced fetal body weight observed at systemic exposures that were 14-fold higher than the human systemic exposure at MRHD. At higher doses, where systemic exposures were 36-fold higher than the human exposure at MRHD, maternal body weight gain and food consumption were reduced, one of 17 pregnant rabbits died, the incidence of fetal death increased, and fetal findings of dilated aorta and cardiomegaly were reported.
- The effects of mirabegron on prenatal and postnatal development was assessed in pregnant rats dosed at 0, 10, 30, or 100 mg/kg/day from the seventh day of gestation until 20 days after birth. Maternal systemic exposures were 0, 1, 6, and 22 times the exposure in women at the MRHD based on AUC. Rat pups exposed to mirabegron in utero and through 21 days of lactation had no discernable adverse effects at maternal systemic exposures 6 times the MRHD. A slight but statistically significant decrease in the survival of pups was observed 4 days after birth at exposures 22 times the MRHD (92.7% survival) compared to the control group (98.8%), however, there was no effect on survival of pups 21 days after birth. Absolute body weight of pups was not affected on the day of birth. However, at the 30 mg/kg dose (22-fold higher systemic exposure than humans at MHRD) body weight gain of pups was reduced 5% to 13% from postnatal day 4 to 7 but not throughout the remainder of the lactation period. In utero and lactational exposure did not affect behavior or fertility of offspring at exposures up to 22 times the MRHD.
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mirabegron in women who are pregnant.
eGFR <15 mL/min/1.73 m2 or patients requiring hemodialysis), and, therefore is not recommended for use in these patient populations.
- In patients with severe renal impairment (CLcr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m2), the daily dose of Myrbetriq should not exceed 25 mg. No dose adjustment is necessary in patients with mild or moderate renal impairment (CLcr 30 to 89 mL/min or eGFR 30 to 89 mL/min/1.73 m2).
- In patients with moderate hepatic impairment (Child-Pugh Class B), the daily dose of Myrbetriq should not exceed 25 mg. No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh Class A).
- The recommended starting dose of Myrbetriq is 25 mg once daily with or without food. Myrbetriq 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.
- Myrbetriq should be taken with water, swallowed whole and should not be chewed, divided, or crushed.
Dose Adjustments in Specific Populations
- The daily dose of Myrbetriq should not exceed 25 mg once daily in the following populations:
- Patients with severe renal impairment (CL cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m 2).
- Patients with moderate hepatic impairment (Child-Pugh Class B).
- Myrbetriq is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C).
DOSAGE FORMS AND STRENGTHS
- Myrbetriq extended-release tablets are supplied in two different strengths as described below:
- 25 mg oval, brown, film coated tablet, debossed with the Astellas logo (Astellas logo) and “325”
- 50 mg oval, yellow, film coated tablet, debossed with theAstellas logo (Astellas logo) and "355"
- Mirabegron is a white powder. It is practically insoluble in water (0.082 mg/mL). It is soluble in methanol and dimethyl sulfoxide.
- Each Myrbetriq extended-release tablet, for oral administration contains either 25 mg or 50 mg of mirabegron and the following inactive ingredients: polyethylene oxide, polyethylene glycol, hydroxypropyl cellulose, butylated hydroxytoluene, magnesium stearate, hypromellose, yellow ferric oxide, and red ferric oxide (25 mg tablet only).
- The effects of Myrbetriq on maximum urinary flow rate and detrusor pressure at maximum flow rate were assessed in a urodynamic study consisting of 200 male patients with lower urinary tract symptoms (LUTS) and BOO. Administration of Myrbetriq once daily for 12 weeks did not adversely affect the mean maximum flow rate or mean detrusor pressure at maximum flow rate in this study. Nonetheless, Myrbetriq should be administered with caution to patients with clinically significant BOO.
Cardiac Electrophysiology
- The effect of multiple doses of Myrbetriq 50 mg, 100 mg and 200 mg once daily on QTc interval was evaluated in a randomized, placebo- and active- controlled (moxifloxacin 400 mg) four-treatment-arm parallel crossover study in 352 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 msec. For the 50 mg Myrbetriq dose group (the maximum approved dosage), the mean difference from placebo on QTcI interval at 4-5 hours post-dose was 3.7 msec (upper bound of the 95% CI 5.1 msec).
- For the Myrbetriq 100 mg and 200 mg doses groups (dosages greater than the maximum approved dose and resulting in substantial multiples of the anticipated maximum blood levels at 50 mg), the mean differences from placebo in QTcI interval at 4-5 hours post-dose were 6.1 msec (upper bound of the 95% CI 7.6 msec) and 8.1 msec (upper bound of the 95% CI 9.8 msec), respectively. At the Myrbetriq 200 mg dose, in females, the mean effect was 10.4 msec (upper bound of the 95% CI 13.4 msec).
- In this thorough QT study, Myrbetriq increased heart rate on ECG in a dose dependent manner. Maximum mean increases from baseline in heart rate for the 50 mg, 100 mg, and 200 mg dose groups compared to placebo were 6.7 beats per minutes (bpm), 11 bpm, and 17 bpm, respectively. In the clinical efficacy and safety studies, the change from baseline in mean pulse rate for Myrbetriq 50 mg was approximately 1 bpm. In this thorough QT study, Myrbetriq also increased blood pressure in a dose dependent manner (see Effects on Blood Pressure).
Effects on Blood Pressure
- In a study of 352 healthy subjects assessing the effect of multiple daily doses of 50 mg, 100 mg, and 200 mg of Myrbetriq for 10 days on the QTc interval, the maximum mean increase in supine SBP/DBP at the maximum recommended dose of 50 mg was approximately 4.0/1.6 mm Hg greater than placebo. The 24-hour average increases in SBP compared to placebo were 3.0, 5.5, and 9.7 mm Hg at Myrbetriq doses of 50 mg, 100 mg and 200 mg, respectively. Increases in DBP were also dose-dependent, but were smaller than SBP.
- In another study in 96 healthy subjects to assess the impact of age on pharmacokinetics of multiple daily doses of 50 mg, 100 mg, 200 mg, and 300 mg of Myrbetriq for 10 days, SBP also increased in a dose-dependent manner. The mean maximum increases in SBP were approximately 2.5, 4.5, 5.5 and 6.5 mm Hg for Myrbetriq exposures associated with doses of 50 mg, 100 mg, 200 mg and 300 mg, respectively.
- In three, 12-week, double-blind, placebo-controlled, safety and efficacy studies (Studies 1, 2 and 3) in OAB patients receiving Myrbetriq 25 mg, 50 mg, or 100 mg once daily, mean increases in SBP/DBP compared to placebo of approximately 0.5 - 1 mm Hg were observed. Morning SBP increased by at least 15 mm Hg from baseline in 5.3%, 5.1%, and 6.7% of placebo, Myrbetriq 25 mg and Myrbetriq 50 mg patients, respectively. Morning DBP increased by at least 10 mm Hg in 4.6%, 4.1% and 6.6% of placebo, Myrbetriq 25 mg, and Myrbetriq 50 mg patients, respectively. Both SBP and DBP increases were reversible upon discontinuation of treatment.
Effect on Intraocular Pressure (IOP)
- Myrbetriq 100 mg once daily did not increase IOP in healthy subjects after 56 days of treatment. In a phase 1 study assessing the effect of Myrbetriq on IOP using Goldmann applanation tonometry in 310 healthy subjects, a dose of Myrbetriq 100 mg was non-inferior to placebo for the primary endpoint of the treatment difference in mean change from baseline to day 56 in subject-average IOP; upper bound of the two-sided 95% CI of the treatment difference between Myrbetriq 100 mg and placebo was 0.3 mm Hg.
- After oral administration of mirabegron in healthy volunteers, mirabegron is absorbed to reach maximum plasma concentrations (Cmax) at approximately 3.5 hours. The absolute bioavailability increases from 29% at a dose of 25 mg to 35% at a dose of 50 mg. Mean Cmax and AUC increase more than dose proportionally. This relationship is more apparent at doses above 50 mg. In the overall population of males and females, a 2-fold increase in dose from 50 mg to 100 mg mirabegron increased Cmax and AUCtau by approximately 2.9- and 2.6-fold, respectively, whereas a 4-fold increase in dose from 50 to 200 mg mirabegron increased Cmax and AUCtau by approximately 8.4- and 6.5-fold. Steady state concentrations are achieved within 7 days of once daily dosing with mirabegron. After once daily administration, plasma exposure of mirabegron at steady state is approximately double that seen after a single dose.
Effect of Food
- Co-administration of a 50 mg tablet with a high-fat meal reduced mirabegron Cmax and AUC by 45% and 17%, respectively. A low-fat meal decreased mirabegron Cmax and AUC by 75% and 51%, respectively. In the phase 3 studies, mirabegron was administered irrespective of food contents and intake (i.e., with or without food) and demonstrated both safety and efficacy. Therefore, mirabegron can be taken with or without food at the recommended dose.
Distribution
- Mirabegron is extensively distributed in the body. The volume of distribution at steady state (Vss) is approximately 1670 L following intravenous administration. Mirabegron is bound (approximately 71%) to human plasma proteins, and shows moderate affinity for albumin and alpha-1 acid glycoprotein. Mirabegron distributes to erythrocytes. Based on in vitro study erythrocyte concentrations of 14C-mirabegron were about 2-fold higher than in plasma.
Metabolism
- Mirabegron is metabolized via multiple pathways involving dealkylation, oxidation, (direct) glucuronidation, and amide hydrolysis. Mirabegron is the major circulating component following a single dose of 14C-mirabegron. Two major metabolites were observed in human plasma and are phase 2 glucuronides representing 16% and 11% of total exposure, respectively. These metabolites are not pharmacologically active toward beta-3 adrenergic receptor. Although in vitro studies suggest a role for CYP2D6 and CYP3A4 in the oxidative metabolism of mirabegron, in vivo results indicate that these isozymes play a limited role in the overall elimination. In healthy subjects who are genotypically poor metabolizers of CYP2D6, mean Cmax and AUCtau were approximately 16% and 17% higher than in extensive metabolizers of CYP2D6, respectively. In vitro and ex vivo studies have shown the involvement of butylcholinesterase, uridine diphospho-glucuronosyltransferases (UGT) and possibly alcohol dehydrogenase in the metabolism of mirabegron, in addition to CYP3A4 and CYP2D6.
Excretion
- Total body clearance (CLtot) from plasma is approximately 57 L/h following intravenous administration. The terminal elimination half-life (t1/2) is approximately 50 hours. Renal clearance (CLR) is approximately 13 L/h, which corresponds to nearly 25% of CLtot. Renal elimination of mirabegron is primarily through active tubular secretion along with glomerular filtration. The urinary elimination of unchanged mirabegron is dose-dependent and ranges from approximately 6.0% after a daily dose of 25 mg to 12.2% after a daily dose of 100 mg. Following the administration of 160 mg 14C-mirabegron solution to healthy volunteers, approximately 55% of the radioactivity dose was recovered in the urine and 34% in the feces. Approximately 25% of unchanged mirabegron was recovered in urine and 0% in feces.
Specific Populations
Geriatric Patients
- The Cmax and AUC of mirabegron following multiple oral doses in elderly volunteers (≥ 65 years) were similar to those in younger volunteers (18 to 45 years).
Pediatric Patients
- The pharmacokinetics of mirabegron in pediatric patients have not been evaluated.
Gender
- The Cmax and AUC of mirabegron were approximately 40% to 50% higher in females than in males. When corrected for differences in body weight, the mirabegron systemic exposure is 20% - 30% higher in females compared to males.
Race
- The pharmacokinetics of mirabegron were comparable between Caucasians and African American Blacks. Cross studies comparison shows that the exposure in Japanese subjects is higher than that in North American subjects. However, when the Cmax and AUC were normalized for dose and body weight, the difference is smaller.
Renal Impairment
- Following single dose administration of 100 mg mirabegron in volunteers with mild renal impairment (eGFR 60 to 89 mL/min/1.73 m2 as estimated by MDRD), mean mirabegron Cmax and AUC were increased by 6% and 31% relative to volunteers with normal renal function. In volunteers with moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2), Cmax and AUC were increased by 23% and 66%, respectively. In patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2), mean Cmax and AUC values were 92% and 118% higher compared to healthy subjects with normal renal function. Mirabegron has not been studied in patients with End Stage Renal Disease-ESRD (CLcr less than 15 mL/min or eGFR less than 15 mL/min/1.73 m2 or patients requiring hemodialysis).
Hepatic Impairment
- Following single dose administration of 100 mg mirabegron in volunteers with mild hepatic impairment (Child-Pugh Class A), mean mirabegron Cmax and AUC were increased by 9% and 19% relative to volunteers with normal hepatic function. In volunteers with moderate hepatic impairment (Child-Pugh Class B), mean Cmax and AUC values were 175% and 65% higher. Mirabegron has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).
Drug Interaction Studies
In Vitro Studies
Effect of Other Drugs on Mirabegron
- Mirabegron is transported and metabolized through multiple pathways. Mirabegron is a substrate for CYP3A4, CYP2D6, butyrylcholinesterase, UGT, the efflux transporter P-glycoprotein (P-gp) and the influx organic cation transporters (OCT) OCT1, OCT2, and OCT3. Sulfonylurea hypoglycemic agents glibenclamide (a CYP3A4 substrate), gliclazide (a CYP2C9 and CYP3A4 substrate) and tolbutamide (a CYP2C9 substrate) did not affect the in vitro metabolism of mirabegron.
Effect of Mirabegron on Other Drugs
- Studies of mirabegron using human liver microsomes and recombinant human CYP enzymes showed that mirabegron is a moderate and time-dependent inhibitor of CYP2D6 and a weak inhibitor of CYP3A. Mirabegron is unlikely to inhibit the metabolism of co-administered drugs metabolized by the following cytochrome P450 enzymes: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2E1 because mirabegron did not inhibit the activity of these enzymes at clinically relevant concentrations. Mirabegron did not induce CYP1A2 or CYP3A. Mirabegron inhibited P-gp-mediated drug transport at high concentrations. Mirabegron is predicted not to cause clinically relevant inhibition of OCT-mediated drug transport. Mirabegron did not affect the metabolism of glibenclamide or tolbutamide.
In Vivo Studies
- The effect of co-administered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of co-administered drugs was studied after single and multiple doses of mirabegron. Most drug-drug interactions (DDI) were studied using mirabegron 100 mg extended-release tablets. However, interaction studies of mirabegron with metoprolol and with metformin were studied using mirabegron 160 mg immediate release (IR) tablets.
- The effect of ketoconazole, rifampicin, solifenacin, tamsulosin, and metformin on systemic mirabegron exposure is shown in Figure 1.
- The effect of mirabegron on metoprolol, desipramine, combined oral contraceptive-COC (ethinyl estradiol-EE, levonorgestrel-LNG), solifenacin, digoxin, warfarin, tamsulosin, and metformin is shown in Figure 2.
- In these studies, the largest increase in mirabegron systemic exposure was seen in the ketoconazole DDI study. As a potent CYP3A4 inhibitor, ketoconazole increased mirabegron Cmax by 45% and mirabegron AUC by 80% after multiple dose administration of 400 mg of ketoconazole for 9 days prior to the administration of a single dose of 100 mg mirabegron in 23 male and female healthy subjects.
- As a moderate CYP2D6 inhibitor, mirabegron increased the systemic exposure to metoprolol and desipramine:
- Mirabegron increased the C max of metoprolol by 90% and metoprolol AUC by 229% after multiple doses of 160 mg mirabegron IR tablets once daily for 5 days and a single dose of 100 mg metoprolol tablet in 12 healthy male subjects administered before and concomitantly with mirabegron.
- Mirabegron increased the C max of desipramine by 79% and desipramine AUC by 241% after multiple dose administration of 100 mg mirabegron once daily for 18 days and a single dose of 50 mg desipramine before and concomitantly with mirabegron in 28 male and female healthy subjects.
- Caution is advised if Myrbetriq is co-administered with CYP2D6 substrates such as metoprolol and desipramine, and especially narrow therapeutic index drugs, such as thioridazine, flecainide, and propafenone.
Figures 1 and 2 show the magnitude of these interactions on the pharmacokinetic parameters and the recommendations for dose adjustment, if any:
- Although no dose adjustment is recommended with solifenacin or tamsulosin based on the lack of pharmacokinetic interaction, Myrbetriq should be administered with caution to patients taking antimuscarinic medications for the treatment of OAB and in patients with clinically significant BOO because of the risk of urinary retention.
- Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index CYP2D6 substrates, such as thioridazine, flecainide, and propafenone.
- For patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should initially be prescribed. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.
- Warfarin was administered as a single 25 mg dose of the racemate (a mixture of R-warfarin and S-warfarin). Based on this single dose study, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as INR and prothrombin time. However, the effect of mirabegron on multiple doses of warfarin and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated.
- Although no dose adjustment is recommended with solifenacin or tamsulosin based on the lack of pharmacokinetic interaction, Myrbetriq should be administered with caution to patients taking antimuscarinic medications for the treatment of OAB and in BOO because of the risk of urinary retention.
Carcinogenicity
- Long-term carcinogenicity studies were conducted in rats and mice dosed orally with mirabegron for two years. Male rats were dosed at 0, 12.5, 25, or 50 mg/kg/day and female rats and both sexes of mice were dosed at 0, 25, 50, or 100 mg/kg/day. Mirabegron showed no carcinogenic potential at systemic exposures (AUC) 38 to 45-fold higher in rats and 21 to 38-fold higher in mice than the human systemic exposure at the 50 mg dose.
Mutagenesis
- Mirabegron was not mutagenic in the Ames bacterial reverse mutation assay, did not induce chromosomal aberrations in human peripheral blood lymphocytes at concentrations that were not cytotoxic, and was not clastogenic in the rat micronucleus assay.
Impairment of Fertility
- Fertility studies in rats showed that mirabegron had no effect on either male or female fertility at non-lethal doses up to 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg in female rats was estimated to be 22 times the MRHD in women and 93 times the MRHD in men.
- In Study 1, patients were randomized to placebo, Myrbetriq 50 mg, Myrbetriq 100 mg, or an active control once daily. In Study 2, patients were randomized to placebo, Myrbetriq 50 mg or Myrbetriq 100 mg once daily. In Study 3, patients were randomized to placebo, Myrbetriq 25 mg or Myrbetriq 50 mg once daily.
- The co-primary efficacy endpoints in all 3 trials were (1) change from baseline to end of treatment (Week 12) in mean number of incontinence episodes per 24 hours and (2) change from baseline to end of treatment (Week 12) in mean number of micturitions per 24 hours, based on a 3-day micturition diary. An important secondary endpoint was the change from baseline to end of treatment (Week 12) in mean volume voided per micturition.
- Results for the co-primary endpoints and mean volume voided per micturition from Studies 1, 2, and 3 are shown in Table 3.
- Myrbetriq 25 mg was effective in treating the symptoms of OAB within 8 weeks, and Myrbetriq 50 mg was effective in treating the symptoms of OAB within 4 weeks. Efficacy of both 25 mg and 50 mg doses of Myrbetriq was maintained through the 12-week treatment period.
- Figures 3 through 8 show the co-primary endpoints, mean change from baseline (BL) over time in number of incontinence episodes per 24 hours and mean change from baseline over time in number of micturitions per 24 hours, in Studies 1, 2 and 3.
- Inform patients that Myrbetriq may increase blood pressure. Periodic blood pressure determinations are recommended, especially in patients with hypertension. Myrbetriq has also been associated with infrequent urinary tract infections, rapid heart beat, rash, and pruritus. Inform patients that urinary retention has been reported when taking mirabegron in combination with antimuscarinic drugs used in the treatment of overactive bladder. Instruct patients to contact their physician if they experience these effects while taking Myrbetriq.
- Patients should read the patient leaflet entitled “Patient Information” before starting therapy with Myrbetriq.
- ↑ "http://www.ismp.org". External link in |title= (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} | https://www.wikidoc.org/index.php/Mirabegron | |
e61edb24a5a5486d6bf284d3fcd3f65691a029c1 | wikidoc | Miriam Lee | Miriam Lee
Miriam Lee is one of the pioneering acupuncturists in the United States and was responsible for acupuncture being legalized in the state of California.
Miriam Lee was born in China but left the mainland in 1949. In China, she was a nurse-midwife before becoming an acupuncturist. Lee lived through the Second Sino-Japanese War. After leaving China, she lived in Singapore for 17 years before coming to the United States. When she arrived in California, acupuncture was illegal. So Lee worked on a factory assembly line and gave treatments quietly out of her home. Later, she shared a space with a supportive medical doctor. In 1974, Lee was arrested for practicing medicine without a license. At her trial, her patients filled the courtroom to protest her arrest, claiming their right to the only medicine that had truly helped them. Within a few days, acupuncture was legally made an experimental procedure by Governor Ronald Regan. In 1976, Governor Jerry Brown signed the legislation that once and for all legalized acupuncture. In 1976, she was one of the first licensed acupuncturists in the state of California.
In the 1970s and early 1980s Lee was the acupuncture teacher of probably 70% of practitioners working in Northern California. She was famous for using a special set of points based on the work of one of her teachers, Dr. Tung known as the "Master Tung Magic Points." These are published in a book by Blue Poppy Press. She remained inventive and innovative throughout her career. During the height of her practice she would see up to 10 patients an hour and worked 80 hours a week.
She popularized a 10 point protocol used in her book, Insights of A Senior Acupuncturist. In her book Lee describes a combination of points that have wide application: ST36, SP6, LI4, LI11, and LU7. This set of points, with slight adjustments is shown to be helpful for the majority of common complaints seen in the Western acupuncture clinic, using the combination of points to balance the major organ systems. She also popularized the Master Tung Magic Points, a nontraditional point system.
The Acupuncture Association of America was founded in 1980, and run by Dr. Lee until 1998 when she retired and passed the care of AAA over to her student, Susan Johnson, L.Ac. The purpose of the organization is to promote public acupuncture education, provide continuing education for licensed practitioners, to engage in legislative advocacy, and to promote acupuncture research. | Miriam Lee
Miriam Lee is one of the pioneering acupuncturists in the United States and was responsible for acupuncture being legalized in the state of California.
Miriam Lee was born in China but left the mainland in 1949. In China, she was a nurse-midwife before becoming an acupuncturist. Lee lived through the Second Sino-Japanese War. After leaving China, she lived in Singapore for 17 years before coming to the United States. When she arrived in California, acupuncture was illegal. So Lee worked on a factory assembly line and gave treatments quietly out of her home. Later, she shared a space with a supportive medical doctor. [1] In 1974, Lee was arrested for practicing medicine without a license. At her trial, her patients filled the courtroom to protest her arrest, claiming their right to the only medicine that had truly helped them. Within a few days, acupuncture was legally made an experimental procedure by Governor Ronald Regan. In 1976, Governor Jerry Brown signed the legislation that once and for all legalized acupuncture. In 1976, she was one of the first licensed acupuncturists in the state of California.
In the 1970s and early 1980s Lee was the acupuncture teacher of probably 70% of practitioners working in Northern California. She was famous for using a special set of points based on the work of one of her teachers, Dr. Tung known as the "Master Tung Magic Points." These are published in a book by Blue Poppy Press. She remained inventive and innovative throughout her career. During the height of her practice she would see up to 10 patients an hour and worked 80 hours a week.[2]
She popularized a 10 point protocol used in her book, Insights of A Senior Acupuncturist. In her book Lee describes a combination of points that have wide application: ST36, SP6, LI4, LI11, and LU7. This set of points, with slight adjustments is shown to be helpful for the majority of common complaints seen in the Western acupuncture clinic, using the combination of points to balance the major organ systems. [3] She also popularized the Master Tung Magic Points, a nontraditional point system.
The Acupuncture Association of America was founded in 1980, and run by Dr. Lee until 1998 when she retired and passed the care of AAA over to her student, Susan Johnson, L.Ac. The purpose of the organization is to promote public acupuncture education, provide continuing education for licensed practitioners, to engage in legislative advocacy, and to promote acupuncture research.[4] | https://www.wikidoc.org/index.php/Miriam_Lee | |
3a2ab09771e7b53d485bef0676c0b76540b32d99 | wikidoc | Mithridate | Mithridate
# Overview
Mithridate, also known as as mithridatum, mithridatium or mithridaticum, is a semi-mythical remedy with as many as 65 ingredients, used as an antidote for poisoning, and said to be created by Mithridates VI of Pontus. It was among one of the most complex, highly sought-after drugs during the Renaissance, particularly in Italy and France, where they were in continual use for centuries. An updated recipe called theriac (Theriacum Andromachi) was known well into the 19th century.
Mithridate takes its name from its inventor, Mithridates, King of Pontus, who is said to have so fortified his body against poisons with antidotes and preservatives, that when he tried to kill himself, he could not find any poison that would have an effect. The recipe of it was found in his cabinet, written with his own hand, and was carried to Rome by Pompey. It was translated into verse by Servilius Damocrates, a famous physician, and was afterwards translated by Galen. It likely underwent considerable alterations since the time of its royal prescriber.
Mithridate was also used as part of a regimen to ward off potential threats of plague. According to Simon Kellwaye (1593), one should "take a great Onyon, make a hole in the myddle of him, then fill the place with Mitridat or Triacle, and some leaues of Rue". Until as late as 1786, physicians in London could officially prescribe mithridate.
The term mithridate has come to refer to any generally all-purpose antidote.
# Formulation
Aulus Cornelius Celsus details one version of the antidote in De Medicina (ca. 30 AD). A recent translation is as follows: "But the most famous antidote is that of Mithridates, which that king is said to have taken daily and by it to have rendered his body safe against danger from poison. It contains costmary 1·66 grams, sweet flag 20 grams, hypericum, gum, sagapenum, acacia juice, Illyrian iris (probably I. germanica), cardamom, 8 grams each, anise 12 grams, Gallic nard (Valeriana italica), gentian root and dried rose-leaves, 16 grams each, poppy-tears (Papaver rhoeas, a wild poppy with low opiate content) and parsley, 17 grams each, casia, saxifrage, darnel, long pepper, 20·66 grams each, storax 21 grams, castoreum, frankincense, hypocistis juice (Cytinus hypocistis), myrrh and opopanax, 24 grams each, malabathrum leaves 24 grams, flower of round rush, turpentine-resin, galbanum, Cretan carrot seeds, 24·66 grams each, nard and opobalsam, 25 grams each, shepherd's purse 25 grams, rhubarb root 28 grams, saffron, ginger, cinnamon, 29 grams each. These are pounded and taken up in honey. Against poisoning, a piece the size of an almond is given in wine. In other affections an amount corresponding in size to an Egyptian bean is sufficient." Of these ingredients, Illyrian iris, darnel, and rhubarb were not commonly found in other versions of the antidote. However, Celsus' formulation, written 100 years after the death of Mithridates, was one of the first published. Galen called the antidote "theriac" and presented versions by Aelius (used by Julius Caesar), Andromachus (physician to Nero), Antipater, Nicostratus, and Damocratis. The Andromachus formulation closely resembles that of Celsus.
The manufacture of antidotes called mithridate or theriac (English "treacle") continued into the nineteenth century. Ephraim Chambers, in his 1728 Cyclopaedia, says "Mithridate is one of the capital Medicines in the Apothecaries Shops, being composed of a vast Number of Drugs, as Opium, Myrrh, Agaric, Saffron, Ginger, Cinnamon, Spikenard, Frankincense, Castor, Pepper, Gentian, &c". It is accounted a Cordial, Opiate, Sudorific, and Alexipharmic" Petrus Andreas Matthiolus considered it more effectual against poisons than venice treacle, and easier to make. Late versions of the antidote incorporated dried blood or the dried flesh of lizards or vipers or Malabathrum
# Criticism
Pliny (Natural History, XXIX.24-25, ca. AD 77) was skeptical of mithridate and other such theriacs, with their numerous ingredients:
# In literature
In A. E. Houseman's collection of poetry titled A Shropshire Lad, there is a poem about King Mithridates and his antidote's amazing abilities: | Mithridate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [7]
# Overview
Mithridate, also known as as mithridatum, mithridatium or mithridaticum, is a semi-mythical remedy with as many as 65 ingredients, used as an antidote for poisoning, and said to be created by Mithridates VI of Pontus. It was among one of the most complex, highly sought-after drugs during the Renaissance, particularly in Italy and France, where they were in continual use for centuries.[1] An updated recipe called theriac (Theriacum Andromachi) was known well into the 19th century.[2]
Mithridate takes its name from its inventor, Mithridates, King of Pontus, who is said to have so fortified his body against poisons with antidotes and preservatives, that when he tried to kill himself, he could not find any poison that would have an effect. The recipe of it was found in his cabinet, written with his own hand, and was carried to Rome by Pompey. It was translated into verse by Servilius Damocrates, a famous physician, and was afterwards translated by Galen. It likely underwent considerable alterations since the time of its royal prescriber.[3]
Mithridate was also used as part of a regimen to ward off potential threats of plague. According to Simon Kellwaye (1593), one should "take a great Onyon, make a hole in the myddle of him, then fill the place with Mitridat or Triacle, and some leaues of Rue".[4] Until as late as 1786, physicians in London could officially prescribe mithridate.[5]
The term mithridate has come to refer to any generally all-purpose antidote.[6]
# Formulation
Aulus Cornelius Celsus details one version of the antidote in De Medicina (ca. 30 AD). A recent translation is as follows: "But the most famous antidote is that of Mithridates, which that king is said to have taken daily and by it to have rendered his body safe against danger from poison. It contains costmary 1·66 grams, sweet flag 20 grams, hypericum, gum, sagapenum, acacia juice, Illyrian iris (probably I. germanica[7]), cardamom, 8 grams each, anise 12 grams, Gallic nard (Valeriana italica[8]), gentian root and dried rose-leaves, 16 grams each, poppy-tears (Papaver rhoeas, a wild poppy with low opiate content[9]) and parsley, 17 grams each, casia, saxifrage, darnel, long pepper, 20·66 grams each, storax 21 grams, castoreum, frankincense, hypocistis juice (Cytinus hypocistis[10]), myrrh and opopanax, 24 grams each, malabathrum leaves 24 grams, flower of round rush, turpentine-resin, galbanum, Cretan carrot seeds, 24·66 grams each, nard and opobalsam, 25 grams each, shepherd's purse 25 grams, rhubarb root 28 grams, saffron, ginger, cinnamon, 29 grams each. These are pounded and taken up in honey. Against poisoning, a piece the size of an almond is given in wine. In other affections an amount corresponding in size to an Egyptian bean is sufficient." Of these ingredients, Illyrian iris, darnel, and rhubarb were not commonly found in other versions of the antidote.[11] However, Celsus' formulation, written 100 years after the death of Mithridates, was one of the first published. Galen called the antidote "theriac" and presented versions by Aelius (used by Julius Caesar), Andromachus (physician to Nero), Antipater, Nicostratus, and Damocratis. The Andromachus formulation closely resembles that of Celsus.[12]
The manufacture of antidotes called mithridate or theriac (English "treacle") continued into the nineteenth century. Ephraim Chambers, in his 1728 Cyclopaedia, says "Mithridate is one of the capital Medicines in the Apothecaries Shops, being composed of a vast Number of Drugs, as Opium, Myrrh, Agaric, Saffron, Ginger, Cinnamon, Spikenard, Frankincense, Castor, Pepper, Gentian, &c". It is accounted a Cordial, Opiate, Sudorific, and Alexipharmic" Petrus Andreas Matthiolus considered it more effectual against poisons than venice treacle, and easier to make.[13] Late versions of the antidote incorporated dried blood or the dried flesh of lizards or vipers[14] or Malabathrum[15]
# Criticism
Pliny (Natural History, XXIX.24-25, ca. AD 77) was skeptical of mithridate and other such theriacs, with their numerous ingredients:
# In literature
In A. E. Houseman's collection of poetry titled A Shropshire Lad, there is a poem about King Mithridates and his antidote's amazing abilities: | https://www.wikidoc.org/index.php/Mithridate | |
597d5390b2108773266a5eef5d88ec8e377a96ad | wikidoc | Mivacurium | Mivacurium
# 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
Mivacurium is {{{aOrAn}}} {{{drugClass}}} that is FDA approved for the {{{indicationType}}} of {{{indication}}}. Common adverse reactions include {{{adverseReactions}}}.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
There is limited information regarding Mivacurium FDA-Labeled Indications and Dosage (Adult) in the drug label.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mivacurium in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mivacurium in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Mivacurium 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 Mivacurium in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mivacurium in pediatric patients.
# Contraindications
There is limited information regarding Mivacurium Contraindications in the drug label.
# Warnings
There is limited information regarding Mivacurium Warnings' in the drug label.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Mivacurium Clinical Trials Experience in the drug label.
## Postmarketing Experience
There is limited information regarding Mivacurium Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Mivacurium Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Mivacurium in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mivacurium in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Mivacurium during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Mivacurium in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Mivacurium in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Mivacurium in geriatric settings.
### Gender
There is no FDA guidance on the use of Mivacurium with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Mivacurium with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Mivacurium in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Mivacurium in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Mivacurium in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Mivacurium in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Mivacurium Administration in the drug label.
### Monitoring
There is limited information regarding Mivacurium Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Mivacurium and IV administrations.
# Overdosage
There is limited information regarding Mivacurium overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
There is limited information regarding Mivacurium Pharmacology in the drug label.
## Mechanism of Action
There is limited information regarding Mivacurium Mechanism of Action in the drug label.
## Structure
There is limited information regarding Mivacurium Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Mivacurium Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Mivacurium Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Mivacurium Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Mivacurium Clinical Studies in the drug label.
# How Supplied
There is limited information regarding Mivacurium How Supplied in the drug label.
## Storage
There is limited information regarding Mivacurium Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Mivacurium Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Mivacurium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Mivacurium Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Mivacurium Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Mivacurium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Mivacurium is {{{aOrAn}}} {{{drugClass}}} that is FDA approved for the {{{indicationType}}} of {{{indication}}}. Common adverse reactions include {{{adverseReactions}}}.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
There is limited information regarding Mivacurium FDA-Labeled Indications and Dosage (Adult) in the drug label.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mivacurium in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mivacurium in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Mivacurium 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 Mivacurium in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mivacurium in pediatric patients.
# Contraindications
There is limited information regarding Mivacurium Contraindications in the drug label.
# Warnings
There is limited information regarding Mivacurium Warnings' in the drug label.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Mivacurium Clinical Trials Experience in the drug label.
## Postmarketing Experience
There is limited information regarding Mivacurium Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Mivacurium Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Mivacurium in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mivacurium in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Mivacurium during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Mivacurium in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Mivacurium in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Mivacurium in geriatric settings.
### Gender
There is no FDA guidance on the use of Mivacurium with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Mivacurium with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Mivacurium in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Mivacurium in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Mivacurium in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Mivacurium in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Mivacurium Administration in the drug label.
### Monitoring
There is limited information regarding Mivacurium Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Mivacurium and IV administrations.
# Overdosage
There is limited information regarding Mivacurium overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
There is limited information regarding Mivacurium Pharmacology in the drug label.
## Mechanism of Action
There is limited information regarding Mivacurium Mechanism of Action in the drug label.
## Structure
There is limited information regarding Mivacurium Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Mivacurium Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Mivacurium Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Mivacurium Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Mivacurium Clinical Studies in the drug label.
# How Supplied
There is limited information regarding Mivacurium How Supplied in the drug label.
## Storage
There is limited information regarding Mivacurium Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Mivacurium Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Mivacurium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Mivacurium Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Mivacurium Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Mivacron | |
f4e4e264e5382ddf5911eca7b48d2a918cba6242 | wikidoc | Mixed nuts | Mixed nuts
Mixed nuts are a snack food consisting of any mixture of mechanically or manually combined nuts. Peanuts (actually a legume), almonds, walnuts, Brazil nuts, cashews, filberts, hazelnuts, and pecans are common constituents of mixed nuts. Mixed nuts may be salted, roasted, cooked, or blanched.
In addition to being eaten directly, mixed nuts can be used in cooking, such as for Tunisian farka, tarts, and toffee. Student food and trail mix consist of nuts mixed with raisins and other dry ingredients.
# Market
In Japan, mixed nuts are the second most popular table nuts, behind sweet chestnuts; in the United States, they are second only to peanuts. Mixed nuts have also gained in popularity in the Argentinian market, which imported some $1.9 million in 1997, nearly half from the U.S. During the year 2002, U.S. companies sold $783 million of mixed nuts incorporating four or more varieties, mostly in canned form, representing hundreds of millions of pounds.
The individual nuts that make up mixed nuts are harvested from all over the world. As a Dallas Fed publication supporting free trade puts it,
This reality provides an incentive for nut salters to favor free trade for nuts, as opposed to nut farmers, who would generally support trade barriers. In fact, one historical argument for United States salters is that importing nuts can encourage domestic production, since mixed nuts provide a "wagon" on which everyone's sales ride. For example, cashews are not produced in North America, and it is necessary to import them because mixed nuts are essential to the sale of pecans, which are grown exclusively in North America.
# Composition
Because they are relatively inexpensive, peanuts are typically a major ingredient in mixed nuts, although they are viewed as less fancy than other nuts; often "deluxe mixed nuts" are advertised as containing no peanuts. In fact, Fisher Nuts' brand of "deluxe" mixed nuts has had to recall a batch because peanuts may have crept into the mix. The move was not to save face: peanuts are the ingredient of mixed nuts most commonly associated with life-threatening food allergies.
Less dramatically, some mixed nuts advertise themselves to contain "less than 50% peanuts". For a 60 Minutes segment that originally aired in 1997, Andy Rooney tested such a 12 oz can of Planters brand nuts, pleading boredom on a Saturday. He determined that "there was a tiny fraction less than six ounces of peanuts . . . amazing precision for a nut factory." Later, in 2004, a cockeyed.com How much is inside? episode estimated that the peanut weight percentage in two such 11.5 oz cans was, in fact, a little over 50%.
Besides peanuts, cashews are usually the next least expensive nut, and in deluxe mixes they tend to be the most common ingredient. Hazelnuts and brazil nuts are also "relatively cheap", while pecans are the most expensive ingredient.
# Regulations
## United States
Percent composition by weight is a serious matter in the U.S., where mixed nuts have been regulated by the Food and Drug Administration since 1977. Up to that point, the phrase "mixed nuts" had been legally meaningless. A 1964 Consumer Reports investigation of 124 cans of mixed nuts, representing 31 brands bought in 17 American cities, determined that most mixed nuts of the time were mostly peanuts, often 75%; peanutless brands were usually dominated by cashews. Many cans bore misleading labels or were underfilled. Consumer Reports concluded, "What's needed of course is a Federal standard of identity...", detailing a list that of requirements that, with the exception of their desire to limit broken nuts, anticipated the 1977 rules.
On March 15, 1977, the FDA promulgated a new standard of identity for mixed nuts in 42 FR 14475. The present standard, as modified by 58 FR 2885, Jan. 6, 1993, requires that mixed nuts must contain at least four different varieties of tree nuts or peanuts. (Products with three or fewer varieties are now commonly labelled as simply "mixes".) The container volume must be at least 85% filled, and the label must state whether any peanuts are unblanched or of the Spanish variety.
The most detailed section deals with weight percentages:
Furthermore, if a variety X exceeds 50%, the label must conspicuously state "contains up to 60% X", and so on in 10% increments up to 80%. (The first example given by the FDA is "contains up to 60% pecans".) When testing mixed nuts for compliance, the FDA samples at least 24 pounds to reduce sampling error.
Modifying words like "fancy" or "choice" have not historically carried any legal meaning in the United States, and they remain absent from the current regulations. In a 1915 federal case against "fancy mixed nuts" that were argued by competitors to be an inferior grade, U. S. v. 25 Bags of Nuts, N. J. No. 4329 (1915), the court declined to accept a trade standard:
# Analogies
- The phrase "mixed nuts" is also used to indicate a mixture of disparate elements other than nuts, as in the film Mixed Nuts.
- When a container of mixed nuts is opened after it has been shaken, the larger nuts tend to be on top. This phenomenon is known as the Brazil nut effect in the study of granular materials. | Mixed nuts
Mixed nuts are a snack food consisting of any mixture of mechanically or manually combined nuts. Peanuts (actually a legume), almonds, walnuts, Brazil nuts, cashews, filberts, hazelnuts, and pecans are common constituents of mixed nuts.[1] Mixed nuts may be salted, roasted, cooked, or blanched.
In addition to being eaten directly, mixed nuts can be used in cooking, such as for Tunisian farka,[2] tarts,[3] and toffee.[4] Student food and trail mix consist of nuts mixed with raisins and other dry ingredients.
# Market
In Japan, mixed nuts are the second most popular table nuts, behind sweet chestnuts;[5] in the United States, they are second only to peanuts.[6] Mixed nuts have also gained in popularity in the Argentinian market, which imported some $1.9 million in 1997, nearly half from the U.S.[7] During the year 2002, U.S. companies sold $783 million of mixed nuts incorporating four or more varieties, mostly in canned form, representing hundreds of millions of pounds.[6]
The individual nuts that make up mixed nuts are harvested from all over the world. As a Dallas Fed publication supporting free trade puts it,
This reality provides an incentive for nut salters to favor free trade for nuts, as opposed to nut farmers, who would generally support trade barriers. In fact, one historical argument for United States salters is that importing nuts can encourage domestic production, since mixed nuts provide a "wagon" on which everyone's sales ride. For example, cashews are not produced in North America, and it is necessary to import them because mixed nuts are essential to the sale of pecans, which are grown exclusively in North America.[9]
# Composition
Because they are relatively inexpensive, peanuts are typically a major ingredient in mixed nuts, although they are viewed as less fancy than other nuts; often "deluxe mixed nuts" are advertised as containing no peanuts. In fact, Fisher Nuts' brand of "deluxe" mixed nuts has had to recall a batch because peanuts may have crept into the mix.[10] The move was not to save face: peanuts are the ingredient of mixed nuts most commonly associated with life-threatening food allergies.
Less dramatically, some mixed nuts advertise themselves to contain "less than 50% peanuts". For a 60 Minutes segment that originally aired in 1997,[11] Andy Rooney tested such a 12 oz can of Planters brand nuts, pleading boredom on a Saturday. He determined that "there was a tiny fraction less than six ounces of peanuts . . . amazing precision for a nut factory."[12] Later, in 2004, a cockeyed.com How much is inside? episode estimated that the peanut weight percentage in two such 11.5 oz cans was, in fact, a little over 50%.[13]
Besides peanuts, cashews are usually the next least expensive nut, and in deluxe mixes they tend to be the most common ingredient.[14] Hazelnuts and brazil nuts are also "relatively cheap", while pecans are the most expensive ingredient.[12]
# Regulations
## United States
Percent composition by weight is a serious matter in the U.S., where mixed nuts have been regulated by the Food and Drug Administration since 1977. Up to that point, the phrase "mixed nuts" had been legally meaningless. A 1964 Consumer Reports investigation of 124 cans of mixed nuts, representing 31 brands bought in 17 American cities, determined that most mixed nuts of the time were mostly peanuts, often 75%; peanutless brands were usually dominated by cashews. Many cans bore misleading labels or were underfilled. Consumer Reports concluded, "What's needed of course is a Federal standard of identity...", detailing a list that of requirements that, with the exception of their desire to limit broken nuts, anticipated the 1977 rules.[14]
On March 15, 1977, the FDA promulgated a new standard of identity for mixed nuts in 42 FR 14475. The present standard, as modified by 58 FR 2885, Jan. 6, 1993, requires that mixed nuts must contain at least four different varieties of tree nuts or peanuts. (Products with three or fewer varieties are now commonly labelled as simply "mixes".) The container volume must be at least 85% filled, and the label must state whether any peanuts are unblanched or of the Spanish variety.[1]
The most detailed section deals with weight percentages:
Furthermore, if a variety X exceeds 50%, the label must conspicuously state "contains up to 60% X", and so on in 10% increments up to 80%. (The first example given by the FDA is "contains up to 60% pecans".) When testing mixed nuts for compliance, the FDA samples at least 24 pounds to reduce sampling error.[1]
Modifying words like "fancy" or "choice" have not historically carried any legal meaning in the United States, and they remain absent from the current regulations.[1] In a 1915 federal case against "fancy mixed nuts" that were argued by competitors to be an inferior grade, U. S. v. 25 Bags of Nuts, N. J. No. 4329 (1915), the court declined to accept a trade standard:
# Analogies
- The phrase "mixed nuts" is also used to indicate a mixture of disparate elements other than nuts, as in the film Mixed Nuts.
- When a container of mixed nuts is opened after it has been shaken, the larger nuts tend to be on top. This phenomenon is known as the Brazil nut effect in the study of granular materials. | https://www.wikidoc.org/index.php/Mixed_nuts | |
7c12d847ad84c1f86e6c69b94294e7e48d0e9724 | wikidoc | Molar mass | Molar mass
Molar mass is the mass of one mole of a chemical element or chemical compound. It is commonly used in stoichiometric calculations of bulk substances in chemistry. Its primary purpose is as a conversion factor between the number of grams of a pure substance, which can be measured directly, and the number of moles of that substance, which has greater chemical significance. This allows for using the appropriate number of molecules of a substance regardless of the mass. For example, if an equal number of molecules of two substances are needed for a reaction but the molar mass of one substance is twice that of the other, twice as many grams will be needed of that substance to give the same number of molecules.
The molar mass of a chemical substance may be computed from the standard atomic weights listed for the elements on a standard periodic table. A mole of a substance is defined to be approximately 6.023x1023 (see Avogadro's number) of particles of the substance. Thus the molar mass is the mass of 6.023x1023 particles of the substance. Molar mass is different from Molecular mass which is the mass of one molecule.
In chemistry, the unit of molar mass is g/mol due to chemical utility. In physics, molar mass is usually defined in kilograms per mole (kg/mol) because the base SI unit of mass is the kilogram.
In linear polymers not every polymer chain consists of the same amount of repeating units. A given polymer sample is said to be made up of a mixture of macromolecules with a certain molar mass distribution.
# Example
Let us see approximately how many grams are in 2.3 moles of table sugar with a chemical formula of C12H22O11. The standard atomic weights of carbon, hydrogen, and oxygen are approximately 12.011 , 1.008 , and 15.999 g/mol respectively. Thus the molar mass of sucrose is its sum: (12.011 - 12) + (1.008 - 22) + (15.999 - 11) = 342.297 g/mol. The mass of 2.3 moles of sugar is then 2.3 mol - 342.297 g/mol = 787.2831 g.
(Note: For simplicity this example ignores the proper use of significant figures)
# Molar mass versus molecular mass
Molar mass is sometimes confused with the related but distinct molecular mass. This is largely due to that when the molar mass and molecular mass are expressed in g/mol and u respectively they will almost always have similar but not identical numerical values. The molar mass is generally computed from isotopically weighted averages, whereas the molecular mass is the mass of a single molecule consisting of well-defined isotopes. The isotopically weighted averages used to compute molar masses are those found in most versions of the periodic table and are numbers recommended by IUPAC. They represent the most likely weights of substances found in the laboratory. The averaging takes into account the natural abundance of, usually heavier, isotopes as well as the variation in their natural abundance in different places on earth. Additionally the confidence, or number of significant figures after the decimal, is different. The significant figures in the standard atomic weights and thus the computed molar masses are often limited by the natural variations in the isotopic distributions and not necessarily by our ability to measure accurately. The confidence in the isotopic masses and resulting molecular masses are only limited by the accuracy of measurement of the invariable isotopic masses.
It is common, even amongst professional chemists, to use the terms interchangeably since for most common applications the difference is insignificant. This can, however, on occasion lead to substantive confusion. Due to this common practice some areas of chemistry have developed their own more specific terms such as monoisotopic mass and average mass. Due to these subtle differences and the inherent nature of the molar mass it is always more correct, accurate and consistent to use molar mass in any bulk stoichiometric calculations. | Molar mass
Molar mass is the mass of one mole of a chemical element or chemical compound.[1] It is commonly used in stoichiometric calculations of bulk substances in chemistry. Its primary purpose is as a conversion factor between the number of grams of a pure substance, which can be measured directly, and the number of moles of that substance, which has greater chemical significance. This allows for using the appropriate number of molecules of a substance regardless of the mass. For example, if an equal number of molecules of two substances are needed for a reaction but the molar mass of one substance is twice that of the other, twice as many grams will be needed of that substance to give the same number of molecules.
The molar mass of a chemical substance may be computed from the standard atomic weights listed for the elements on a standard periodic table. A mole of a substance is defined to be approximately 6.023x1023 (see Avogadro's number) of particles of the substance. Thus the molar mass is the mass of 6.023x1023 particles of the substance. Molar mass is different from Molecular mass which is the mass of one molecule.
In chemistry, the unit of molar mass is g/mol due to chemical utility. In physics, molar mass is usually defined in kilograms per mole (kg/mol) because the base SI unit of mass is the kilogram.
In linear polymers not every polymer chain consists of the same amount of repeating units. A given polymer sample is said to be made up of a mixture of macromolecules with a certain molar mass distribution.[2]
# Example
Let us see approximately how many grams are in 2.3 moles of table sugar with a chemical formula of C12H22O11. The standard atomic weights of carbon, hydrogen, and oxygen are approximately 12.011 , 1.008 , and 15.999 g/mol respectively. Thus the molar mass of sucrose is its sum: (12.011 * 12) + (1.008 * 22) + (15.999 * 11) = 342.297 g/mol. The mass of 2.3 moles of sugar is then 2.3 mol * 342.297 g/mol = 787.2831 g.
(Note: For simplicity this example ignores the proper use of significant figures)
# Molar mass versus molecular mass
Molar mass is sometimes confused with the related but distinct molecular mass. This is largely due to that when the molar mass and molecular mass are expressed in g/mol and u respectively they will almost always have similar but not identical numerical values. The molar mass is generally computed from isotopically weighted averages, whereas the molecular mass is the mass of a single molecule consisting of well-defined isotopes. The isotopically weighted averages used to compute molar masses are those found in most versions of the periodic table and are numbers recommended by IUPAC. They represent the most likely weights of substances found in the laboratory. The averaging takes into account the natural abundance of, usually heavier, isotopes as well as the variation in their natural abundance in different places on earth. Additionally the confidence, or number of significant figures after the decimal, is different. The significant figures in the standard atomic weights and thus the computed molar masses are often limited by the natural variations in the isotopic distributions and not necessarily by our ability to measure accurately. The confidence in the isotopic masses and resulting molecular masses are only limited by the accuracy of measurement of the invariable isotopic masses.
It is common, even amongst professional chemists, to use the terms interchangeably since for most common applications the difference is insignificant. This can, however, on occasion lead to substantive confusion. Due to this common practice some areas of chemistry have developed their own more specific terms such as monoisotopic mass and average mass. Due to these subtle differences and the inherent nature of the molar mass it is always more correct, accurate and consistent to use molar mass in any bulk stoichiometric calculations. | https://www.wikidoc.org/index.php/Molar_mass | |
b3fd147b286833a83cdd1a17b86502f6fa728032 | wikidoc | Monochrome | Monochrome
Monochrome comes from the Greek μονόχρωμος (monochromos), meaning “of one color”, which is a combination of μόνος (monos), meaning “alone” or “solitary”, and χρώμα (chroma), meaning “color”. Monochromatic light is light of a single wavelength, though in practice it can refer to light of a narrow wavelength range. A monochromatic object or image is one whose range of colors consists of shades of a single color or hue; monochrome images in neutral colors are also known as grayscale or black-and-white.
# Theory
In physics, the word is used more generally to refer to electromagnetic radiation of a single wavelength. In the physical sense, no real source of electromagnetic radiation is purely monochromatic, since that would require a wave of infinite duration as a consequence of the Fourier transform's localization property (cf. spectral coherence). Even sources such as lasers have some narrow range of wavelengths (known as the spectral linewidth) within which they operate. In practice, filtered light, diffraction grating separated light and laser light are all routinely referred to as monochromatic. Often light sources can be compared and one be labeled as “more monochromatic” (in a similar usage as monodispersity). And a device which isolates light sources of a narrow bandwidth are called monochromators, even though the bandwidth is often explicitly specified, and thus a collection of wavelengths is understood.
# Application
For an image, the term monochrome is usually taken to mean the same as black-and-white or, more likely, grayscale, but may also be used to refer to other combinations containing only tones of a single color, such as green-and-white or green-and-black. It may also refer to sepia displaying tones from light tan to dark brown or cyanotype (“blueprint”) images, and early photographic methods such as Ambrotype, Tintype and Daguerreotype, each of which may be used to produce a monochromatic image.
In computing, monochrome has two meanings:
- it may mean having only one color which is either on or off,
- allowing shades of that color, although the latter is more correctly known as grayscale.
A monochrome computer display is able to display only a single color, often green, amber, red or white, and often also shades of that color.
In film photography, monochrome is typically the use of black and white film.
Originally, all photography was done in monochrome until the invention of color film plates in the early 20th century.
In digital photography, monochrome is the capture of only shades of black by the sensor, or by post-processing a color image to present only the perceived brightness by combining the values of multiple channels (usually red, blue, and green). The weighting of individual channels may be selected to achieve a desired artistic effect - if only the red channel is selected by the weighting then the effect will be similar to that of using a red filter on panchromatic film. If the red channel is eliminated and the green and blue combined then the effect will be similar to that of Orthochromatic film or the use of a cyan filter on panchromatic film. The selection of weighting thus allows a wide range of artistic expression in the final monochromatic image.
For production of an anaglyph image the original color stereogram source may first be reduced to monochrome in order to simplify the rendering of the image. This is sometimes required in cases where a color image would render in a confusing manner given the colors and patterns present in the source image and the selection filters used (typically red and its complement cyan), | Monochrome
Monochrome comes from the Greek μονόχρωμος (monochromos), meaning “of one color”, which is a combination of μόνος (monos), meaning “alone” or “solitary”, and χρώμα (chroma), meaning “color”.[1] Monochromatic light is light of a single wavelength, though in practice it can refer to light of a narrow wavelength range. A monochromatic object or image is one whose range of colors consists of shades of a single color or hue; monochrome images in neutral colors are also known as grayscale or black-and-white.
# Theory
In physics, the word is used more generally to refer to electromagnetic radiation of a single wavelength. In the physical sense, no real source of electromagnetic radiation is purely monochromatic, since that would require a wave of infinite duration as a consequence of the Fourier transform's localization property (cf. spectral coherence). Even sources such as lasers have some narrow range of wavelengths (known as the spectral linewidth) within which they operate. In practice, filtered light, diffraction grating separated light and laser light are all routinely referred to as monochromatic. Often light sources can be compared and one be labeled as “more monochromatic” (in a similar usage as monodispersity). And a device which isolates light sources of a narrow bandwidth are called monochromators, even though the bandwidth is often explicitly specified, and thus a collection of wavelengths is understood.
# Application
For an image, the term monochrome is usually taken to mean the same as black-and-white or, more likely, grayscale, but may also be used to refer to other combinations containing only tones of a single color, such as green-and-white or green-and-black. It may also refer to sepia displaying tones from light tan to dark brown or cyanotype (“blueprint”) images, and early photographic methods such as Ambrotype, Tintype and Daguerreotype, each of which may be used to produce a monochromatic image.
In computing, monochrome has two meanings:
- it may mean having only one color which is either on or off,
- allowing shades of that color, although the latter is more correctly known as grayscale.
A monochrome computer display is able to display only a single color, often green, amber, red or white, and often also shades of that color.
In film photography, monochrome is typically the use of black and white film.
Originally, all photography was done in monochrome until the invention of color film plates in the early 20th century.
In digital photography, monochrome is the capture of only shades of black by the sensor, or by post-processing a color image to present only the perceived brightness by combining the values of multiple channels (usually red, blue, and green). The weighting of individual channels may be selected to achieve a desired artistic effect - if only the red channel is selected by the weighting then the effect will be similar to that of using a red filter on panchromatic film. If the red channel is eliminated and the green and blue combined then the effect will be similar to that of Orthochromatic film or the use of a cyan filter on panchromatic film. The selection of weighting thus allows a wide range of artistic expression in the final monochromatic image.
For production of an anaglyph image the original color stereogram source may first be reduced to monochrome in order to simplify the rendering of the image. This is sometimes required in cases where a color image would render in a confusing manner given the colors and patterns present in the source image and the selection filters used (typically red and its complement cyan), | https://www.wikidoc.org/index.php/Monochromatic | |
f6c68ab70f6cecef0fe4c6798cc2b0c3a5e9d1d0 | wikidoc | Monorchism | Monorchism
Monorchism is the state of having only one testicle within the scrotum.
# Causes
This can be due to:
- One testicle not descending into the scrotum during normal embryonic or fetal development (3–4% of 'normal' live births), also known as: undescended testis or cryptorchidism. In this case the testis is within the abdominal cavity, somewhere along the normal route of descent — most commonly, within the inguinal canal. Such a testis has an increased risk of malignancy.
- One testicle may disappear during development (the so called vanishing testis) due to some intrauterine insult. This is thought most likely vascular, such as testicular torsion.
- One testicle being surgically removed through Orchidectomy
# Notable cases
It has been claimed that both Hitler and Napoleon were afflicted by such a lack of symmetry, and suggested that this may have played a role in their particular psychological makeup. See Hitler Has Only Got One Ball.
Former Australian politician Mark Latham, American bicyclist Lance Armstrong and Canadian comedian/actor Tom Green all have monorchism, as one testicle was removed to treat testicular cancer in each case. The late Frank Church, U.S. Senator (D-Idaho) from 1957 to 1981 and a Presidential aspirant in 1976, also had monorchism, having had one testicle removed in the late 1940s while attending Stanford Law School. Although Church had been given only a year to live, the surgery plus X-Ray treatment put the cancer into remission. Church eventually lived until 1984, when he succumbed to pancreatic cancer, a quarter-century later. His monorchism was revealed publicly during the 1976 Presidential campaign.
# Terminology
An individual having monorchism can be referred to as monorchid. | Monorchism
Monorchism is the state of having only one testicle within the scrotum.
# Causes
This can be due to:
- One testicle not descending into the scrotum during normal embryonic or fetal development (3–4% of 'normal' live births), also known as: undescended testis or cryptorchidism. In this case the testis is within the abdominal cavity, somewhere along the normal route of descent — most commonly, within the inguinal canal. Such a testis has an increased risk of malignancy.
- One testicle may disappear during development (the so called vanishing testis) due to some intrauterine insult. This is thought most likely vascular, such as testicular torsion.
- One testicle being surgically removed through Orchidectomy
# Notable cases
It has been claimed that both Hitler and Napoleon were afflicted by such a lack of symmetry, and suggested that this may have played a role in their particular psychological makeup.[citation needed] See Hitler Has Only Got One Ball.
Former Australian politician Mark Latham[1], American bicyclist Lance Armstrong[2] and Canadian comedian/actor Tom Green[3] all have monorchism, as one testicle was removed to treat testicular cancer in each case. The late Frank Church, U.S. Senator (D-Idaho) from 1957 to 1981 and a Presidential aspirant in 1976, also had monorchism, having had one testicle removed in the late 1940s while attending Stanford Law School. Although Church had been given only a year to live, the surgery plus X-Ray treatment put the cancer into remission. Church eventually lived until 1984, when he succumbed to pancreatic cancer[1], a quarter-century later. His monorchism was revealed publicly during the 1976 Presidential campaign.
# Terminology
An individual having monorchism can be referred to as monorchid. | https://www.wikidoc.org/index.php/Monorchism | |
590c144ce5a611b783aff02dfb05330f2b81d20b | wikidoc | Mons pubis | Mons pubis
# Overview
The mons pubis (Latin, pubic mound), also known as the mons veneris (Latin, mound of Venus) or simply the mons, is the soft mound of flesh present in women just above the genitals, raised above the surrounding area due to a pad of fat lying just beneath it which protects the pubic bone. It is anterior to the symphysis pubis.
The size of the mons pubis varies with the general level of body fat. After puberty it is normally covered with pubic hair.
In humans, the mons pubis divides into the labia majora (literally "major lips") on either side of the furrow, known as the cleft of venus, that surrounds the clitoris, vaginal opening, and other structures of the vulva. The fatty tissue of the mons veneris is sensitive to estrogen, causing a distinct mound to form with the onset of puberty. This pushes the forward portion of the labia majora out and away from the pubic bone, and parallel to the ground (when standing).
# Additional images
- Vulva anatomy.
- Organs of the female reproductive system.
- Mons pubis
Mons pubis | Mons pubis
Template:Infobox Anatomy
# Overview
The mons pubis (Latin, pubic mound), also known as the mons veneris (Latin, mound of Venus) or simply the mons, is the soft mound of flesh present in women just above the genitals, raised above the surrounding area due to a pad of fat lying just beneath it which protects the pubic bone. It is anterior to the symphysis pubis.
The size of the mons pubis varies with the general level of body fat. After puberty it is normally covered with pubic hair.
In humans, the mons pubis divides into the labia majora (literally "major lips") on either side of the furrow, known as the cleft of venus, that surrounds the clitoris, vaginal opening, and other structures of the vulva. The fatty tissue of the mons veneris is sensitive to estrogen, causing a distinct mound to form with the onset of puberty. This pushes the forward portion of the labia majora out and away from the pubic bone, and parallel to the ground (when standing).
# Additional images
- Vulva anatomy.
- Organs of the female reproductive system.
- Mons pubis
Mons pubis | https://www.wikidoc.org/index.php/Mons_pubis | |
f45b9376c78822452fea8d4c6bdb50546b56fbaa | wikidoc | Moracizine | Moracizine
# Overview
Moracizine (INN, or moricizine, trade name Ethmozine) is an antiarrhythmic of class IC. It was used for the prophylaxis and treatment of serious and life-threatening ventricular arrhythmias, but was withdrawn in 2007 for commercial reasons.
# Pharmacology
Moracizine, a phenothiazine derivative, undergoes extensive first-pass metabolism and is also extensively metabolized after it has entered the circulation. It may have pharmacologically active metabolites. A clinical study has shown that moracizine is slightly less effective than encainide or flecainide in suppressing ventricular premature depolarizations. Compared with disopyramide and quinidine, moracizine was equally or more effective in suppressing premature ventricular contractions, couplets, and nonsustained ventricular tachycardia.
In the Cardiac Arrhythmia Suppression Trial (CAST), a large study testing the influence of antiarrhythmics on mortality, showed a non-significant increase of mortality from 5.4 to 7.2% under moracizine. This is in line with other class IC antiarrhythmics. | Moracizine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Moracizine (INN,[1] or moricizine, trade name Ethmozine) is an antiarrhythmic of class IC.[2] It was used for the prophylaxis and treatment of serious and life-threatening ventricular arrhythmias,[3] but was withdrawn in 2007 for commercial reasons.[4]
# Pharmacology
Moracizine, a phenothiazine derivative, undergoes extensive first-pass metabolism and is also extensively metabolized after it has entered the circulation. It may have pharmacologically active metabolites. A clinical study has shown that moracizine is slightly less effective than encainide or flecainide in suppressing ventricular premature depolarizations.[citation needed] Compared with disopyramide and quinidine, moracizine was equally or more effective in suppressing premature ventricular contractions, couplets, and nonsustained ventricular tachycardia.[citation needed]
In the Cardiac Arrhythmia Suppression Trial (CAST), a large study testing the influence of antiarrhythmics on mortality, showed a non-significant increase of mortality from 5.4 to 7.2% under moracizine. This is in line with other class IC antiarrhythmics.[5] | https://www.wikidoc.org/index.php/Moracizine | |
96b8b0027ad11c0c5a0a30dd03faaa5e4d5a08bb | wikidoc | Morgellons | Morgellons
Morgellons (also called Morgellons disease or Morgellons syndrome) is a name given in 2002 by Mary Leitao to a proposed infectious condition characterized by a range of cutaneous (skin) symptoms including crawling, biting, and stinging sensations; finding fibers on or under the skin; and persistent skin lesions (e.g., rashes or sores). Current scientific consensus holds that Morgellons is not a new disorder and is instead a new and misleading name for known illnesses. Most doctors, including dermatologists and psychiatrists, regard Morgellons as a manifestation of known medical conditions, including delusional parasitosis, although some health professionals say that an infectious cause could one day be found. Illnesses such as delusional parasitosis can be serious and debilitating, but tested and effective treatments exist.
Despite the lack of evidence that Morgellons is a novel or distinct condition and the absence of any agreed set of diagnostic symptoms, the Morgellons Research Foundation and self-diagnosed Morgellons patients have successfully lobbied members of Congress and the U.S. government's Centers for Disease Control and Prevention (CDC) to investigate the proposed condition. The CDC states that while it is not known at present whether the condition represents a new disease entity, or whether persons who identify themselves as having Morgellons have a common cause for their symptoms, share common risk factors, or are contagious, it has begun an epidemiological investigation of the "Unexplained Dermopathy (aka 'Morgellons')."
# History
## Mary Leitao and the MRF
In 2001, according to Mary Leitao, her then two-year-old son developed sores under his lip and began to complain of "bugs." Leitao, who graduated with a BS in Biology, and worked for five years at Boston hospitals as an electron microscopist and a immunohistochemist before becoming a stay-at-home mother, says she examined the sores and discovered red, blue, black, and white fibers. She states that she took her son to see at least eight different doctors who were unable to find any disease, allergy, or anything unusual about her son's described symptoms. Dr. Fred Heldrich, a Johns Hopkins pediatrician with a reputation "for solving mystery cases," examined Leitao's son. Heldrich found nothing abnormal about the boy's skin, wrote to the referring physician that "Leitao would benefit from a psychiatric evaluation and support," and registered his worry about Leitao's "use" of her son. Psychology Today reports that Leitao last consulted an unnamed Johns Hopkins infectious disease specialist who after reviewing her son's records refused to see him, suggesting Leitao herself might suffer from "Munchausen's by proxy, a psychiatric syndrome in which a parent pretends a child is sick or makes him sick to get attention from the medical system." This opinion of a potential psychological disorder, according to Leitao, was shared by several medical professionals she sought out:
"(Leitao) said she long ago grew accustomed to being doubted by doctors whenever she sought help for her son, who is now 7 and still suffering from recurring lesions. 'They suggested that maybe I was neurotic,' Leitao said, 'They said they were not interested in seeing him because I had Munchausen Syndrome by Proxy.'"
Leitao says that her son developed more sores, and more fibers continued to poke out of them. She and her husband, Edward Leitao, an internist with South Allegheny Internal Medicine in Pennsylvania, felt their son suffered from "something unknown." She chose the name Morgellons disease (with a hard g) from a description of an illness in the monograph A Letter to a Friend by Sir Thomas Browne, in 1690, wherein Browne describes several medical conditions in his experience, including "that endemial distemper of children in Languedoc, called the morgellons, wherein they critically break out with harsh hairs on their backs." There is no suggestion that the symptoms described by Browne are linked to the putative modern cases.
Leitao founded the Morgellons Research Foundation (MRF) in 2002 (informally) and as an official non-profit in 2004. The MRF states on its website that its purpose is to raise awareness and funding for research into the proposed condition, described by the organization as a "poorly understood illness, which can be disfiguring and disabling". Leitao stated that she initially hoped to receive information from scientists or physicians who might understand the problem, but instead, thousands of others contacted her describing their sores and fibers, as well as neurological symptoms, fatigue, muscle and joint pain, and other symptoms. The MRF claims to have received self-identified reports of Morgellons from all 50 US states and 15 other countries, including Canada, the UK, Australia, and the Netherlands, and states that they have been contacted by over 12,000 families.
## Media coverage
In May 2006, a CBS news segment on Morgellons aired in Southern California, The same day the Los Angeles County Department of Health services issued a statement saying, "No credible medical or public health association has verified the existence or diagnosis of 'Morgellons Disease'," and "at this time there is no reason for individuals to panic over unsubstantiated reports of this disease". In June and July 2006 there were segments on CNN, ABC's Good Morning America, and NBC's The Today Show. In August 2006, a segment of the ABC show Medical Mysteries was devoted to the subject. The disease was featured on ABC's Nightline on January 16, 2008 and as the cover story of the January 20, 2008 issue of the Washington Post Magazine.
The first article to propose Morgellons as a new disease in a scientific journal was a review article co-authored by V. R. Savely, M. M. Leitao, and R. B. Stricker, members of the MRF. It was published in July, 2006 by the American Journal of Clinical Dermatology. An article in the San Francisco Chronicle reported, "There have been no clinical studies" (of Morgellons disease). A New Scientist article in September 2007 also covered the mystery noting that people are reporting similar symptoms in Europe and Australia.
## CDC investigation
A Centers for Disease Control and Prevention (CDC) task force first met in June 2006. In July 2006, Dan Rutz, MPH, a communications specialist for the CDC, said, "We're not ready to concede there's a new disease, but the volume of concern has stepped up because a lot of people are writing or calling their congressmen about it." By August 2006, the task force consisted of 12 people, including two pathologists, a toxicologist, an ethicist, a mental health expert and specialists in infectious, parasitic, environmental and chronic diseases. In May 2007, KGW-TV Newschannel 8's Laural Porter asked Rutz if he had any information about the nature of the fibers. At that time Rutz said, "None. We don't know. We haven't studied them in a lab yet. There is nothing to imply there is , but our mind is open to everything, including that remote possibility." Since then, the CDC has launched a funded study (see below) that will include further examination of fibers taken from Morgellons lesions by the CDC.
In June 2007, the CDC opened a website on "Unexplained Dermopathy (aka 'Morgellons')."
By November 2007, the CDC had announced an investigation process, stating that, "The primary goals of the investigation are to better describe the clinical and epidemiologic features of this condition and to generate hypotheses about possible risk factors." Kaiser Permanente in Northern California was chosen to assist with investigation, which will begin when the scientific protocols and review board structure have been prepared and approved. Investigators will report on the geographic distribution of the illness and estimate rates of illness in affected communities. The investigation will involve skin biopsies from affected patients and characterization of foreign material such as fibers or threads obtained from patients to determine their potential source. In January 2008 it was reported that CDC was enlisting the aid of the U.S. Armed Forces Institute of Pathology and the American Academy of Dermatology "to conduct 'immediate' and 'rigorous' research."
On January 2008 the CDC, in conjunction with Kaiser Permanente's Northern California Division of Research, launched a funded study of the unexplained skin condition known as Morgellons. A press conference was held on Jan 16, 2008 with Dr. Michele Pearson, principal investigator for the CDC, and Dr. Joe Selby, Director of Kaiser Permanente's Northern California Division of Research. During the press conference, Dr. Pearson stated: "What I can tell you is real is the suffering that these patients are experiencing. I cannot characterize this as a syndrome, as disease. I can tell you it's an unexplained illness." Clinical examinations for the study will be done in Oakland, California.
The CDC investigation follows a mailing campaign coordinated by the Morgellons Research Foundation in which "self-described sufferers clicked on the foundation Web site and sent thousands of form letters to members of Congress."
# Symptoms and diagnosis
Morgellons is currently not recognized as a unique disorder, so there is currently no list of symptoms or differential diagnosis for Morgellons that is generally accepted by the medical community. Patients usually self-diagnose based on media reports and information published by the Morgellons Research Foundation. Symptoms usually include:
- Disturbing sensations of insect-like crawling, stinging or biting on or under the skin (i.e. formication)
- Skin rashes and lesions that do not heal
- Fiber-like filaments, granules or crystals that appear on or under the skin or that can be extracted from lesions
- Joint, muscle and connective tissue pain, including fibromyalgia
- Debilitating fatigue
- Cognitive dysfunction, including difficulty with concentration, short-term memory, and attention
Dr. William T. Harvey, director of the MRF medical advisory board, states in a 2007 letter to the editor of the Journal of the American Academy of Dermatology that Morgellons patients exhibit laboratory findings including increased levels of inflammatory cytokines, increased insulin, and antibodies to three bacterial pathogens, but did not provide evidence for these claims. Many Morgellons patients have symptoms that are also consistent with Chronic Fatigue Syndrome, depression, obsessive-compulsive disorder, and attention deficit disorder. Dr. Rhonda Casey, chief of pediatrics at Oklahoma State University Hospital, while working with the OSU-CHS Center for the Investigation of Morgellons Disease, noted all her Morgellons patients looked ill with neurological symptoms, which included confusion, difficulty walking and controlling their feet (foot drop), and a sagging mouth when speaking; the OSU Center has issued a list of symptoms similar to that of the MRF.
The Morgellons Research Foundation has adopted a case definition of Morgellons symptoms that has been referenced in other articles.
The 2007 Atlas of Human Parasitology covers the proposed condition in its section on "Pseudoparasites and Artifacts":
Many dermatologists refute the suggestion that this is an actual disease but instead indicate that many of these patients have psychological problems or other common skin disorders. Given the large numbers of individuals who feel that they have this affliction, it will be most helpful over the coming years to have a valid scientific assessment of Morgellons diesease and its possible etiology (or etiologies). One of the chief criticisms by many patients has been that they feel the medical community and other scientists consulted have not been open to the idea that there is possibly an as yet undescribed infectious or physiologic causation for the disease. However it is certainly true that in fact many expert parasitologists, medical entomologists and other microbiologists have in fact carefully examined fibers and other materials expressed or extracted from such patients and found that biological organisms are not present. Although an apparent association of the condition with the presence of Lyme disease has been reported (Savely et al, 2006, Am J Clin Dermatol, 7:1–6), further research will be needed to help resolve the validity of Morgellons disease. Until then, whether Morgellons disease is another name for delusional parasitosis or a real disease entity with a biologic or physiologic basis will remain up in the air.
# Proposed causes and pathophysiology
## Delusional parasitosis and other neuropsychological disorders
Many dermatologists, psychiatrists, and other medical professionals view Morgellons as a new name for an old condition, delusional parasitosis, also known as "delusions of parasitosis" (DP or DOP) and Ekbom's Syndrome: Morgellons is "a pattern of dermatologic symptoms very similar, if not identical, to those of delusions of parasitosis", and "the vast majority" (elsewhere, 95%) of Morgellons patients are diagnosed with delusional parasitosis or another psychosomatic illness. In delusional parasitosis, patients hold a delusional belief that they are infested with parasites. They may experience formication, the sensation that insects are crawling under the skin. Individuals suffering from this condition may develop elaborate rituals of inspection and cleansing to locate and remove parasites and fibers, resulting in a form of self-mutilation; they injure themselves in attempts to be rid of the "parasites" by picking at the skin, causing lesions, and then pick at the lesions, preventing them from healing. Patients with delusional parasitosis often present at the doctor's office with what MDs term the "matchbox sign" -- a medical sign characterized by the patient making collections of fibers and other foreign objects supposedly retrieved from the skin -- and, because of "unshakeable delusional ideation", strongly reject diagnoses that do not involve parasites. A significant minority of DP cases occur in groups of two, three, or more individuals in close proximity, even families, known by the French terms folie à deux, folie à trois, and folie à famille. Delusional parasitosis, with symptoms that have "extraordinary similarities" to Morgellons, has been described in the medical literature for over 75 years. Dr. Noah Craft, a dermatologist at the Harbor-UCLA Medical Center, Torrance, CA, has seen a handful of Morgellons patients and biopsied their skin lesions, but found only normal skin and inflammation, as one would find in a bump that has been picked at.
Some cases of delusional parasitosis have organic causes other than those associated with neurological/psychological conditions of unknown etiology. For example, formication, the sensation that bugs are crawling under ones' skin, can be caused by allergies, diabetic neuropathy, menopause, skin cancer, or herpes zoster. Both dementia and mental retardation have been reported in association with DOP. Symptoms associated with delusional parasitosis, including urticaria (hives), paresthesia (unexplained tingling sensations in the skin), and pruritis (itching), are common side-effects of many prescription drugs or drug abuse. The sensations are real, but the attribution of the sensations to unknown parasites and the collection of fibers is part of the delusion.
The MRF's William Harvey has written that non-healing "Morgellons lesions" have been found on infants' bodies in locations that the infants cannot themselves reach to scratch. In his letter to the editor, he does not provide evidence to support this claim.
Some cases of Morgellons have been diagnosed as "cutaneous dysaesthesia."
## Role of the internet
In a 2006 report to the Journal of the American Academy of Dermatology, Waddell and Burke cite the influence of the internet on their self-diagnosed Morgellons patients: "physicians are becoming more and more challenged by the many persons who attempt self-diagnosis on-line. In many cases, these attempts are well-intentioned, yet wrong, and a patient's belief in some of these oftentimes unscientific sites online may preclude their trust in the evidence-based approaches and treatment recommendations of their physician." Dermatologist Caroline Koblenzer specifically faults the MRF website for misleading patients, "Clearly, as more and more of our patients discover this site (MRF), there will be an ever greater waste of valuable time and resources on fruitless research into fibers, fluffs, irrelevant bacteria, and innocuous worms and insects."
The LA Times, in an article on Morgellons, notes that "(t)he recent upsurge in symptoms can be traced directly to the Internet, following the naming of the disease by Mary Leitao, a Pennsylvania mother." Robert Bartholomew, a sociologist who has studied the Morgellons phenomenon, states that the "World Wide Web has become the incubator for mass delusion and it (Morgellons) seems to be a socially transmitted disease over the Internet." According to this hypothesis, patients with delusions of parasitosis and other psychological disorders become convinced they have "Morgellons" after reading internet accounts of others with similar symptoms. A 2005 Popular Mechanics article stated that Morgellons symptoms are well-known and characterized in the context of other disorders, and that "widespread reports of the strange fibers date back" only a few years to when the MRF first described them on the internet.
The Dallas Observer writes that Morgellons may be spread via the Internet and mass media, and "(i)f this is the case, then Morgellons is one in a long line of weird diseases that have swept through populations, only to disappear without a trace once public concern subsides." The article draws parallels to several mass media-spread mass delusions.
## Known skin conditions
It has been hypothesized that some cases of (self-diagnosed) Morgellons disease are actually other recognized skin disorders, including allergic dermatitis, contact dermatitis, and the parasite scabies.
## Theories about the fibers
Randy Wymore, a former research director of the MRF and presently Director of the Oklahoma State University Center for Health Sciences' Center for the Investigation of Morgellons Disease, claims that Morgellons patients have masses of dark fibers visible at 60x magnification under the unbroken skin, while unaffected individuals do not. Wymore sent samples of fibers supplied by Morgellons patients to the Police Crime Lab in Tulsa, Oklahoma for analysis. A forensic scientist at the Tulsa Police Crime Lab in Oklahoma searched the FBI's national database, but the Morgellons sample did not match any known fiber in the database. Lab director Mark Boese said the fibers were "consistent with something that the body may be producing," adding, "These fibers cannot be manmade and do not come from a plant. This could be a byproduct of a biological organism."
Dr. Rhonda Casey, chief of pediatrics at Oklahoma State University Hospital and part of the MRF research team at OSU, claimed that she has examined many patients' skin via a dermatoscope and performed biopsies on both lesions and apparently healthy skin, and that "she saw fibers embedded in both places. The white ones, she says, are hard to see. A dermatologist who either didn't look at all, or didn't use a dermatoscope, might not see them under the skin."
Dermatologists say any fibers are from clothing embedded in self-imposed sores, and the fibers patients bring in bags are textile in nature.
## Bacterial hypothesis
Three members of the Morgellons Research Foundation, including Raphael Stricker, Director and former President of the International Lyme and Associated Diseases Society (ILADS), and Ginger Savely, also an ILADS member, authored an article about Morgellons published by the American Journal of Clinical Dermatology in early 2006. The authors wrote that "Morgellons disease may be linked to an undefined infectious process," and reported that many patients with Morgellons disease have positive Western blots for Borrelia burgdorferi, the causative agent of Lyme disease, and treatment with anti-bacterials appropriate for Lyme disease leads to remission of Morgellons symptoms in most patients. Dr. Harvey, another member of ILADS, has also stated there is serological evidence of bacterial pathogens in Morgellons patients, but did not provide any such evidence.
Stricker, along with Citovsky, MRF board member from the State University of New York at Stony Brook and a researcher on plant pathogens, reported in January, 2007, that Morgellons skin fibers appear to contain cellulose, and PCR screening of samples from two Morgellons patients produced evidence of DNA from Agrobacterium, a plant-infecting organism known to induce cellulose fibers at infected sites within plant tissues. They stated that if confirmed, Agrobacterium could be the first instance of plant infecting bacteria involvement in human disease. However, Agrobacterium is already known to be responsible for opportunistic infections in humans with weakened immune systems, but has not been shown to be a primary pathogen in otherwise healthy individuals.
## Environmental toxins
Richard Fagerlund, an entomologist who has a column titled "Ask the Bugman" in the San Francisco Chronicle, stated that he takes Morgellons disease seriously, and he receives letters from people with Morgellons symptoms daily. Twenty years ago, he got three to four letters like this a year. He believes the condition is reaching epidemic proportions and speculates only a small percentage of cases are delusional parasitosis, while the rest may be caused by something else, such as pollutants, especially pesticides.
## Conspiracy theories
Some self-identified Morgellons sufferers and various conspiracy theorists provide their own origin hypotheses: "Perhaps it is caused by chemical spills or bio-terror or even alien abductions. On a radio program called Coast to Coast--popular among people who believe in UFOs and ghosts--a New Mexico doctor reports that a former CIA agent told him the disease was caused by the French. A botched government experiment, he says, contaminated the water. All Evian drinkers are at risk."
# Treatment
## Treatment for delusional parasitosis
Many dermatologists treat Morgellons as delusional parasitosis. After a thorough medical examination to rule out known organic causes for the symptoms, delusional parasitosis patients are typically prescribed one of several typical antipsychotic drugs. In the past, pimozide was the drug of choice; in addition to antipsychotic activity, it also has antipruritic activity, meaning it inhibits the sensation of itching. However, pimozide requires frequent electrocardiographic monitoring. Currently, atypical antipsychotics such as olanzapine or risperidone are used as first line treatment. Antipsychotics are effective at treating delusional parasitosis at doses as low as one-fifth to one-tenth the dose typically prescribed for schizophrenia. It is common for patients who believe they have Morgellons to reject a physician's diagnosis of delusional parasitosis. It has been suggested that the term Morgellons should be adopted by dermatologists to enhance their rapport with their patients, allowing them to overcome this resistance.
A Popular Mechanics article described a dermatologist who would not allow the use of his name, citing "concern for his safety." He said he has "diagnosed 50 or so Morgellons patients" with a disorder that can result in the sensation of insects, and "typically puts a cast over the lesions to prevent further irritation and after four weeks removes it." According to the doctor, the patients' lesions heal under the cast.
## Treatment for infectious disease
People who say they have Morgellons frequently reject the diagnosis of delusional parasitosis, "report that their symptoms are not taken seriously," and refuse psychotropic medicine. Hypothesizing that Morgellons is the result of an infectious process, some medical practitioners associated with the MRF recommend the use of antibiotics, antifungals, antiparasitic medications, herbal supplements, and light therapy. Randy Wymore, a former MRF director, has claimed on his website that some Morgellons patients who test positive for Lyme disease obtain symptom relief using aggressive, long-term antibiotic treatment similar to what is used by some doctors to treat "chronic" Lyme disease, another proposed but medically disputed condition. Virginia Savely, a nurse with the MRF and member of the International Lyme and Associated Diseases Society (ILADS), claims to have similar unpublished results. The antibiotic treatment is not curative, because when it is discontinued, the symptoms return. Dermatologists say that these positive effects of antibiotic use for some patients are likely the result of a placebo effect or anti-inflammatory actions of the drugs. They advise against prescribing antibiotics, which may reinforce the patients' delusions instead of addressing what these doctors consider the core problem: delusional parasitosis. In addition, long-term antibiotic use can have serious side effects.
## Self-treatment
Persons with Morgellons symptoms may turn to alternative remedies described on web sites and discussion groups. Some treatments are dangerous, however, and have included the use of bleach, veterinary medicines intended for de-worming horses, and industrial insecticides. | Morgellons
Morgellons (also called Morgellons disease or Morgellons syndrome) is a name given in 2002 by Mary Leitao[1] to a proposed infectious condition characterized by a range of cutaneous (skin) symptoms including crawling, biting, and stinging sensations; finding fibers on or under the skin; and persistent skin lesions (e.g., rashes or sores). Current scientific consensus holds that Morgellons is not a new disorder and is instead a new and misleading name for known illnesses. Most doctors,[2] including dermatologists[3] and psychiatrists,[4] regard Morgellons as a manifestation of known medical conditions, including delusional parasitosis,[5][6][7] although some health professionals say that an infectious cause could one day be found.[8] Illnesses such as delusional parasitosis can be serious and debilitating, but tested and effective treatments exist.
Despite the lack of evidence that Morgellons is a novel or distinct condition and the absence of any agreed set of diagnostic symptoms,[9] the Morgellons Research Foundation and self-diagnosed Morgellons patients have successfully lobbied members of Congress and the U.S. government's Centers for Disease Control and Prevention (CDC) to investigate the proposed condition.[2] The CDC states that while it is not known at present whether the condition represents a new disease entity, or whether persons who identify themselves as having Morgellons have a common cause for their symptoms, share common risk factors, or are contagious, it has begun an epidemiological investigation of the "Unexplained Dermopathy (aka 'Morgellons')."[10]
# History
## Mary Leitao and the MRF
In 2001,[1][11] according to Mary Leitao, her then two-year-old son developed sores under his lip and began to complain of "bugs."[12] Leitao, who graduated with a BS in Biology, and worked for five years at Boston hospitals as an electron microscopist and a immunohistochemist before becoming a stay-at-home mother, says she examined the sores and discovered red, blue, black, and white fibers.[1][13][14] She states that she took her son to see at least eight different doctors who were unable to find any disease, allergy, or anything unusual about her son's described symptoms. Dr. Fred Heldrich, a Johns Hopkins pediatrician with a reputation "for solving mystery cases," examined Leitao's son.[1] Heldrich found nothing abnormal about the boy's skin, wrote to the referring physician that "Leitao would benefit from a psychiatric evaluation and support," and registered his worry about Leitao's "use" of her son.[1] Psychology Today reports that Leitao last consulted an unnamed Johns Hopkins infectious disease specialist who after reviewing her son's records refused to see him, suggesting Leitao herself might suffer from "Munchausen's by proxy, a psychiatric syndrome in which a parent pretends a child is sick or makes him sick to get attention from the medical system."[14] This opinion of a potential psychological disorder, according to Leitao, was shared by several medical professionals she sought out:[15]
"(Leitao) said she long ago grew accustomed to being doubted by doctors whenever she sought help for her son, who is now 7 and still suffering from recurring lesions. 'They suggested that maybe I was neurotic,' Leitao said, 'They said they were not interested in seeing him because I had Munchausen Syndrome by Proxy.'"[16]
Leitao says that her son developed more sores, and more fibers continued to poke out of them.[14][12] She and her husband, Edward Leitao, an internist with South Allegheny Internal Medicine in Pennsylvania, felt their son suffered from "something unknown."[1] She chose the name Morgellons disease (with a hard g) from a description of an illness in the monograph A Letter to a Friend by Sir Thomas Browne, in 1690, wherein Browne describes several medical conditions in his experience, including "that endemial distemper of children in Languedoc, called the morgellons, wherein they critically break out with harsh hairs on their backs."[14][17] There is no suggestion that the symptoms described by Browne are linked to the putative modern cases.
Leitao founded the Morgellons Research Foundation (MRF) in 2002 (informally) and as an official non-profit in 2004.[14][18] The MRF states on its website that its purpose is to raise awareness and funding for research into the proposed condition, described by the organization as a "poorly understood illness, which can be disfiguring and disabling".[19] Leitao stated that she initially hoped to receive information from scientists or physicians who might understand the problem, but instead, thousands of others contacted her describing their sores and fibers, as well as neurological symptoms, fatigue, muscle and joint pain, and other symptoms.[14] The MRF claims to have received self-identified reports of Morgellons from all 50 US states and 15 other countries, including Canada, the UK, Australia, and the Netherlands, and states that they have been contacted by over 12,000 families.[19]
## Media coverage
In May 2006, a CBS news segment on Morgellons aired in Southern California,[20] The same day the Los Angeles County Department of Health services issued a statement saying, "No credible medical or public health association has verified the existence or diagnosis of 'Morgellons Disease'," and "at this time there is no reason for individuals to panic over unsubstantiated reports of this disease".[21] In June and July 2006 there were segments on CNN,[22] ABC's Good Morning America,[23] and NBC's The Today Show. In August 2006, a segment of the ABC show Medical Mysteries[12] was devoted to the subject. The disease was featured on ABC's Nightline on January 16, 2008[24] and as the cover story of the January 20, 2008 issue of the Washington Post Magazine.[25]
The first article to propose Morgellons as a new disease in a scientific journal was a review article co-authored by V. R. Savely, M. M. Leitao, and R. B. Stricker, members of the MRF. It was published in July, 2006 by the American Journal of Clinical Dermatology.[26] An article in the San Francisco Chronicle reported, "There have been no clinical studies" (of Morgellons disease).[27] A New Scientist article in September 2007 also covered the mystery noting that people are reporting similar symptoms in Europe and Australia.[28]
## CDC investigation
A Centers for Disease Control and Prevention (CDC) task force first met in June 2006.[29] In July 2006, Dan Rutz, MPH, a communications specialist for the CDC, said, "We're not ready to concede there's a new disease, but the volume of concern has stepped up because a lot of people are writing or calling their congressmen about it."[30] By August 2006, the task force consisted of 12 people, including two pathologists, a toxicologist, an ethicist, a mental health expert and specialists in infectious, parasitic, environmental and chronic diseases.[31] In May 2007, KGW-TV Newschannel 8's Laural Porter asked Rutz if he had any information about the nature of the fibers. At that time Rutz said, "None. We don't know. We haven't studied them in a lab yet. There is nothing to imply there is [an infectious process], but our mind is open to everything, including that remote possibility." Since then, the CDC has launched a funded study (see below) that will include further examination of fibers taken from Morgellons lesions by the CDC.
In June 2007, the CDC opened a website on "Unexplained Dermopathy (aka 'Morgellons')."
[10] By November 2007, the CDC had announced an investigation process, stating that, "The primary goals of the investigation are to better describe the clinical and epidemiologic features of this condition and to generate hypotheses about possible risk factors."[10] Kaiser Permanente in Northern California was chosen to assist with investigation, which will begin when the scientific protocols and review board structure have been prepared and approved. Investigators will report on the geographic distribution of the illness and estimate rates of illness in affected communities. The investigation will involve skin biopsies from affected patients and characterization of foreign material such as fibers or threads obtained from patients to determine their potential source.[10][32] In January 2008 it was reported that CDC was enlisting the aid of the U.S. Armed Forces Institute of Pathology and the American Academy of Dermatology "to conduct 'immediate' and 'rigorous' research."[33]
On January 2008 the CDC, in conjunction with Kaiser Permanente's Northern California Division of Research, launched a funded study of the unexplained skin condition known as Morgellons. A press conference was held on Jan 16, 2008 with Dr. Michele Pearson, principal investigator for the CDC, and Dr. Joe Selby, Director of Kaiser Permanente's Northern California Division of Research.[34] During the press conference, Dr. Pearson stated: "What I can tell you is real is the suffering that these patients are experiencing. I cannot characterize this as a syndrome, as disease. I can tell you it's an unexplained illness." Clinical examinations for the study will be done in Oakland, California.
The CDC investigation follows a mailing campaign coordinated by the Morgellons Research Foundation in which "self-described sufferers clicked on the foundation Web site and sent thousands of form letters to members of Congress."[2]
# Symptoms and diagnosis
Morgellons is currently not recognized as a unique disorder, so there is currently no list of symptoms or differential diagnosis for Morgellons that is generally accepted by the medical community. Patients usually self-diagnose based on media reports and information published by the Morgellons Research Foundation. Symptoms usually include:[26][35]
- Disturbing sensations of insect-like crawling, stinging or biting on or under the skin (i.e. formication)
- Skin rashes and lesions that do not heal
- Fiber-like filaments, granules or crystals that appear on or under the skin or that can be extracted from lesions
- Joint, muscle and connective tissue pain, including fibromyalgia
- Debilitating fatigue
- Cognitive dysfunction, including difficulty with concentration, short-term memory, and attention
Dr. William T. Harvey, director of the MRF medical advisory board, states in a 2007 letter to the editor of the Journal of the American Academy of Dermatology that Morgellons patients exhibit laboratory findings including increased levels of inflammatory cytokines, increased insulin, and antibodies to three bacterial pathogens, but did not provide evidence for these claims.[36] Many Morgellons patients have symptoms that are also consistent with Chronic Fatigue Syndrome, depression, obsessive-compulsive disorder, and attention deficit disorder.[37] Dr. Rhonda Casey, chief of pediatrics at Oklahoma State University Hospital, while working with the OSU-CHS Center for the Investigation of Morgellons Disease, noted all her Morgellons patients looked ill with neurological symptoms, which included confusion, difficulty walking and controlling their feet (foot drop), and a sagging mouth when speaking[14]; the OSU Center has issued a list of symptoms similar to that of the MRF.[38]
The Morgellons Research Foundation has adopted a case definition[39] of Morgellons symptoms that has been referenced in other articles.[37][8]
The 2007 Atlas of Human Parasitology covers the proposed condition in its section on "Pseudoparasites and Artifacts":
Many dermatologists refute the suggestion that this is an actual disease but instead indicate that many of these patients have psychological problems or other common skin disorders. Given the large numbers of individuals who feel that they have this affliction, it will be most helpful over the coming years to have a valid scientific assessment of Morgellons diesease and its possible etiology (or etiologies). One of the chief criticisms by many patients has been that they feel the medical community and other scientists consulted have not been open to the idea that there is possibly an as yet undescribed infectious or physiologic causation for the disease. However it is certainly true that in fact many expert parasitologists, medical entomologists and other microbiologists have in fact carefully examined fibers and other materials expressed or extracted from such patients and found that biological organisms are not present. Although an apparent association of the condition with the presence of Lyme disease has been reported (Savely et al, 2006, Am J Clin Dermatol, 7:1–6), further research will be needed to help resolve the validity of Morgellons disease. Until then, whether Morgellons disease is another name for delusional parasitosis or a real disease entity with a biologic or physiologic basis will remain up in the air.[40]
# Proposed causes and pathophysiology
## Delusional parasitosis and other neuropsychological disorders
Many dermatologists, psychiatrists, and other medical professionals view Morgellons as a new name for an old condition, delusional parasitosis,[41] also known as "delusions of parasitosis" (DP or DOP) and Ekbom's Syndrome: Morgellons is "a pattern of dermatologic symptoms very similar, if not identical, to those of delusions of parasitosis",[41] and "the vast majority"[26] (elsewhere, 95%[42]) of Morgellons patients are diagnosed with delusional parasitosis or another psychosomatic illness. In delusional parasitosis, patients hold a delusional belief that they are infested with parasites. They may experience formication, the sensation that insects are crawling under the skin. Individuals suffering from this condition may develop elaborate rituals of inspection and cleansing to locate and remove parasites and fibers, resulting in a form of self-mutilation; they injure themselves in attempts to be rid of the "parasites" by picking at the skin, causing lesions, and then pick at the lesions, preventing them from healing.[4] Patients with delusional parasitosis often present at the doctor's office with what MDs term the "matchbox sign"[26][43] -- a medical sign characterized by the patient making collections of fibers and other foreign objects supposedly retrieved from the skin[4] -- and, because of "unshakeable delusional ideation", strongly reject diagnoses that do not involve parasites.[44][26] A significant minority of DP cases occur in groups of two, three, or more individuals in close proximity, even families, known by the French terms folie à deux, folie à trois, and folie à famille.[26] Delusional parasitosis, with symptoms that have "extraordinary similarities" to Morgellons, has been described in the medical literature for over 75 years.[45] Dr. Noah Craft, a dermatologist at the Harbor-UCLA Medical Center, Torrance, CA, has seen a handful of Morgellons patients and biopsied their skin lesions, but found only normal skin and inflammation, as one would find in a bump that has been picked at.[14]
Some cases of delusional parasitosis have organic causes other than those associated with neurological/psychological conditions of unknown etiology. For example, formication, the sensation that bugs are crawling under ones' skin, can be caused by allergies, diabetic neuropathy, menopause, skin cancer, or herpes zoster. Both dementia and mental retardation have been reported in association with DOP.[46] Symptoms associated with delusional parasitosis, including urticaria (hives), paresthesia (unexplained tingling sensations in the skin), and pruritis (itching), are common side-effects of many prescription drugs or drug abuse.[47] The sensations are real, but the attribution of the sensations to unknown parasites and the collection of fibers is part of the delusion.
The MRF's William Harvey has written that non-healing "Morgellons lesions" have been found on infants' bodies in locations that the infants cannot themselves reach to scratch.[36] In his letter to the editor, he does not provide evidence to support this claim.
Some cases of Morgellons have been diagnosed as "cutaneous dysaesthesia."[48]
## Role of the internet
In a 2006 report to the Journal of the American Academy of Dermatology, Waddell and Burke cite the influence of the internet on their self-diagnosed Morgellons patients: "physicians are becoming more and more challenged by the many persons who attempt self-diagnosis on-line. In many cases, these attempts are well-intentioned, yet wrong, and a patient's belief in some of these oftentimes unscientific sites online may preclude their trust in the evidence-based approaches and treatment recommendations of their physician." Dermatologist Caroline Koblenzer specifically faults the MRF website for misleading patients, "Clearly, as more and more of our patients discover this site (MRF), there will be an ever greater waste of valuable time and resources on fruitless research into fibers, fluffs, irrelevant bacteria, and innocuous worms and insects."
The LA Times, in an article on Morgellons, notes that "(t)he recent upsurge in symptoms can be traced directly to the Internet, following the naming of the disease by Mary Leitao, a Pennsylvania mother."[49] Robert Bartholomew, a sociologist who has studied the Morgellons phenomenon, states that the "World Wide Web has become the incubator for mass delusion and it (Morgellons) seems to be a socially transmitted disease over the Internet." According to this hypothesis, patients with delusions of parasitosis and other psychological disorders become convinced they have "Morgellons" after reading internet accounts of others with similar symptoms.[50][51] A 2005 Popular Mechanics article stated that Morgellons symptoms are well-known and characterized in the context of other disorders, and that "widespread reports of the strange fibers date back" only a few years to when the MRF first described them on the internet.[48]
The Dallas Observer writes that Morgellons may be spread via the Internet and mass media, and "(i)f this is the case, then Morgellons is one in a long line of weird diseases that have swept through populations, only to disappear without a trace once public concern subsides."[18] The article draws parallels to several mass media-spread mass delusions.
## Known skin conditions
It has been hypothesized that some cases of (self-diagnosed) Morgellons disease are actually other recognized skin disorders, including allergic dermatitis, contact dermatitis, and the parasite scabies.[3][45]
## Theories about the fibers
Randy Wymore, a former research director of the MRF and presently Director of the Oklahoma State University Center for Health Sciences' Center for the Investigation of Morgellons Disease, claims that Morgellons patients have masses of dark fibers visible at 60x magnification under the unbroken skin, while unaffected individuals do not.[3] Wymore sent samples of fibers supplied by Morgellons patients to the Police Crime Lab in Tulsa, Oklahoma for analysis. A forensic scientist at the Tulsa Police Crime Lab in Oklahoma searched the FBI's national database, but the Morgellons sample did not match any known fiber in the database.[12] Lab director Mark Boese said the fibers were "consistent with something that the body may be producing," adding, "These fibers cannot be manmade and do not come from a plant. This could be a byproduct of a biological organism."[12]
Dr. Rhonda Casey, chief of pediatrics at Oklahoma State University Hospital and part of the MRF research team at OSU, claimed that she has examined many patients' skin via a dermatoscope and performed biopsies on both lesions and apparently healthy skin, and that "she saw fibers embedded in both places. The white ones, she says, are hard to see. A dermatologist who either didn't look at all, or didn't use a dermatoscope, might not see them under the skin."[14]
Dermatologists say any fibers are from clothing embedded in self-imposed sores, and the fibers patients bring in bags are textile in nature.[14]
[52]
## Bacterial hypothesis
Three members of the Morgellons Research Foundation, including Raphael Stricker, Director and former President of the International Lyme and Associated Diseases Society (ILADS), and Ginger Savely, also an ILADS member,[53] authored an article about Morgellons published by the American Journal of Clinical Dermatology in early 2006. The authors wrote that "Morgellons disease may be linked to an undefined infectious process," and reported that many patients with Morgellons disease have positive Western blots for Borrelia burgdorferi, the causative agent of Lyme disease, and treatment with anti-bacterials appropriate for Lyme disease leads to remission of Morgellons symptoms in most patients.[26] Dr. Harvey, another member of ILADS, has also stated there is serological evidence of bacterial pathogens in Morgellons patients, but did not provide any such evidence.[36]
Stricker, along with Citovsky, MRF board member from the State University of New York at Stony Brook and a researcher on plant pathogens, reported in January, 2007, that Morgellons skin fibers appear to contain cellulose, and PCR screening of samples from two Morgellons patients produced evidence of DNA from Agrobacterium, a plant-infecting organism known to induce cellulose fibers at infected sites within plant tissues. They stated that if confirmed, Agrobacterium could be the first instance of plant infecting bacteria involvement in human disease.[54] However, Agrobacterium is already known to be responsible for opportunistic infections in humans with weakened immune systems, but has not been shown to be a primary pathogen in otherwise healthy individuals.[55]
## Environmental toxins
Richard Fagerlund, an entomologist who has a column titled "Ask the Bugman" in the San Francisco Chronicle, stated that he takes Morgellons disease seriously, and he receives letters from people with Morgellons symptoms daily. Twenty years ago, he got three to four letters like this a year. He believes the condition is reaching epidemic proportions and speculates only a small percentage of cases are delusional parasitosis, while the rest may be caused by something else, such as pollutants, especially pesticides.[56]
## Conspiracy theories
Some self-identified Morgellons sufferers and various conspiracy theorists provide their own origin hypotheses: "Perhaps it is caused by chemical spills or bio-terror or even alien abductions. On a radio program called Coast to Coast--popular among people who believe in UFOs and ghosts--a New Mexico doctor reports that a former CIA agent told him the disease was caused by the French. A botched government experiment, he says, contaminated the water. All Evian drinkers are at risk."[18]
# Treatment
## Treatment for delusional parasitosis
Many dermatologists treat Morgellons as delusional parasitosis. After a thorough medical examination to rule out known organic causes for the symptoms, delusional parasitosis patients are typically prescribed one of several typical antipsychotic drugs.[57][58] In the past, pimozide was the drug of choice; in addition to antipsychotic activity, it also has antipruritic activity, meaning it inhibits the sensation of itching.[59] However, pimozide requires frequent electrocardiographic monitoring.[58] Currently, atypical antipsychotics such as olanzapine or risperidone are used as first line treatment.[58] Antipsychotics are effective at treating delusional parasitosis at doses as low as one-fifth to one-tenth the dose typically prescribed for schizophrenia.[58] It is common for patients who believe they have Morgellons to reject a physician's diagnosis of delusional parasitosis. It has been suggested that the term Morgellons should be adopted by dermatologists to enhance their rapport with their patients, allowing them to overcome this resistance.[60]
A Popular Mechanics article described a dermatologist who would not allow the use of his name, citing "concern for his safety." He said he has "diagnosed 50 or so Morgellons patients" with a disorder that can result in the sensation of insects, and "typically puts a cast over the lesions to prevent further irritation and after four weeks removes it." According to the doctor, the patients' lesions heal under the cast.[48]
## Treatment for infectious disease
People who say they have Morgellons frequently reject the diagnosis of delusional parasitosis,[48] "report that their symptoms are not taken seriously,"[26] and refuse psychotropic medicine. Hypothesizing that Morgellons is the result of an infectious process, some medical practitioners associated with the MRF recommend the use of antibiotics, antifungals, antiparasitic medications, herbal supplements, and light therapy.[49][27][61][48][1][28][62] Randy Wymore, a former MRF director, has claimed on his website that some Morgellons patients who test positive for Lyme disease obtain symptom relief using aggressive, long-term antibiotic treatment similar to what is used by some doctors to treat "chronic" Lyme disease, another proposed but medically disputed condition.[63] Virginia Savely, a nurse with the MRF and member of the International Lyme and Associated Diseases Society (ILADS), claims to have similar unpublished results.[26] The antibiotic treatment is not curative, because when it is discontinued, the symptoms return.[37] Dermatologists say that these positive effects of antibiotic use for some patients are likely the result of a placebo effect or anti-inflammatory actions of the drugs. They advise against prescribing antibiotics, which may reinforce the patients' delusions instead of addressing what these doctors consider the core problem: delusional parasitosis.[41] In addition, long-term antibiotic use can have serious side effects[citation needed].
## Self-treatment
Persons with Morgellons symptoms may turn to alternative remedies described on web sites and discussion groups. Some treatments are dangerous, however, and have included the use of bleach, veterinary medicines intended for de-worming horses, and industrial insecticides.[31] | https://www.wikidoc.org/index.php/Morgellons | |
76c1bf61fe339569c2f49dd48bbfacc48ebc0a93 | wikidoc | Morphinone | Morphinone
Morphinone is itself not a very potent opioid but it is the intermediate when morphine is being converted to hydromorphone (trade name Dilaudid®) which is 4-6 times as potent as morphine. Dilaudid is generally used only in palliative care or for pain in individuals who are already tolerant to opiates. In the United Kingdom, Dilaudid is marketed as Palladone® and Palladone SR®. The equivalent of Palladone SR® was removed from the US market when it was discovered that mixing alcohol with the sustained release capsules could cause the whole dose to be released at once, often with fatal consequences.
# Chemical structure
Morphinone can be also described as the ketone of morphine: morphin-6-on.
# Legal status
Morphinone itself is an active opiate although its potency is closer to codeine than morphine. It is, however, an important precursor and would fall under the purview of the Controlled Substances Act within the United States. Its legal status in other countries varies.
th:มอร์ฟิโนน | Morphinone
Template:OrganicBox small
Morphinone is itself not a very potent opioid but it is the intermediate when morphine is being converted to hydromorphone (trade name Dilaudid®) which is 4-6 times as potent as morphine. Dilaudid is generally used only in palliative care or for pain in individuals who are already tolerant to opiates. In the United Kingdom, Dilaudid is marketed as Palladone® and Palladone SR®. The equivalent of Palladone SR® was removed from the US market when it was discovered that mixing alcohol with the sustained release capsules could cause the whole dose to be released at once, often with fatal consequences.
# Chemical structure
Morphinone can be also described as the ketone of morphine: morphin-6-on.
# Legal status
Morphinone itself is an active opiate although its potency is closer to codeine than morphine. It is, however, an important precursor and would fall under the purview of the Controlled Substances Act within the United States. Its legal status in other countries varies.
Template:Pharm-stub
th:มอร์ฟิโนน | https://www.wikidoc.org/index.php/Morphinone | |
ef8ed2bbb606cd36c9bb9aaaee5e004cd8394351 | wikidoc | Morpholine | Morpholine
# Overview
Morpholine is an organic chemical compound having the chemical formula O(CH2CH2)2NH. This heterocycle, pictured at right, features both amine and ether functional groups. Because of the amine, morpholine is a base; its conjugate acid is called morpholinium. For example, when morpholine is neutralized by hydrochloric acid, one obtains the salt morpholinium chloride.
# Production
Morpholine may be produced by the dehydration of diethanolamine with sulfuric acid:
# Uses
## Industrial applications
Morpholine is a common additive, in ppm concentrations, for pH adjustment in both fossil fuel and nuclear power plant steam systems. Morpholine is used because its volatility is about the same as water, so once it is added to the water, its concentration becomes distributed rather evenly in both the water and steam phases. Its pH adjusting qualities then become distributed throughout the steam plant to provide corrosion protection. Morpholine is often used in conjunction with low concentrations of hydrazine or ammonia to provide a comprehensive all-volatile treatment chemistry for corrosion protection for the steam systems of such plants. Morpholine decomposes reasonably slowly in the absence of oxygen even at the high temperatures and pressures in these steam systems.
## Organic synthesis
Morpholine undergoes most chemical reactions typical for other secondary amines, though the presence of the ether oxygen withdraws electron density from the nitrogen, rendering it less nucleophilic (and less basic) than structurally similar secondary amines such as piperidine. For this reason, it forms a stable chloramine (CAS#23328-69-0).
It is commonly used to generate enamines.
Morpholine is widely used in organic synthesis. For example, it is a building block in the preparation of the antibiotic linezolid and the anticancer agent gefitinib (Iressa).
Morpholine is used as a chemical emulsifier in the process of waxing fruit. Fruits make waxes naturally to protect against insects and fungal contamination, but this can be lost by means of the food processing companies when they clean the fruit. As a result, an extremely small amount of new wax is applied and morpholine is then added and used as an emulsifier to evenly coat a fruit with the wax.
In research and in industry, the low cost and polarity of morpholine lead to its common use as a solvent for chemical reactions.
## As a component in fungicides
Morpholine derivatives used as agricultural fungicides in cereals are known as ergosterol biosynthesis inhibitors.
- Fenpropimorph
- Tridemorph | Morpholine
Template:Chembox new
# Overview
Morpholine is an organic chemical compound having the chemical formula O(CH2CH2)2NH. This heterocycle, pictured at right, features both amine and ether functional groups. Because of the amine, morpholine is a base; its conjugate acid is called morpholinium. For example, when morpholine is neutralized by hydrochloric acid, one obtains the salt morpholinium chloride.
# Production
Morpholine may be produced by the dehydration of diethanolamine with sulfuric acid:[1]
# Uses
## Industrial applications
Morpholine is a common additive, in ppm concentrations, for pH adjustment in both fossil fuel and nuclear power plant steam systems. Morpholine is used because its volatility is about the same as water, so once it is added to the water, its concentration becomes distributed rather evenly in both the water and steam phases. Its pH adjusting qualities then become distributed throughout the steam plant to provide corrosion protection. Morpholine is often used in conjunction with low concentrations of hydrazine or ammonia to provide a comprehensive all-volatile treatment chemistry for corrosion protection for the steam systems of such plants. Morpholine decomposes reasonably slowly in the absence of oxygen even at the high temperatures and pressures in these steam systems.
## Organic synthesis
Morpholine undergoes most chemical reactions typical for other secondary amines, though the presence of the ether oxygen withdraws electron density from the nitrogen, rendering it less nucleophilic (and less basic) than structurally similar secondary amines such as piperidine. For this reason, it forms a stable chloramine (CAS#23328-69-0).[2]
It is commonly used to generate enamines.[3]
Morpholine is widely used in organic synthesis. For example, it is a building block in the preparation of the antibiotic linezolid and the anticancer agent gefitinib (Iressa).
Morpholine is used as a chemical emulsifier in the process of waxing fruit. Fruits make waxes naturally to protect against insects and fungal contamination, but this can be lost by means of the food processing companies when they clean the fruit. As a result, an extremely small amount of new wax is applied and morpholine is then added and used as an emulsifier to evenly coat a fruit with the wax.
In research and in industry, the low cost and polarity of morpholine lead to its common use as a solvent for chemical reactions.
## As a component in fungicides
Morpholine derivatives used as agricultural fungicides in cereals are known as ergosterol biosynthesis inhibitors.
- Fenpropimorph
- Tridemorph | https://www.wikidoc.org/index.php/Morpholine | |
60a72b0f495b9590a57a86a1114ada833f745e8b | wikidoc | Motherwort | Motherwort
Motherwort (Leonurus cardiaca) is a flowering plant in the family Lamiaceae. Other common names include Throw-wort, Lion's Ear, and Lion's Tail. The latter two are also common names for Leonotis leonurus. Originally from Central Asia it is now found worldwide, spread largely due to its use as a herbal remedy.
L. cardiaca, a member of the mint family, has a square stem and opposite leaves. The basal leaves are wedge shaped with 3 points while the upper leaves are more latticed. Flowers appear in leaf axils on the upper part of the plant and it blooms between June - August. The flowers are small, pink to lilac in colour often with furry lower lips. The plant grows to about 60-100 cm in height. It can be found along roadsides and in vacant fields and other waste areas.
# Medicinal uses
Motherwort has a long history of medicinal use. The plant, and its use as a medicinal herb, originated in Central Europe and Asia, although it has long been in use in the North America as well. It is very useful for a variety of ills, and is very nourishing, much like stinging nettle or dandelion. The herb contains the alkaloid leonurine, which is a mild vasodilator and has a relaxing effect on smooth muscles. For this reason, it has long been used as a cardiac tonic, nervine, and an emmenagogue.
Among other biochemical constituents, it also contains bitter iridoid glycosides, diterpinoids, flavonoids (including rutin and quercetin), tannins, volatile oils, and vitamin A. Midwives use it for a variety of purposes, including uterine tonic and prevention of uterine infection. Susun Weed recommends it for combating stress and promoting relaxation during pregnancy and says that, given during labor, it prevents hemorrhage.
Michael Tierra, on the other hand, contraindicates it for internal use during pregnancy, as it does have the tendency to cause bleeding and may induce miscarriage. It was historically used in China to prevent pregnancy and to regulate menstruation. Motherwort is also used to ease stomach gas and cramping, menopausal problems, and insomnia, although Susun Weed warns it may be habit forming if used regularly to combat sleeplessness. According to Tierra, the traditional Chinese medicine energy and flavors are bitter, spicy, and slightly cold, and the systems affected are the pericardium and liver. The fresh or dried leaves are used, and the recommended dosage is the standard infusion of one ounce herb to one pint boiling water or 10-30 drops of tincture three times daily. | Motherwort
Template:Expand
Motherwort (Leonurus cardiaca) is a flowering plant in the family Lamiaceae. Other common names include Throw-wort, Lion's Ear, and Lion's Tail. The latter two are also common names for Leonotis leonurus. Originally from Central Asia it is now found worldwide, spread largely due to its use as a herbal remedy.
L. cardiaca, a member of the mint family, has a square stem and opposite leaves. The basal leaves are wedge shaped with 3 points while the upper leaves are more latticed. Flowers appear in leaf axils on the upper part of the plant and it blooms between June - August. The flowers are small, pink to lilac in colour often with furry lower lips. The plant grows to about 60-100 cm in height. It can be found along roadsides and in vacant fields and other waste areas.
# Medicinal uses
Motherwort has a long history of medicinal use. The plant, and its use as a medicinal herb, originated in Central Europe and Asia, although it has long been in use in the North America as well. It is very useful for a variety of ills, and is very nourishing, much like stinging nettle or dandelion. The herb contains the alkaloid leonurine, which is a mild vasodilator and has a relaxing effect on smooth muscles. For this reason, it has long been used as a cardiac tonic, nervine, and an emmenagogue.
Among other biochemical constituents, it also contains bitter iridoid glycosides, diterpinoids, flavonoids (including rutin and quercetin), tannins, volatile oils, and vitamin A. Midwives use it for a variety of purposes, including uterine tonic and prevention of uterine infection. Susun Weed recommends it for combating stress and promoting relaxation during pregnancy and says that, given during labor, it prevents hemorrhage.
Michael Tierra, on the other hand, contraindicates it for internal use during pregnancy, as it does have the tendency to cause bleeding and may induce miscarriage. It was historically used in China to prevent pregnancy and to regulate menstruation. Motherwort is also used to ease stomach gas and cramping, menopausal problems, and insomnia, although Susun Weed warns it may be habit forming if used regularly to combat sleeplessness. According to Tierra, the traditional Chinese medicine energy and flavors are bitter, spicy, and slightly cold, and the systems affected are the pericardium and liver. The fresh or dried leaves are used, and the recommended dosage is the standard infusion of one ounce herb to one pint boiling water or 10-30 drops of tincture three times daily. | https://www.wikidoc.org/index.php/Motherwort | |
49d25fb7f3435bd495d4152ba03ff37297e09154 | wikidoc | Motivation | Motivation
Motivation is a word used to refer to the reason or reasons for engaging in a particular behavior, especially human behavior as studied in psychology and neuropsychology. These reasons may include basic needs such as food or a desired object, goal, state of being, or ideal. The motivation for a behavior may also be attributed to less-apparent reasons such as altruism or morality. According to Geen, motivation refers to the initiation, direction, intensity and persistence of human behavior.
# Etymology
Motive is the root word of Motivation.
# Motivational concepts
## Reward and reinforcement
A reward, tangible or intangible, is presented after the occurrence of an action (i.e. behavior) with the intent to cause the behavior to occur again. This is done by associating positive meaning to the behavior. Studies show that if the person receives the reward immediately, the effect would be greater, and decreases as duration lengthens. Repetitive action-reward combination can cause the action to become habit.
Rewards can also be organized as extrinsic or intrinsic. Extrinsic rewards are external to the person; for example, praise or money. Intrinsic rewards are internal to the person; for example, satisfaction or accomplishment.
Some authors distinguish between two forms of intrinsic motivation: one based on enjoyment, the other on obligation. In this context, obligation refers to motivation based on what an individual thinks ought to be done. For instance, a feeling of responsibility for a mission may lead to helping others beyond what is easily observable, rewarded, or fun.
A reinforcer is different from reward, in that reinforcement is intended to create a measured increase in the rate of a desirable behavior following the addition of something to the environment.
## Intrinsic and extrinsic motivation
Intrinsic motivation is when people engage in an activity, without obvious external incentives, such as a hobby.
Intrinsic motivation has been studied by educational psychologists since the 1970s, and numerous studies have found it to be associated with high educational achievement and enjoyment by students. There is currently no universal theory to explain the origin or elements of intrinsic motivation, and most explanations combine elements of Bernard Weiner's attribution theory, Bandura's work on self-efficacy and other studies relating to locus of control and goal orientation. Thus it is thought that students are more likely to be intrinsically motivated if they:
- Attribute their educational results to internal factors that they can control (e.g. the amount of effort they put in),
- Believe they can be effective agents in reaching desired goals (i.e. the results are not determined by dumb luck),
- Are interested in mastering a topic, rather than just rote-learning to achieve good grades.
Note that the idea of reward for achievement is absent from this model of intrinsic motivation, since rewards are an extrinsic factor.
In knowledge-sharing communities and organizations, people often cite altruistic reasons for their participation, including contributing to a common good, a moral obligation to the group, mentorship or 'giving back'.
In work environments, money may provide a more powerful extrinsic factor than the intrinsic motivation provided by an enjoyable workplace.
The most obvious form of motivation is coercion, where the avoidance of pain or other negative consequences has an immediate effect. Extreme use of coercion is considered slavery. While coercion is considered morally reprehensible in many philosophies, it is widely practiced on prisoners, students in mandatory schooling, within the nuclear family unit (on children), and in the form of conscription. Critics of modern capitalism charge that without social safety networks, wage slavery is inevitable. However, many capitalists such as Ayn Rand have been very vocal against coercion. Successful coercion sometimes can take priority over other types of motivation. Self-coercion is rarely substantially negative (typically only negative in the sense that it avoids a positive, such as forgoing an expensive dinner or a period of relaxation), however it is interesting in that it illustrates how lower levels of motivation may be sometimes tweaked to satisfy higher ones.
## Self-control
The self-control of motivation is increasingly understood as a subset of emotional intelligence; a person may be highly intelligent according to a more conservative definition (as measured by many intelligence tests), yet unmotivated to dedicate this intelligence to certain tasks. Yale School of Management professor Victor Vroom's "expectancy theory" provides an account of when people will decide whether to exert self control to pursue a particular goal.
Drives and desires can be described as a deficiency or need that activates behaviour that is aimed at a goal or an incentive. These are thought to originate within the individual and may not require external stimuli to encourage the behaviour. Basic drives could be sparked by deficiencies such as hunger, which motivates a person to seek food; whereas more subtle drives might be the desire for praise and approval, which motivates a person to behave in a manner pleasing to others.
By contrast, the role of extrinsic rewards and stimuli can be seen in the example of training animals by giving them treats when they perform a trick correctly. The treat motivates the animals to perform the trick consistently, even later when the treat is removed from the process.
# Motivational Theories
## Drive Reduction Theories
There are a number of drive theories. The Drive Reduction Theory grows out of the concept that we have certain biological needs, such as hunger. As time passes the strength of the drive increases as it is not satisfied. Then as we satisfy that drive by fulfilling its desire, such as eating, the drive's strength is reduced. It is based on the theories of Freud and the idea of feedback control systems, such as a thermostat.
There are several problems, however, that leave the validity of the Drive Reduction Theory open for debate. The first problem is that it does not explain how Secondary Reinforcers reduce drive. For example, money does not satisfy any biological or psychological need but reduces drive on a regular basis through a pay check second-order conditioning. Secondly, if the drive reduction theory held true we would not be able to explain how a hungry human being can prepare a meal without eating the food before they finished cooking it.
However, when comparing this to a real life situation such as preparing food, one does get hungrier as the food is being made (drive increases), and after the food has been consumed the drive decreases. The only reason the food does not get eaten before is the human element of restraint and has nothing to do with drive theory. Also, the food will either be nicer after it is cooked, or it wont be edible at all before it is cooked.
### Cognitive dissonance theory
Suggested by Leon Festinger, this occurs when an individual experiences some degree of discomfort resulting from an incompatibility between two cognitions. For example, a consumer may seek to reassure himself regarding a purchase, feeling that another decision may have been, in retrospect, preferable.
Another example of cognitive dissonance is when a belief and a behavior are in conflict. A person may believe smoking is bad for one's health and yet continues to smoke.
## Affective-Arousal Theories
### Need Achievement Theory
David McClelland’s achievement motivation theory envisages that a person has need for three things but people differ in degree in which the various needs influence their behavior:
Need for achievement,
Need for power, and
Need for affiliation.
### Interests Theory
Holland Codes are used in the assessment of interests as in Vocational Preference Inventory (VPI; Holland, 1985). One way to look at interests is that if a person has a very strong interest in one of the 6 Holland areas, then obtaining outcomes in that area will be very strongly reinforcing relative to obtaining outcomes in areas of weak interest.
## Need Theories
### Need Hierarchy Theory
Abraham Maslow's hierarchy of human needs theory is the most widely discussed theory of motivation.
The theory can be summarized as thus:
- Human beings have wants and desires which influence their behaviour; only unsatisfied needs can influence behavior, satisfied needs cannot.
- Since needs are many, they are arranged in order of importance, from the basic to the complex.
- The person advances to the next level of needs only after the lower level need is at least minimally satisfied.
- The further the progress up the hierarchy, the more individuality, humanness and psychological health a person will show.
The needs, listed from basic (lowest, earliest) to most complex (highest, latest) are as follows:
- Physiological
- Safety and security
- Social
- Self esteem
- Self actualization
### Herzberg’s two factor theory
Frederick Herzberg's two factor theory, concludes that certain factors in the workplace result in job satisfaction, while others do not, but if absent lead to dissatisfaction.
He distinguished between:
- Motivators; (e.g. challenging work, recognition, responsibility) which give positive satisfaction, and
- Hygiene factors; (e.g. status, job security, salary and fringe benefits) which do not motivate if present, but if absent will result in demotivation.
The name Hygiene factors is used because, like hygiene, the presence will not make you healthier, but absence can cause health deterioration.
The theory is sometimes called the "Motivator-Hygiene Theory."
### Alderfer’s ERG theory
Created by Clayton Alderfer, Maslow's hierarchy of needs was expanded, leading to his ERG theory (existence, relatedness and growth). Physiological and safety, the lower order needs, are placed in the existence category, Love and self esteem needs in the relatedness category. The growth category contained the self actualization and self esteem needs.
### Self-determination theory
Self-determination theory, developed by Edward Deci and Richard Ryan, focuses on the importance of intrinsic motivation in driving human behavior. Like Maslow's hierarchical theory and others that built on it, SDT posits a natural tendency toward growth and development. Unlike these other theories, however, SDT does not include any sort of "autopilot" for achievement, but instead requires active encouragement from the environment. The primary factors that encourage motivation and development are autonomy, competence feedback, and relatedness.
## Cognitive theories
### Goal-setting theory
Goal-setting theory is based on the notion that individuals sometimes have a drive to reach a clearly defined end state. Often, this end state is a reward in itself. A goal's efficiency is affected by three features; proximity, difficulty and specificity. An ideal goal should present a situation where the time between the initiation of behavior and the end state is close in time. This explains why some children are more motivated to learn how to ride a bike than mastering algebra. A goal should be moderate, not too hard or too easy to complete. In both cases, most people are not optimally motivated, as many want a challenge (which assumes some kind of insecurity of success). At the same time people want to feel that there is a substantial probability that they will succeed. Specificity concerns the description of the goal in their class. The goal should be objectively defined and intelligible for the individual. A classic example of a poorly specified goal is to get the highest possible grade. Most children have no idea how much effort they need to reach that goal. For further reading, see Locke and Latham (2002).
## Unconscious motivation
Some psychologists believe that a significant portion of human behavior is energized and directed by unconscious motives. According to Maslow: "Psychoanalysis has often demonstrated that the relationship between a conscious desire and the ultimate unconscious aim that underlies it need not be at all direct ." In other words, stated motives do not always match those inferred by skilled observers. For example, it is possible that a person can be accident-prone because he has an unconscious desire to hurt himself and not because he is careless or ignorant of the safety rules. Similarly, some overweight people are not really hungry for food but for attention and love. Eating is merely a defensive reaction to lack of attention. Some workers damage more equipment than others because they harbor unconscious feelings of aggression toward authority figures.
Psychotherapists point out that some behavior is so automatic that the reasons for it are not available in the individual's conscious mind. Compulsive cigarette smoking is an example. Sometimes maintaining self-esteem is so important and the motive for an activity is so threatening that it is simply not recognized and, in fact, may be disguised or repressed. Rationalization, or "explaining away", is one such disguise, or defense mechanism, as it is called. Another is projecting or attributing one's own faults to others. "I feel I am to blame", becomes "It is her fault; she is selfish". Repression of powerful but socially unacceptable motives may result in outward behavior that is the opposite of the repressed tendencies. An example of this would be the employee who hates his boss but overworks himself on the job to show that he holds him in high regard.
Unconscious motives add to the hazards of interpreting human behavior and, to the extent that they are present, complicate the life of the administrator. On the other hand, knowledge that unconscious motives exist can lead to a more careful assessment of behavioral problems. Although few contemporary psychologists deny the existence of unconscious factors, many do believe that these are activated only in times of anxiety and stress, and that in the ordinary course of events, human behavior — from the subject's point of view — is rationally purposeful.
# Controlling motivation
The control of motivation is only understood to a limited extent. There are many different approaches of motivation training, but many of these are considered pseudoscientific by critics. To understand how to control motivation it is first necessary to understand why many people lack motivation.
## Early programming
Modern imaging has provided solid empirical support for the psychological theory that emotional programming is largely defined in childhood. Harold Chugani, Medical Director of the PET Clinic at the Children's Hospital of Michigan and professor of pediatrics, neurology and radiology at Wayne State University School of Medicine, has found that children's brains are much more capable of consuming new information (linked to emotions) than those of adults. Brain activity in cortical regions is about twice as high in children as in adults from the third to the ninth year of life. After that period, it declines constantly to the low levels of adulthood. Brain volume, on the other hand, is already at about 95% of adult levels in the ninth year of life.
## Organization
Besides the very direct approaches to motivation, beginning in early life, there are solutions which are more abstract but perhaps nevertheless more practical for self-motivation. Virtually every motivation guidebook includes at least one chapter about the proper organization of one's tasks and goals. It is usually suggested that it is critical to maintain a list of tasks, with a distinction between those which are completed and those which are not, thereby moving some of the required motivation for their completion from the tasks themselves into a "meta-task", namely the processing of the tasks in the task list, which can become a routine. The viewing of the list of completed tasks may also be considered motivating, as it can create a satisfying sense of accomplishment.
Most electronic to-do lists have this basic functionality, although the distinction between completed and non-completed tasks is not always clear (completed tasks are sometimes simply deleted, instead of kept in a separate list).
Other forms of information organization may also be motivational, such as the use of mind maps to organize one's ideas, and thereby "train" the neural network that is the human brain to focus on the given task. Simpler forms of idea notation such as simple bullet-point style lists may also be sufficient, or even more useful to less visually oriented persons.
## Drugs
Some authors, especially in the transhumanist movement, have suggested the use of "smart drugs", also known as nootropics, as "motivation-enhancers". The effects of many of these drugs on the brain are emphatically not well understood, and their legal status often makes open experimentation difficult.
Converging neurobiological evidence also supports the idea that addictive drugs such as cocaine, nicotine, alcohol, and heroin act on brain systems underlying motivation for natural rewards, such as the mesolimbic dopamine system. Normally, these brain systems serve to guide us toward fitness-enhancing rewards (food, water, sex, etc.), but they can be co-opted by repeated use of drugs of abuse, causing addicts to excessively pursue drug rewards. Therefore, drugs can hijack brain systems underlying other motivations, causing the almost singular pursuit of drugs characteristic of addiction.
# Applications
## Education
Motivation is of particular interest to Educational psychologists because of the crucial role it plays in student learning. However, the specific kind of motivation that is studied in the specialized setting of education differs qualitatively from the more general forms of motivation studied by psychologists in other fields.
Motivation in education can have several effects on how students learn and their behavior towards subject matter (Ormrod, 2003). It can:
- Direct behavior toward particular goals
- Lead to increased effort and energy
- Increase initiation of, and persistence in, activities
- Enhance cognitive processing
- Determine what consequences are reinforcing
- Lead to improved performance.
Because students are not always internally motivated, they sometimes need situated motivation, which is found in environmental conditions that the teacher creates.
There are two kinds of motivation:
- Intrinsic motivation occurs when people are internally motivated to do something because it either brings them pleasure, they think it is important, or they feel that what they are learning is morally significant.
- Extrinsic motivation comes into play when a student is compelled to do something or act a certain way because of factors external to him or her (like money or good grades).
Note also that there is already questioning and expansion about this dichotomy on motivation, e.g., Self-Determination Theory.
## Business
At lower levels of Maslow's hierarchy of needs, such as Physiological needs, money is a motivator, however it tends to have a motivating effect on staff that lasts only for a short period (in accordance with Herzberg's two-factor model of motivation). At higher levels of the hierarchy, praise, respect, recognition, empowerment and a sense of belonging are far more powerful motivators than money, as both Abraham Maslow's theory of motivation and Douglas McGregor's Theory X and theory Y (pertaining to the theory of leadership) demonstrate.
Maslow has money at the lowest level of the hierarchy and shows other needs are better motivators to staff. McGregor places money in his Theory X category and feels it is a poor motivator. Praise and recognition are placed in the Theory Y category and are considered stronger motivators than money.
- Motivated employees always look for better ways to do a job.
- Motivated employees are more quality oriented.
- Motivated workers are more productive.
The average workplace is about midway between the extremes of high threat and high opportunity. Motivation by threat is a dead-end strategy, and naturally staff are more attracted to the opportunity side of the motivation curve than the threat side.
Managers need to understand how company employees see them in order to manage the impression they make, not just their intentions. Don Sheelen notes that "If a business wants its people to make a lot of money for them, then it must set high standards and give employees something they can get excited about."
According to the system of scientific management developed by Frederick Winslow Taylor, a worker's motivation is solely determined by pay, and therefore management need not consider psychological or social aspects of work. In essence scientific management bases human motivation wholly on extrinsic rewards and discards the idea of intrinsic rewards.
In contrast, David McClelland believed that workers could not be motivated by the mere need for money-- in fact, extrinsic motivation (e.g., money) could extinguish intrinsic motivation such as achievement motivation, though money could be used as an indicator of success for various motives, e.g., keeping score. In keeping with this view, his consulting firm, McBer & Company, had as its first motto "To make everyone productive, happy, and free." For McClelland, satisfaction lay in aligning a person's life with their fundamental motivations.
Elton Mayo found out that the social contacts a worker has at the workplace are very important and that boredom and repetitiveness of tasks lead to reduced motivation. Mayo believed that workers could be motivated by acknowledging their social needs and making them feel important. As a result, employees were given freedom to make decisions on the job and greater attention was paid to informal work groups.
Mayo named the model the Hawthorne effect. His model has been judged as placing undue reliance on social contacts at work situations for motivating employees. | Motivation
Motivation is a word used to refer to the reason or reasons for engaging in a particular behavior, especially human behavior as studied in psychology and neuropsychology. These reasons may include basic needs such as food or a desired object, goal, state of being, or ideal. The motivation for a behavior may also be attributed to less-apparent reasons such as altruism or morality. According to Geen,[1] motivation refers to the initiation, direction, intensity and persistence of human behavior.
# Etymology
Motive is the root word of Motivation.
# Motivational concepts
Template:Refimprovesect
## Reward and reinforcement
A reward, tangible or intangible, is presented after the occurrence of an action (i.e. behavior) with the intent to cause the behavior to occur again. This is done by associating positive meaning to the behavior. Studies show that if the person receives the reward immediately, the effect would be greater, and decreases as duration lengthens. Repetitive action-reward combination can cause the action to become habit.
Rewards can also be organized as extrinsic or intrinsic. Extrinsic rewards are external to the person; for example, praise or money. Intrinsic rewards are internal to the person; for example, satisfaction or accomplishment.
Some authors distinguish between two forms of intrinsic motivation: one based on enjoyment, the other on obligation. In this context, obligation refers to motivation based on what an individual thinks ought to be done. For instance, a feeling of responsibility for a mission may lead to helping others beyond what is easily observable, rewarded, or fun.
A reinforcer is different from reward, in that reinforcement is intended to create a measured increase in the rate of a desirable behavior following the addition of something to the environment.
## Intrinsic and extrinsic motivation
Intrinsic motivation is when people engage in an activity, without obvious external incentives, such as a hobby.
Intrinsic motivation has been studied by educational psychologists since the 1970s, and numerous studies have found it to be associated with high educational achievement and enjoyment by students. There is currently no universal theory to explain the origin or elements of intrinsic motivation, and most explanations combine elements of Bernard Weiner's attribution theory, Bandura's work on self-efficacy and other studies relating to locus of control and goal orientation. Thus it is thought that students are more likely to be intrinsically motivated if they:
- Attribute their educational results to internal factors that they can control (e.g. the amount of effort they put in),
- Believe they can be effective agents in reaching desired goals (i.e. the results are not determined by dumb luck),
- Are interested in mastering a topic, rather than just rote-learning to achieve good grades.
Note that the idea of reward for achievement is absent from this model of intrinsic motivation, since rewards are an extrinsic factor.
In knowledge-sharing communities and organizations, people often cite altruistic reasons for their participation, including contributing to a common good, a moral obligation to the group, mentorship or 'giving back'.
In work environments, money may provide a more powerful extrinsic factor than the intrinsic motivation provided by an enjoyable workplace.
The most obvious form of motivation is coercion, where the avoidance of pain or other negative consequences has an immediate effect. Extreme use of coercion is considered slavery. While coercion is considered morally reprehensible in many philosophies, it is widely practiced on prisoners, students in mandatory schooling, within the nuclear family unit (on children), and in the form of conscription. Critics of modern capitalism charge that without social safety networks, wage slavery is inevitable. However, many capitalists such as Ayn Rand have been very vocal against coercion[citation needed]. Successful coercion sometimes can take priority over other types of motivation. Self-coercion is rarely substantially negative (typically only negative in the sense that it avoids a positive, such as forgoing an expensive dinner or a period of relaxation), however it is interesting in that it illustrates how lower levels of motivation may be sometimes tweaked to satisfy higher ones.
## Self-control
The self-control of motivation is increasingly understood as a subset of emotional intelligence; a person may be highly intelligent according to a more conservative definition (as measured by many intelligence tests), yet unmotivated to dedicate this intelligence to certain tasks. Yale School of Management professor Victor Vroom's "expectancy theory" provides an account of when people will decide whether to exert self control to pursue a particular goal.
Drives and desires can be described as a deficiency or need that activates behaviour that is aimed at a goal or an incentive. These are thought to originate within the individual and may not require external stimuli to encourage the behaviour. Basic drives could be sparked by deficiencies such as hunger, which motivates a person to seek food; whereas more subtle drives might be the desire for praise and approval, which motivates a person to behave in a manner pleasing to others.
By contrast, the role of extrinsic rewards and stimuli can be seen in the example of training animals by giving them treats when they perform a trick correctly. The treat motivates the animals to perform the trick consistently, even later when the treat is removed from the process.
# Motivational Theories
Template:Refimprovesect
## Drive Reduction Theories
There are a number of drive theories. The Drive Reduction Theory grows out of the concept that we have certain biological needs, such as hunger. As time passes the strength of the drive increases as it is not satisfied. Then as we satisfy that drive by fulfilling its desire, such as eating, the drive's strength is reduced. It is based on the theories of Freud and the idea of feedback control systems, such as a thermostat.
There are several problems, however, that leave the validity of the Drive Reduction Theory open for debate. The first problem is that it does not explain how Secondary Reinforcers reduce drive. For example, money does not satisfy any biological or psychological need but reduces drive on a regular basis through a pay check second-order conditioning. Secondly, if the drive reduction theory held true we would not be able to explain how a hungry human being can prepare a meal without eating the food before they finished cooking it.
However, when comparing this to a real life situation such as preparing food, one does get hungrier as the food is being made (drive increases), and after the food has been consumed the drive decreases. The only reason the food does not get eaten before is the human element of restraint and has nothing to do with drive theory. Also, the food will either be nicer after it is cooked, or it wont be edible at all before it is cooked.
### Cognitive dissonance theory
Suggested by Leon Festinger, this occurs when an individual experiences some degree of discomfort resulting from an incompatibility between two cognitions. For example, a consumer may seek to reassure himself regarding a purchase, feeling that another decision may have been, in retrospect, preferable.
Another example of cognitive dissonance is when a belief and a behavior are in conflict. A person may believe smoking is bad for one's health and yet continues to smoke.
## Affective-Arousal Theories
### Need Achievement Theory
David McClelland’s achievement motivation theory envisages that a person has need for three things but people differ in degree in which the various needs influence their behavior:
Need for achievement,
Need for power, and
Need for affiliation.
### Interests Theory
Holland Codes are used in the assessment of interests as in Vocational Preference Inventory (VPI; Holland, 1985). One way to look at interests is that if a person has a very strong interest in one of the 6 Holland areas, then obtaining outcomes in that area will be very strongly reinforcing relative to obtaining outcomes in areas of weak interest.
## Need Theories
### Need Hierarchy Theory
Abraham Maslow's hierarchy of human needs theory is the most widely discussed theory of motivation.
The theory can be summarized as thus:
- Human beings have wants and desires which influence their behaviour; only unsatisfied needs can influence behavior, satisfied needs cannot.
- Since needs are many, they are arranged in order of importance, from the basic to the complex.
- The person advances to the next level of needs only after the lower level need is at least minimally satisfied.
- The further the progress up the hierarchy, the more individuality, humanness and psychological health a person will show.
The needs, listed from basic (lowest, earliest) to most complex (highest, latest) are as follows:
- Physiological
- Safety and security
- Social
- Self esteem
- Self actualization
### Herzberg’s two factor theory
Frederick Herzberg's two factor theory, concludes that certain factors in the workplace result in job satisfaction, while others do not, but if absent lead to dissatisfaction.
He distinguished between:
- Motivators; (e.g. challenging work, recognition, responsibility) which give positive satisfaction, and
- Hygiene factors; (e.g. status, job security, salary and fringe benefits) which do not motivate if present, but if absent will result in demotivation.
The name Hygiene factors is used because, like hygiene, the presence will not make you healthier, but absence can cause health deterioration.
The theory is sometimes called the "Motivator-Hygiene Theory."
### Alderfer’s ERG theory
Created by Clayton Alderfer, Maslow's hierarchy of needs was expanded, leading to his ERG theory (existence, relatedness and growth). Physiological and safety, the lower order needs, are placed in the existence category, Love and self esteem needs in the relatedness category. The growth category contained the self actualization and self esteem needs.
### Self-determination theory
Self-determination theory, developed by Edward Deci and Richard Ryan, focuses on the importance of intrinsic motivation in driving human behavior. Like Maslow's hierarchical theory and others that built on it, SDT posits a natural tendency toward growth and development. Unlike these other theories, however, SDT does not include any sort of "autopilot" for achievement, but instead requires active encouragement from the environment. The primary factors that encourage motivation and development are autonomy, competence feedback, and relatedness.[2]
## Cognitive theories
### Goal-setting theory
Goal-setting theory is based on the notion that individuals sometimes have a drive to reach a clearly defined end state. Often, this end state is a reward in itself. A goal's efficiency is affected by three features; proximity, difficulty and specificity. An ideal goal should present a situation where the time between the initiation of behavior and the end state is close in time. This explains why some children are more motivated to learn how to ride a bike than mastering algebra. A goal should be moderate, not too hard or too easy to complete. In both cases, most people are not optimally motivated, as many want a challenge (which assumes some kind of insecurity of success). At the same time people want to feel that there is a substantial probability that they will succeed. Specificity concerns the description of the goal in their class. The goal should be objectively defined and intelligible for the individual. A classic example of a poorly specified goal is to get the highest possible grade. Most children have no idea how much effort they need to reach that goal. For further reading, see Locke and Latham (2002).
## Unconscious motivation
Some psychologists believe that a significant portion of human behavior is energized and directed by unconscious motives. According to Maslow: "Psychoanalysis has often demonstrated that the relationship between a conscious desire and the ultimate unconscious aim that underlies it need not be at all direct [3]." In other words, stated motives do not always match those inferred by skilled observers. For example, it is possible that a person can be accident-prone because he has an unconscious desire to hurt himself and not because he is careless or ignorant of the safety rules. Similarly, some overweight people are not really hungry for food but for attention and love. Eating is merely a defensive reaction to lack of attention. Some workers damage more equipment than others because they harbor unconscious feelings of aggression toward authority figures.
Psychotherapists point out that some behavior is so automatic that the reasons for it are not available in the individual's conscious mind. Compulsive cigarette smoking is an example. Sometimes maintaining self-esteem is so important and the motive for an activity is so threatening that it is simply not recognized and, in fact, may be disguised or repressed. Rationalization, or "explaining away", is one such disguise, or defense mechanism, as it is called. Another is projecting or attributing one's own faults to others. "I feel I am to blame", becomes "It is her fault; she is selfish". Repression of powerful but socially unacceptable motives may result in outward behavior that is the opposite of the repressed tendencies. An example of this would be the employee who hates his boss but overworks himself on the job to show that he holds him in high regard.
Unconscious motives add to the hazards of interpreting human behavior and, to the extent that they are present, complicate the life of the administrator. On the other hand, knowledge that unconscious motives exist can lead to a more careful assessment of behavioral problems. Although few contemporary psychologists deny the existence of unconscious factors, many do believe that these are activated only in times of anxiety and stress, and that in the ordinary course of events, human behavior — from the subject's point of view — is rationally purposeful.
# Controlling motivation
Template:Refimprovesect
The control of motivation is only understood to a limited extent. There are many different approaches of motivation training, but many of these are considered pseudoscientific by critics. To understand how to control motivation it is first necessary to understand why many people lack motivation.
## Early programming
Modern imaging has provided solid empirical support for the psychological theory that emotional programming is largely defined in childhood. Harold Chugani, Medical Director of the PET Clinic at the Children's Hospital of Michigan and professor of pediatrics, neurology and radiology at Wayne State University School of Medicine, has found that children's brains are much more capable of consuming new information (linked to emotions) than those of adults. Brain activity in cortical regions is about twice as high in children as in adults from the third to the ninth year of life. After that period, it declines constantly to the low levels of adulthood. Brain volume, on the other hand, is already at about 95% of adult levels in the ninth year of life.
## Organization
Besides the very direct approaches to motivation, beginning in early life, there are solutions which are more abstract but perhaps nevertheless more practical for self-motivation. Virtually every motivation guidebook includes at least one chapter about the proper organization of one's tasks and goals. It is usually suggested that it is critical to maintain a list of tasks, with a distinction between those which are completed and those which are not, thereby moving some of the required motivation for their completion from the tasks themselves into a "meta-task", namely the processing of the tasks in the task list, which can become a routine. The viewing of the list of completed tasks may also be considered motivating, as it can create a satisfying sense of accomplishment.
Most electronic to-do lists have this basic functionality, although the distinction between completed and non-completed tasks is not always clear (completed tasks are sometimes simply deleted, instead of kept in a separate list).
Other forms of information organization may also be motivational, such as the use of mind maps to organize one's ideas, and thereby "train" the neural network that is the human brain to focus on the given task. Simpler forms of idea notation such as simple bullet-point style lists may also be sufficient, or even more useful to less visually oriented persons.
## Drugs
Some authors, especially in the transhumanist movement, have suggested the use of "smart drugs", also known as nootropics, as "motivation-enhancers". The effects of many of these drugs on the brain are emphatically not well understood, and their legal status often makes open experimentation difficult.
Converging neurobiological evidence also supports the idea that addictive drugs such as cocaine, nicotine, alcohol, and heroin act on brain systems underlying motivation for natural rewards, such as the mesolimbic dopamine system. Normally, these brain systems serve to guide us toward fitness-enhancing rewards (food, water, sex, etc.), but they can be co-opted by repeated use of drugs of abuse, causing addicts to excessively pursue drug rewards. Therefore, drugs can hijack brain systems underlying other motivations, causing the almost singular pursuit of drugs characteristic of addiction.
# Applications
## Education
Template:Refimprovesect
Motivation is of particular interest to Educational psychologists because of the crucial role it plays in student learning. However, the specific kind of motivation that is studied in the specialized setting of education differs qualitatively from the more general forms of motivation studied by psychologists in other fields.
Motivation in education can have several effects on how students learn and their behavior towards subject matter (Ormrod, 2003). It can:
- Direct behavior toward particular goals
- Lead to increased effort and energy
- Increase initiation of, and persistence in, activities
- Enhance cognitive processing
- Determine what consequences are reinforcing
- Lead to improved performance.
Because students are not always internally motivated, they sometimes need situated motivation, which is found in environmental conditions that the teacher creates.
There are two kinds of motivation:
- Intrinsic motivation occurs when people are internally motivated to do something because it either brings them pleasure, they think it is important, or they feel that what they are learning is morally significant.
- Extrinsic motivation comes into play when a student is compelled to do something or act a certain way because of factors external to him or her (like money or good grades).
Note also that there is already questioning and expansion about this dichotomy on motivation, e.g., Self-Determination Theory.
## Business
Template:Refimprovesect
At lower levels of Maslow's hierarchy of needs, such as Physiological needs, money is a motivator, however it tends to have a motivating effect on staff that lasts only for a short period (in accordance with Herzberg's two-factor model of motivation). At higher levels of the hierarchy, praise, respect, recognition, empowerment and a sense of belonging are far more powerful motivators than money, as both Abraham Maslow's theory of motivation and Douglas McGregor's Theory X and theory Y (pertaining to the theory of leadership) demonstrate.
Maslow has money at the lowest level of the hierarchy and shows other needs are better motivators to staff. McGregor places money in his Theory X category and feels it is a poor motivator. Praise and recognition are placed in the Theory Y category and are considered stronger motivators than money.
- Motivated employees always look for better ways to do a job.
- Motivated employees are more quality oriented.
- Motivated workers are more productive.
The average workplace is about midway between the extremes of high threat and high opportunity. Motivation by threat is a dead-end strategy, and naturally staff are more attracted to the opportunity side of the motivation curve than the threat side.
Managers need to understand how company employees see them in order to manage the impression they make, not just their intentions. Don Sheelen notes that "If a business wants its people to make a lot of money for them, then it must set high standards and give employees something they can get excited about."
According to the system of scientific management developed by Frederick Winslow Taylor, a worker's motivation is solely determined by pay, and therefore management need not consider psychological or social aspects of work. In essence scientific management bases human motivation wholly on extrinsic rewards and discards the idea of intrinsic rewards.
In contrast, David McClelland believed that workers could not be motivated by the mere need for money-- in fact, extrinsic motivation (e.g., money) could extinguish intrinsic motivation such as achievement motivation, though money could be used as an indicator of success for various motives, e.g., keeping score. In keeping with this view, his consulting firm, McBer & Company, had as its first motto "To make everyone productive, happy, and free." For McClelland, satisfaction lay in aligning a person's life with their fundamental motivations.
Elton Mayo found out that the social contacts a worker has at the workplace are very important and that boredom and repetitiveness of tasks lead to reduced motivation. Mayo believed that workers could be motivated by acknowledging their social needs and making them feel important. As a result, employees were given freedom to make decisions on the job and greater attention was paid to informal work groups.
Mayo named the model the Hawthorne effect. His model has been judged as placing undue reliance on social contacts at work situations for motivating employees.[4] | https://www.wikidoc.org/index.php/Motivation | |
1f7f8b888bd3c00b05892be693218b79d0ee673a | wikidoc | Mouthparts | Mouthparts
The mouthparts of arthropods have evolved into a number of forms, each adapted to a different style or mode of feeding. Most mouthparts represent modified, paired appendages, which in ancestral forms would have appeared more like legs than mouthparts. In general, arthropods have mouthparts for cutting and chewing, piercing and sucking, siphoning, and filtering. This article outlines the basic elements of four arthropod groups: insects, myriapods, crustaceans and chelicerates. Insects are used as the model, with the novel mouthparts of the other groups introduced in turn. Insects are not, however, the ancestral form of the other arthropods discussed here.
# Insects
Insect mouthparts exhibit a range of forms. The earliest insects had chewing mouthparts. Specialisation includes mouthparts modified for siphoning, piercing, sucking and sponging. These modifications have evolved a number of times. For example, mosquitoes (which are flies) and aphids (which are bugs) both pierce and suck, however female mosquitoes feed on animal blood whereas aphids feed on plant fluids. This section provides an overview of the individual mouthparts of chewing insects.
## Labrum
The labrum is a flat extension of the head (below the clypeus), covering the mandibles. Unlike other mouthparts, the labrum is a single, fused plate (though it originally was — and embryonically is — two structures). It is the upper-most of the mouthparts and located on the midline. It serves to hold food in place during chewing by the mandibles and thus can simply be described as an upper lip.
## Mandible
Chewing insects have two mandibles, one on each side of the head. They are typically the largest mouthpart of chewing insects, being used to masticate (cut, tear, crush, chew) food items. They open outwards (to the sides of the head) and come together medially.
## Maxilla
Paired maxillae cut food and manipulate it during mastication. Maxillae can have hairs and “teeth” along their inner margins. At the outer margin, the galea is a cupped or scoop-like structure, which sits over the outer edge of the labium. They also have palps, which are used to sense the characteristics of potential foods.
## Labium
The labium is a single structure, although it is formed from two fused secondary maxillae. It can be described as the floor of the mouth. With the maxillae, it assists manipulation of food during mastication.
## Hypopharynx
The hypopharynx is a somewhat globular structure, arising from the base of the labium. It assists swallowing.
# Myriapods
Myriapods comprise four classes of arthropod, each with a similar morphology: Class Chilopoda (centipedes); Class Diplopoda (millipedes); Class Pauropoda; and Class Symphyla.
Myriapod mouthparts are similar to those of chewing insects, although there is some variation between the myriapod classes. A labrum is present but sometimes is not obvious and forms an upper lip, often in association with an epistome. The labium is formed by first or second maxillae. The preoral cavity so-formed contains paired mandibles and a hypopharynx.
## Forcipules
Centipedes, in addition to their mouthparts, possess a pair of "poison claws" or forcipules. These, like the maxillipeds of crustaceans, are modified legs and not true mouthparts. The forcipules arise from the first body segment, curving forward and to the midline. The tip is a pointed fang, which has an opening from a venom gland. The forcipules are used to capture and poison prey.
# Crustaceans
Crustaceans comprise a number of classes, with various feeding modes supported by a range of adaptions to the mouthparts. In general, however, crustaceans possess paired mandibles with opposing biting and grinding surfaces. The mandibles are followed by paired first and second maxillae. Both the mandibles and the maxillae have been variously modified in different crustacean groups for filter feeding with the use of setae.
## Maxillipeds
Up to the first three pairs of legs are modified to maxillipeds, which assist manipulation of food items, by passing food forward to the mandibles for chewing or to the maxillae for cutting into smaller pieces.
## Setae
Filter feeding crustaceans have setae on modified appendages that act as filters. Filter feeding may have developed in association with swimming, with early morphological adaptions occurring on the appendages of the body trunk. Subsequent adaptions appear to have favoured forward filtering appendages. Filtering appendages generate water currents that bring food items into reach for collection by setae. Other setae may be used to brush the filtering setae clean, and yet other setae may transport food items to the mouth.
## Cirri
Barnacles have thoracic appendages modified for feeding, the cirri, which filter suspended food particles from water currents and pass the food to the mouth.
# Chelicerates
Chelicerates comprise four classes of arthropod, with similar gross morphology but defining differences: Class Xiphosura (horseshoe crabs); Class Eurypterida (the extinct eurypterids); Class Arachnida (spiders, scorpions, ticks and mite)s; and Class Pycnogonida (sea spiders).
Chelicerates are in part defined by possessing chelicerate appendages, although crustaceans also possess chelate appendages. Chelicerates are more easily distinguished from other arthropods in lacking antennae.
## Chelicerae
Chelicerae are chelate appendages that are used to grasp food. For example, in horseshoe crabs they are like pincers, where-as in spiders they are hollow and contain (or are connected to) venom glands, and are used to inject venom to disable prey prior to feeding. In some spiders, the chelicerae have teeth, which are used to macerate prey items to assist digestion by secreted enzymes. Those spiders without toothed chelicerae inject digestive enzymes directly into their prey. Mites and ticks have a range of chelicerae. Carnivores have chelicerae that tear and crush prey, where-as herbivores can have chelicerae that are modified for piercing and sucking (as do parasitic species). In sea spiders, the chelicerae (also known as chelifores) are short and chelate, and are positioned either side of the base of the proboscis or sometimes vestigial or absent.
## Pedipalps
In addition to chelicerae, arachnids also possess a pair of pedipalps. In scorpions, the pedipalps are large and chelate (of the scissor type at Figure 4). They are used to capture and hold prey items for stinging before the chelicerae tear the prey into items for digestion. In spiders, the pedipalps of males are modified and function as secondary sex organs (transmission of sperm to the female). The pedipalps of mites and ticks vary depending on the species’ feeding mode. They are segmented and may be leg-like or chelate, like a second pair of chelicerae.
## Proboscis
Sea spiders possess a tubular proboscis forward from the body trunk, at the end of which is the opening to the mouth. In those species that lack chelifores and palps, the proboscis is well developed and more mobile and flexible. In such cases it can be equipped with sensory bristles and strong rasping ridges around the mouth. | Mouthparts
The mouthparts of arthropods have evolved into a number of forms, each adapted to a different style or mode of feeding. Most mouthparts represent modified, paired appendages, which in ancestral forms would have appeared more like legs than mouthparts. In general, arthropods have mouthparts for cutting and chewing, piercing and sucking, siphoning, and filtering. This article outlines the basic elements of four arthropod groups: insects, myriapods, crustaceans and chelicerates. Insects are used as the model, with the novel mouthparts of the other groups introduced in turn. Insects are not, however, the ancestral form of the other arthropods discussed here.
# Insects
Insect mouthparts exhibit a range of forms. The earliest insects had chewing mouthparts. Specialisation includes mouthparts modified for siphoning, piercing, sucking and sponging. These modifications have evolved a number of times. For example, mosquitoes (which are flies) and aphids (which are bugs) both pierce and suck, however female mosquitoes feed on animal blood whereas aphids feed on plant fluids. This section provides an overview of the individual mouthparts of chewing insects.
## Labrum
The labrum is a flat extension of the head (below the clypeus), covering the mandibles. Unlike other mouthparts, the labrum is a single, fused plate (though it originally was — and embryonically is — two structures). It is the upper-most of the mouthparts and located on the midline. It serves to hold food in place during chewing by the mandibles and thus can simply be described as an upper lip.
## Mandible
Chewing insects have two mandibles, one on each side of the head. They are typically the largest mouthpart of chewing insects, being used to masticate (cut, tear, crush, chew) food items. They open outwards (to the sides of the head) and come together medially.
## Maxilla
Paired maxillae cut food and manipulate it during mastication. Maxillae can have hairs and “teeth” along their inner margins. At the outer margin, the galea is a cupped or scoop-like structure, which sits over the outer edge of the labium. They also have palps, which are used to sense the characteristics of potential foods.
## Labium
The labium is a single structure, although it is formed from two fused secondary maxillae. It can be described as the floor of the mouth. With the maxillae, it assists manipulation of food during mastication.
## Hypopharynx
The hypopharynx is a somewhat globular structure, arising from the base of the labium. It assists swallowing.
# Myriapods
Myriapods comprise four classes of arthropod, each with a similar morphology: Class Chilopoda (centipedes); Class Diplopoda (millipedes); Class Pauropoda; and Class Symphyla.
Myriapod mouthparts are similar to those of chewing insects, although there is some variation between the myriapod classes. A labrum is present but sometimes is not obvious and forms an upper lip, often in association with an epistome. The labium is formed by first or second maxillae. The preoral cavity so-formed contains paired mandibles and a hypopharynx.
## Forcipules
Centipedes, in addition to their mouthparts, possess a pair of "poison claws" or forcipules. These, like the maxillipeds of crustaceans, are modified legs and not true mouthparts[1]. The forcipules arise from the first body segment, curving forward and to the midline. The tip is a pointed fang, which has an opening from a venom gland. The forcipules are used to capture and poison prey.
# Crustaceans
Crustaceans comprise a number of classes, with various feeding modes supported by a range of adaptions to the mouthparts. In general, however, crustaceans possess paired mandibles with opposing biting and grinding surfaces. The mandibles are followed by paired first and second maxillae. Both the mandibles and the maxillae have been variously modified in different crustacean groups for filter feeding with the use of setae.
## Maxillipeds
Up to the first three pairs of legs are modified to maxillipeds, which assist manipulation of food items, by passing food forward to the mandibles for chewing or to the maxillae for cutting into smaller pieces.
## Setae
Filter feeding crustaceans have setae on modified appendages that act as filters. Filter feeding may have developed in association with swimming, with early morphological adaptions occurring on the appendages of the body trunk. Subsequent adaptions appear to have favoured forward filtering appendages. Filtering appendages generate water currents that bring food items into reach for collection by setae. Other setae may be used to brush the filtering setae clean, and yet other setae may transport food items to the mouth.
## Cirri
Barnacles have thoracic appendages modified for feeding, the cirri, which filter suspended food particles from water currents and pass the food to the mouth.
# Chelicerates
Chelicerates comprise four classes of arthropod, with similar gross morphology but defining differences: Class Xiphosura (horseshoe crabs); Class Eurypterida (the extinct eurypterids); Class Arachnida (spiders, scorpions, ticks and mite)s; and Class Pycnogonida (sea spiders).
Chelicerates are in part defined by possessing chelicerate appendages, although crustaceans also possess chelate appendages. Chelicerates are more easily distinguished from other arthropods in lacking antennae.
## Chelicerae
Chelicerae are chelate appendages that are used to grasp food. For example, in horseshoe crabs they are like pincers, where-as in spiders they are hollow and contain (or are connected to) venom glands, and are used to inject venom to disable prey prior to feeding. In some spiders, the chelicerae have teeth, which are used to macerate prey items to assist digestion by secreted enzymes. Those spiders without toothed chelicerae inject digestive enzymes directly into their prey. Mites and ticks have a range of chelicerae. Carnivores have chelicerae that tear and crush prey, where-as herbivores can have chelicerae that are modified for piercing and sucking (as do parasitic species). In sea spiders, the chelicerae (also known as chelifores) are short and chelate, and are positioned either side of the base of the proboscis or sometimes vestigial or absent.
## Pedipalps
In addition to chelicerae, arachnids also possess a pair of pedipalps. In scorpions, the pedipalps are large and chelate (of the scissor type at Figure 4). They are used to capture and hold prey items for stinging before the chelicerae tear the prey into items for digestion. In spiders, the pedipalps of males are modified and function as secondary sex organs (transmission of sperm to the female). The pedipalps of mites and ticks vary depending on the species’ feeding mode. They are segmented and may be leg-like or chelate, like a second pair of chelicerae.
## Proboscis
Sea spiders possess a tubular proboscis forward from the body trunk, at the end of which is the opening to the mouth. In those species that lack chelifores and palps, the proboscis is well developed and more mobile and flexible. In such cases it can be equipped with sensory bristles and strong rasping ridges around the mouth. | https://www.wikidoc.org/index.php/Mouthparts | |
945db7fea7293a8604a2aa647f530d11aca0bba7 | wikidoc | Moxidectin | Moxidectin
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# Overview
Moxidectin is an anthelmintic that is FDA approved for the treatment of onchocerciasis due to Onchocerca volvulus in patients aged 12 years and older. Common adverse reactions include eosinophilia, pruritus, musculoskeletal pain, headache, lymphopenia, tachycardia, rash, abdominal pain, hypotension, pyrexia, leukocytosis, influenza-like illness, neutropenia, cough, lymph node pain, dizziness, diarrhea, hyponatremia and peripheral swelling.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Indication
- Moxidectin Tablets are indicated for the treatment of onchocerciasis due to Onchocerca volvulus in patients aged 12 years and older.
Limitations of Use
- Moxidectin Tablets do not kill adult O. volvulus. Follow-up evaluation is advised.
- The safety and efficacy of repeat administration of Moxidectin Tablets in patients with O. volvulus has not been studied.
Dosage
- The recommended dosage of Moxidectin Tablet is a single dose of 8 mg (four 2 mg tablets) taken orally with or without food.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding moxidectin Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding moxidectin Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Indication
- Moxidectin Tablets are indicated for the treatment of onchocerciasis due to Onchocerca volvulus in patients aged 12 years and older.
- The safety and effectiveness of Moxidectin Tablets in pediatric patients under 12 years of age has not been established.
Limitations of Use
- Moxidectin Tablets do not kill adult O. volvulus. Follow-up evaluation is advised.
- The safety and efficacy of repeat administration of Moxidectin Tablets in patients with O. volvulus has not been studied.
Dosage
- The recommended dosage of Moxidectin Tablet for pediatric patients 12 years and older is a single dose of 8 mg (four 2 mg tablets) taken orally with or without food.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding moxidectin Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding moxidectin Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
None.
# Warnings
- Treatment with Moxidectin Tablets may cause cutaneous, ophthalmological and/or systemic reactions of varying severity (Mazzotti reaction). These adverse reactions are due to allergic and inflammatory host responses to the death of microfilariae. There is a trend toward an increased incidence of these adverse reactions in patients with higher microfilarial burden.
- The clinical manifestations of Mazzotti reaction includes pruritus, headache, pyrexia, rash, urticaria, hypotension (including symptomatic orthostatic hypotension and dizziness), tachycardia, edema, lymphadenopathy, arthralgia, myalgia, chills, paresthesia and asthenia. Ophthalmological manifestations include conjunctivitis, eye pain, eye pruritus, eyelid swelling, blurred vision, photophobia, changes in visual acuity, hyperemia, ocular discomfort and watery eyes. These adverse reactions generally occur and resolve in the first week post-treatment. Laboratory changes include eosinophilia, eosinopenia, lymphocytopenia, neutropenia, and increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT) and lactate dehydrogenase (LDH). Proteinuria has also been reported.
- Treatment of severe Mazzotti reactions has not been evaluated in controlled clinical trials. Symptomatic treatments such as oral hydration, recumbency, intravenous normal saline, and/or parenteral corticosteroids have been used to treat orthostatic hypotension. Antihistamines and/or analgesics have been used for most mild to moderate cases.
- An increased number of patients who received Moxidectin Tablets developed symptomatic orthostatic hypotension with inability to stand without support after lying down for 5 minutes (in an orthostatic hypotension provocation test); 47/978 (5%) compared with 8/494 (2%) who received ivermectin. The decreases in blood pressure were transient, managed by resumption of recumbency and most commonly occurred on Days 1 and 2 post-treatment. Advise patients that if they feel dizzy or light-headed after taking Moxidectin Tablets, they should lie down until the symptoms resolve.
- Patients with onchocerciasis who are also infected with Loa loa may develop a serious or even fatal
encephalopathy following treatment with Moxidectin Tablets.
- Moxidectin Tablets have not been studied in patients co-infected with Loa loa. Therefore, it is recommended that individuals who warrant treatment with Moxidectin Tablets and have had exposure to Loa loa-endemic areas undergo diagnostic screening for loiasis prior to treatment.
- Patients with hyper-reactive onchodermatitis (sowda) may be more likely than others to experience severe edema and worsening of onchodermatitis following the use of Moxidectin Tablets. Symptomatic treatment has been used to manage patients who have experienced edema and worsening of onchodermatitis.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under varying controlled conditions, adverse reaction rates observed in one clinical trial cannot be directly compared to rates observed in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- The safety of Moxidectin Tablets was evaluated in two randomized, double-blind, active-controlled studies (Trial 1 and Trial 2) . In Trial 1, 978 patients received Moxidectin Tablets as a single oral dose of 8 mg and 494 patients received ivermectin as a single oral dose of approximately 150 mcg/kg. In Trial 2, 127 patients received Moxidectin Tablets as a single oral dose ranging from 2 mg (this is not an approved dose) to 8 mg (38 received the recommended 8 mg dose) and 45 patients received ivermectin as a single oral dose of approximately 150 mcg/kg.
Most Common Adverse Reactions
- No patients withdrew from either trial due to adverse reactions. Adverse Reactions reported in Trial 1 in > 10% of patients are summarized in Table 1. Most were related to physical, vital signs and laboratory changes associated with Mazzotti reaction.
- The most common adverse reactions in patients (n = 38) treated with 8 mg moxidectin in Trial 2 were similar to the adverse reactions noted in Trial 1 described in Table 1 above.
Other Adverse Reactions Reported in Clinical Trials
- The following adverse reactions occurred in less than 10% of subjects receiving Moxidectin Tablets in Trial 1:
- Ocular Adverse Reactions: In Trial 1, the most common ocular adverse reactions (occurring in ≥ 0.5% of patients) are shown in Table 2.
Hepatobiliary Adverse Reactions
- More patients in the moxidectin arm experienced elevation in bilirubin above the upper limit of normal and elevation in transaminases > 5x upper limit of normal. Twenty-seven (2.8%) patients in the moxidectin arm and 3 (0.6%) patients in the ivermectin arm had hyperbilirubinemia. Most of the patients had single measurements of hyperbilirubinemia without concurrent elevation in transaminases.
- Nine (1%) patients in the moxidectin arm and 2 (0.4%) patients in the ivermectin arm had elevation in ALT of more than 5x upper limit of normal; ten (1%) patients in the moxidectin arm and 3 (0.6%) patients in the ivermectin arm had elevation in AST to more than 5x upper limit of normal.
Laboratory Abnormalities
- Laboratory abnormalities occurring in at least 1% of patients in the Trial 1 are described in Table 3.
## Postmarketing Experience
There is limited information regarding Moxidectin Postmarketing Experience in the drug label.
# Drug Interactions
- In healthy subjects, concomitant administration of a single 8 mg oral dose of Moxidectin Tablets did not have an effect on the pharmacokinetics of midazolam. Moxidectin can be co-administered with CYP3A4 substrates.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- Limited available data on the use of Moxidectin Tablets in pregnant women are insufficient to establish whether there is a moxidectin-associated risk for major birth defects and miscarriage. Moxidectin administered orally to pregnant rats during the period of organogenesis (Gestation Days (GD) 6 to 15), was not associated with significant embryo-fetal developmental effects at doses of approximately 15 times the recommended human dose based on body surface area. When moxidectin was dosed orally to pregnant rabbits during the period of organogenesis (GD 7 - 19), no embryo-fetal developmental effects were observed at oral doses of moxidectin up to 24 times the recommended human dose based on body surface area.
- Daily parental oral administration of dietary moxidectin to rats prior to mating, and through mating, gestation, and lactation was associated with decreased survival and body weights for first-generation offspring without maternal toxicity at moxidectin doses less than 2-times the recommended human dose based on body surface area comparison. Daily dietary moxidectin did not produce maternal toxicity or adverse effects for first- and second-generation offspring at doses approximately equivalent to the recommended human dose based on body surface area comparison. Offspring were assessed for survival, body weights, and fertility. Developmental milestones were not assessed in this study.
- The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Animal Data
- In a rat embryo-fetal development study, daily oral administration of moxidectin at 12 mg/kg/day (approximately 15 times the recommended human dose of 8 mg based on body surface area comparison) during Gestation Days (GDs) 6 to 15 significantly increased the fetal incidence, but not the litter incidence of cleft palate and the fetal and litter incidence of a skeletal variation, wavy ribs, at a maternally toxic dose. Mean maternal food consumption, body weights, and body weight gain were significantly decreased at moxidectin doses of 10 and 12 mg/kg/day compared to control values. The no observed adverse effect level (NOAEL) value for maternal and fetal toxicity was considered to be 5 and 10 mg/kg/day respectively (approximately 6 and 12 times, respectively, the recommended human dose based on body surface area comparison). In the rabbit, daily oral administration of moxidectin at ≥ 5 mg/kg/day from GD7 to GD19 was not associated with fetal weight loss or malformations but resulted in significantly decreased maternal food consumption and body weight gains. The NOAEL value for maternal and fetal toxicity in the rabbit was 1 mg/kg/day and 10 mg/kg/day respectively (approximately 2 times and 24 times, respectively, the recommended human dose based on body surface area comparison). In a pre-postnatal study in rats, parental oral administration of dietary moxidectin prior to mating, through mating, gestation, and lactation did not produce adverse effects in first-generation or second- generation offspring at a maternal NOAEL dose of 0.824 mg/kg/day (approximately equivalent to the recommended human dose based on body surface area comparison). However, at moxidectin doses
≥ 1.1 mg/kg/day (approximately equivalent to 1.3 times the recommended human dose based on body surface area comparison), the survival and body weights of first-generation offspring were significantly decreased during the lactation period, and the number of live fetuses at birth was significantly decreased with a maternal moxidectin dose of 11 mg/kg/day (approximately equivalent to 13 times the recommended human dose based on body surface area comparison). In this study, offspring were assessed for survival, body weights, and fertility, and developmental milestones were not assessed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Moxidectin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Moxidectin during labor and delivery.
### Nursing Mothers
Risk Summary
- Moxidectin was detected in the milk of lactating women following a single 8 mg dose of Moxidectin Tablets . There are no data on the effects of Moxidectin Tablets on the breast-fed infant or milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Moxidectin Tablets and any potential adverse effects on the breastfed child from Moxidectin Tablets or from the underlying maternal condition.
Data
- A pharmacokinetic study in twelve healthy adult lactating women who were 21 to 100 weeks post partum evaluated the concentrations of moxidectin in plasma and breast milk collected over a period of 28 days following a single 8 mg dose of Moxidectin Tablets. The mean (± SD) exposure ratio of moxidectin present in human breast milk to that of human plasma was approximately 1.77 (± 0.66) over a collection period of
28 days. The estimated mean (± SD) total infant dose, assuming the infants would consume all the breast milk collected during the study, was 0.056 mg (± 0.024 mg), which would be approximately 0.70% (± 0.30%) of the maternal dose. The effects of moxidectin or its metabolites on the breast-fed child or milk production were not evaluated.
### Pediatric Use
- The safety and effectiveness of Moxidectin Tablets have been established in pediatric patients 12 years of age and older. In Trial 1, (n = 53 patients aged 12 to 17 years), the safety and effectiveness was similar to that observed in adults. The safety and effectiveness of Moxidectin Tablets in pediatric patients under 12 years of age has not been established.
### Geriatic Use
- Of the total number of patients included in Trial 1 that were treated with Moxidectin Tablets, 83 were aged 65 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Moxidectin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Moxidectin with respect to specific racial populations.
### Renal Impairment
- No dose adjustment of Moxidectin Tablets is necessary for patients with mild (creatinine clearance (CrCL) 60 to 89 mL/min) to moderate (CrCL 30 to 59 mL/min) renal impairment. The safety of Moxidectin Tablets in patients with severe renal impairment (CrCL 15 to 29 mL/min) or end stage renal disease, is unknown.
### Hepatic Impairment
There is no FDA guidance on the use of Moxidectin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Moxidectin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Moxidectin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- The recommended dosage of Moxidectin Tablet is a single dose of 8 mg (four 2 mg tablets) taken orally with or without food.
### Monitoring
There is limited information regarding Moxidectin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Moxidectin and IV administrations.
# Overdosage
- No specific antidote is available for overdose with Moxidectin Tablets. If overdose occurs, the patient should be monitored for evidence of toxicity. Treatment of overdose with Moxidectin Tablets consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Supportive therapy, if indicated, should include parenteral fluids and electrolytes, respiratory support (oxygen and mechanical ventilation if necessary) and pressor agents if clinically significant hypotension is present.
# Pharmacology
## Mechanism of Action
- Moxidectin, a macrocyclic lactone, is an anthelmintic drug.
## Structure
- The empirical formula is C37H53NO8 and the molecular weight is 639.82 Dalton. The structural formula is:
## Pharmacodynamics
Cardiac Electrophysiology
- At a dose 4.5 times the approved recommended dose, moxidectin does not prolong the QT interval to any clinically relevant extent.
## Pharmacokinetics
- The pharmacokinetic parameters of moxidectin following a single 8 mg oral dose of Moxidectin Tablets to healthy subjects and patients with onchocerciasis under fasted conditions are shown in Table 4. Mean moxidectin Cmax and AUC increased approximately proportionally to dose over a dose range of 2 to 36 mg (0.25 to 4.5 times the approved recommended dose) in healthy subjects under fasted conditions.
Absorption
Effect of Food
- Moxidectin mean Cmax and AUC increased on average by 34% and 39%, respectively, when administered with a standard high fat meal (900 calories, with a nutritional distribution of approximately 55% fat, 31% carbohydrates and 14% protein), compared to fasted conditions.
Distribution
- The apparent mean ± SD volume of distribution of moxidectin is 2421 ± 1658 L in patients with onchocerciasis. The plasma protein binding in humans is unknown.
Elimination
- The mean terminal half-life of moxidectin in patients with onchocerciasis is 23.3 days (559 hours) following a single 8 mg dose of Moxidectin Tablets.
- The apparent mean ± SD total clearance of moxidectin is approximately 3.50 ± 1.23 L/hour in patients with onchocerciasis.
Metabolism
- The hepatic metabolism of moxidectin is minimal.
Excretion
- Following administration of a single 8 mg oral dose of Moxidectin Tablets to healthy subjects, 2% of the dose is eliminated unchanged in the feces within the first 72 hours. Renal elimination of intact drug is negligible.
Specific Populations
- In clinical studies, no clinically significant differences in the pharmacokinetics of moxidectin were observed based on age (18 to 60 years), sex, weight (42.7 to 107.2 kg), or renal impairment (creatinine clearance (CrCL) 47 to 89 mL/min, estimated by Cockcroft-Gault). The pharmacokinetics of moxidectin in patients with CrCL less than 47 mL/min is unknown. The pharmacokinetics of moxidectin in patients with hepatic impairment is unknown.
Patients with Renal Impairment
- Based on a population pharmacokinetic analysis and the fact that renal elimination of intact drug is negligible, mild (creatinine clearance (CrCL), estimated by Cockcroft-Gault of 60 to 89 mL/min) and moderate (CrCL 30 to 59 mL/min) renal impairment is not likely to have an impact on the exposure of moxidectin. The effect of severe renal impairment (CrCL 15 to 29 mL/min) or of end-stage renal disease on the pharmacokinetics of moxidectin is unknown.
Drug Interaction Studies
Clinical Study with Midazolam (CYP3A4 substrate)
- Co-administration of a single 8 mg dose of Moxidectin Tablets with a single oral 7.5 mg dose of midazolam (a sensitive CYP3A substrate) to healthy subjects (n = 37) did not affect the pharmacokinetics of midazolam or its major metabolite, 1-hydroxy midazolam.
In Vitro Studies
- CYP Enzymes: Moxidectin is not a substrate or inhibitor of CYP enzymes.
- Uridine 5'-diphospho-glucuronosyltransferases (UGTs): Moxidectin is not a UGT substrate.
- Transporter Systems: Moxidectin is not a substrate of P-glycoprotein (P-gp) nor breast cancer resistance protein 1 (BCRP1).
## Microbiology
Mechanism of Action
- The mechanism by which moxidectin exhibits its effect against O. volvulus is not known. Studies with other nematodes suggest that moxidectin binds to glutamate-gated chloride channels (GluCl), gamma-aminobutyric acid (GABA) receptors and/or ATP-binding cassette (ABC) transporters. This leads to increased permeability, influx of chloride ions, hyperpolarization and muscle paralysis. Additionally, there is a reduction in motility of all stages of the parasite, excretion of immunomodulatory proteins, and the fertility of both male and female adult worms.
Antimicrobial Activity
- Moxidectin is active against the microfilariae of O. volvulus.
- Studies suggest that moxidectin is not effective in killing the adult worms, however, it inhibits intra-uterine embryogenesis and release of microfilariae from the adult worms.
Resistance
- Studies in vitro and infected animals suggest a potential for development of resistance to moxidectin and cross-resistance with other macrocyclic lactones, such as ivermectin. However, the clinical relevance of these findings is not known.
- The mechanism of resistance may be multifactorial that include alteration in the target GluCl, GABA receptors and/or ABC transporters.
## Nonclinical Toxicology
- Moxidectin was shown to be negative for genotoxicity in a battery of in vitro assays including a bacterial mutagenicity assay, mouse lymphoma cell mutagenicity assay, unscheduled DNA synthesis assay, and a chromosome aberration assay, as well as in vivo in a micronucleus assay in mice and a chromosome aberration assay in rats.
- Two-year carcinogenicity studies in mice and rats were conducted with moxidectin. Mice were administered a mean dietary dose of 8.7 mg/kg/day moxidectin which is approximately equivalent to 5 times the recommended human dose based on body surface area comparison. Rats were administered a mean dietary dose of 6.1 mg/kg/day moxidectin which is approximately equivalent to 7 times the recommended human dose based on body surface area comparison. There was no evidence of tumorigenicity in either study.
- In fertility evaluations, male and female mating and fertility indices were not inhibited by oral-dietary moxidectin doses of approximately 0.86 mg/kg/day which is approximately equivalent to the recommended human dose based on body surface area comparison.
- Moxidectin was associated with transient CNS-related clinical signs. In rats, a single dose of 20 mg/kg (equivalent to approximately 24 times the recommended human dose based on body surface area comparison) moxidectin was associated with piloerection, reduced arousal and body tone, abnormal gait, slowed breathing, and impaired righting reflex. In dogs, repeated doses of 1.6 mg/kg/day moxidectin (equivalent to approximately 7 times the recommended human dose based on body surface area comparison) was associated with lacrimation, languid appearance, tremors, slight salivation, and slight ataxia.
# Clinical Studies
- The assessment of the safety and efficacy of Moxidectin Tablets 8 mg in the treatment of onchocerciasis is based on data from two randomized, double-blind, active-controlled trials in patients with O. volvulus infection, Trial 1 in 1472 patients (NCT 00790998), and Trial 2, a dose-ranging trial (NCT 00300768). Patients in the trials received a single oral dose of moxidectin or ivermectin, the active control medication.
- Efficacy was assessed by skin microfilarial density (microfilariae/mg skin) from the mean of 4 skin snips per person per time point up to 18 months post-treatment.
- Trial 1 recruited adult and adolescent patients ≥ 12 years with a body weight ≥ 30 kg and ≥ 10 microfilariae/mg skin. Mean (± SD) age was 42.5 (± 16.3) years, height 1.59 (± 0.09) meters, weight 51.6 (± 8.2) kg; 36.1% were female and 100% were black. Mean (± SD) pretreatment skin microfilarial density was 39.5 (± 30.7), 69.6% had ≥ 20 microfilariae/mg skin and 39.7% had at least one ocular microfilaria.
- Patients who were not previously exposed to ivermectin community directed treatment programs were recruited from the sub-Saharan African region (Democratic Republic of Congo, Liberia, and Ghana). Table 5 reports mean skin microfilarial density and the proportion of patients with undetectable skin microfilariae at Months 1, 6, and 12.
- Additionally, safety and efficacy was assessed in a smaller single ascending dose trial (Trial 2, NCT 00300768) comparing 2 mg (n = 44), 4 mg (n = 45) (2 mg and 4 mg are not approved doses) and 8 mg (n = 38) single doses of moxidectin to ivermectin. Trial 2 was conducted in Ghana in adults aged ≥ 18 to ≤ 60 years with O. volvulus infection. Analysis of the baseline-to-12-month change in skin microfilarial density for the proposed moxidectin 8 mg dose showed statistically significant superiority to ivermectin, p < 0.001.
# How Supplied
- Moxidectin Tablets containing 2 mg moxidectin are white to pale yellow uncoated oval-shaped tablets, debossed on one side with “AKKA”. Each high-density polyethylene bottle contains 500 tablets
(NDC 71705-050-01), a silica gel desiccant and polyester coil.
## Storage
- Store below 30°C (86°F).
Protect from light.
Once open, the full contents of the container should be used within 24 hours with any unused content discarded.
- Protect from light.
- Once open, the full contents of the container should be used within 24 hours with any unused content discarded.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Signs and Symptoms Associated with Microfilarial Death
- Advise patients that they are likely to have flu like symptoms including malaise, myalgia, headache, tachycardia, hypotension and pruritus, most commonly during the first week after treatment.
Symptomatic Orthostatic Hypotension
- Advise patients that if they feel dizzy, faint or light-headed after taking Moxidectin Tablets, they should lie down until the symptoms resolve.
Absence of Macrofilarial Activity
- Advise patients that treatment with Moxidectin Tablets does not kill adult O. volvulus and that follow up evaluation is usually required.
Edema and Worsening of Onchodermatitis
- Advise patients with hyper-reactive onchodermatitis that they may be more likely to experience severe adverse reactions.
Encephalopathy in Loa loa Co-infected Patients
- Advise patients to report any symptoms of encephalopathy to their healthcare provider.
# Precautions with Alcohol
Alcohol-Moxidectin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Moxidectin
# Look-Alike Drug Names
There is limited information regarding Moxidectin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Moxidectin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [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
Moxidectin is an anthelmintic that is FDA approved for the treatment of onchocerciasis due to Onchocerca volvulus in patients aged 12 years and older. Common adverse reactions include eosinophilia, pruritus, musculoskeletal pain, headache, lymphopenia, tachycardia, rash, abdominal pain, hypotension, pyrexia, leukocytosis, influenza-like illness, neutropenia, cough, lymph node pain, dizziness, diarrhea, hyponatremia and peripheral swelling.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Indication
- Moxidectin Tablets are indicated for the treatment of onchocerciasis due to Onchocerca volvulus in patients aged 12 years and older.
Limitations of Use
- Moxidectin Tablets do not kill adult O. volvulus. Follow-up evaluation is advised.
- The safety and efficacy of repeat administration of Moxidectin Tablets in patients with O. volvulus has not been studied.
Dosage
- The recommended dosage of Moxidectin Tablet is a single dose of 8 mg (four 2 mg tablets) taken orally with or without food.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding moxidectin Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding moxidectin Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Indication
- Moxidectin Tablets are indicated for the treatment of onchocerciasis due to Onchocerca volvulus in patients aged 12 years and older.
- The safety and effectiveness of Moxidectin Tablets in pediatric patients under 12 years of age has not been established.
Limitations of Use
- Moxidectin Tablets do not kill adult O. volvulus. Follow-up evaluation is advised.
- The safety and efficacy of repeat administration of Moxidectin Tablets in patients with O. volvulus has not been studied.
Dosage
- The recommended dosage of Moxidectin Tablet for pediatric patients 12 years and older is a single dose of 8 mg (four 2 mg tablets) taken orally with or without food.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding moxidectin Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding moxidectin Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
None.
# Warnings
- Treatment with Moxidectin Tablets may cause cutaneous, ophthalmological and/or systemic reactions of varying severity (Mazzotti reaction). These adverse reactions are due to allergic and inflammatory host responses to the death of microfilariae. There is a trend toward an increased incidence of these adverse reactions in patients with higher microfilarial burden.
- The clinical manifestations of Mazzotti reaction includes pruritus, headache, pyrexia, rash, urticaria, hypotension (including symptomatic orthostatic hypotension and dizziness), tachycardia, edema, lymphadenopathy, arthralgia, myalgia, chills, paresthesia and asthenia. Ophthalmological manifestations include conjunctivitis, eye pain, eye pruritus, eyelid swelling, blurred vision, photophobia, changes in visual acuity, hyperemia, ocular discomfort and watery eyes. These adverse reactions generally occur and resolve in the first week post-treatment. Laboratory changes include eosinophilia, eosinopenia, lymphocytopenia, neutropenia, and increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT) and lactate dehydrogenase (LDH). Proteinuria has also been reported.
- Treatment of severe Mazzotti reactions has not been evaluated in controlled clinical trials. Symptomatic treatments such as oral hydration, recumbency, intravenous normal saline, and/or parenteral corticosteroids have been used to treat orthostatic hypotension. Antihistamines and/or analgesics have been used for most mild to moderate cases.
- An increased number of patients who received Moxidectin Tablets developed symptomatic orthostatic hypotension with inability to stand without support after lying down for 5 minutes (in an orthostatic hypotension provocation test); 47/978 (5%) compared with 8/494 (2%) who received ivermectin. The decreases in blood pressure were transient, managed by resumption of recumbency and most commonly occurred on Days 1 and 2 post-treatment. Advise patients that if they feel dizzy or light-headed after taking Moxidectin Tablets, they should lie down until the symptoms resolve.
- Patients with onchocerciasis who are also infected with Loa loa may develop a serious or even fatal
encephalopathy following treatment with Moxidectin Tablets.
- Moxidectin Tablets have not been studied in patients co-infected with Loa loa. Therefore, it is recommended that individuals who warrant treatment with Moxidectin Tablets and have had exposure to Loa loa-endemic areas undergo diagnostic screening for loiasis prior to treatment.
- Patients with hyper-reactive onchodermatitis (sowda) may be more likely than others to experience severe edema and worsening of onchodermatitis following the use of Moxidectin Tablets. Symptomatic treatment has been used to manage patients who have experienced edema and worsening of onchodermatitis.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under varying controlled conditions, adverse reaction rates observed in one clinical trial cannot be directly compared to rates observed in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- The safety of Moxidectin Tablets was evaluated in two randomized, double-blind, active-controlled studies (Trial 1 and Trial 2) [see Clinical Studies]. In Trial 1, 978 patients received Moxidectin Tablets as a single oral dose of 8 mg and 494 patients received ivermectin as a single oral dose of approximately 150 mcg/kg. In Trial 2, 127 patients received Moxidectin Tablets as a single oral dose ranging from 2 mg (this is not an approved dose) to 8 mg (38 received the recommended 8 mg dose) and 45 patients received ivermectin as a single oral dose of approximately 150 mcg/kg.
Most Common Adverse Reactions
- No patients withdrew from either trial due to adverse reactions. Adverse Reactions reported in Trial 1 in > 10% of patients are summarized in Table 1. Most were related to physical, vital signs and laboratory changes associated with Mazzotti reaction.
- The most common adverse reactions in patients (n = 38) treated with 8 mg moxidectin in Trial 2 were similar to the adverse reactions noted in Trial 1 described in Table 1 above.
Other Adverse Reactions Reported in Clinical Trials
- The following adverse reactions occurred in less than 10% of subjects receiving Moxidectin Tablets in Trial 1:
- Ocular Adverse Reactions: In Trial 1, the most common ocular adverse reactions (occurring in ≥ 0.5% of patients) are shown in Table 2.
Hepatobiliary Adverse Reactions
- More patients in the moxidectin arm experienced elevation in bilirubin above the upper limit of normal and elevation in transaminases > 5x upper limit of normal. Twenty-seven (2.8%) patients in the moxidectin arm and 3 (0.6%) patients in the ivermectin arm had hyperbilirubinemia. Most of the patients had single measurements of hyperbilirubinemia without concurrent elevation in transaminases.
- Nine (1%) patients in the moxidectin arm and 2 (0.4%) patients in the ivermectin arm had elevation in ALT of more than 5x upper limit of normal; ten (1%) patients in the moxidectin arm and 3 (0.6%) patients in the ivermectin arm had elevation in AST to more than 5x upper limit of normal.
Laboratory Abnormalities
- Laboratory abnormalities occurring in at least 1% of patients in the Trial 1 are described in Table 3.
## Postmarketing Experience
There is limited information regarding Moxidectin Postmarketing Experience in the drug label.
# Drug Interactions
- In healthy subjects, concomitant administration of a single 8 mg oral dose of Moxidectin Tablets did not have an effect on the pharmacokinetics of midazolam. Moxidectin can be co-administered with CYP3A4 substrates.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- Limited available data on the use of Moxidectin Tablets in pregnant women are insufficient to establish whether there is a moxidectin-associated risk for major birth defects and miscarriage. Moxidectin administered orally to pregnant rats during the period of organogenesis (Gestation Days (GD) 6 to 15), was not associated with significant embryo-fetal developmental effects at doses of approximately 15 times the recommended human dose based on body surface area. When moxidectin was dosed orally to pregnant rabbits during the period of organogenesis (GD 7 - 19), no embryo-fetal developmental effects were observed at oral doses of moxidectin up to 24 times the recommended human dose based on body surface area.
- Daily parental oral administration of dietary moxidectin to rats prior to mating, and through mating, gestation, and lactation was associated with decreased survival and body weights for first-generation offspring without maternal toxicity at moxidectin doses less than 2-times the recommended human dose based on body surface area comparison. Daily dietary moxidectin did not produce maternal toxicity or adverse effects for first- and second-generation offspring at doses approximately equivalent to the recommended human dose based on body surface area comparison. Offspring were assessed for survival, body weights, and fertility. Developmental milestones were not assessed in this study.
- The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Animal Data
- In a rat embryo-fetal development study, daily oral administration of moxidectin at 12 mg/kg/day (approximately 15 times the recommended human dose of 8 mg based on body surface area comparison) during Gestation Days (GDs) 6 to 15 significantly increased the fetal incidence, but not the litter incidence of cleft palate and the fetal and litter incidence of a skeletal variation, wavy ribs, at a maternally toxic dose. Mean maternal food consumption, body weights, and body weight gain were significantly decreased at moxidectin doses of 10 and 12 mg/kg/day compared to control values. The no observed adverse effect level (NOAEL) value for maternal and fetal toxicity was considered to be 5 and 10 mg/kg/day respectively (approximately 6 and 12 times, respectively, the recommended human dose based on body surface area comparison). In the rabbit, daily oral administration of moxidectin at ≥ 5 mg/kg/day from GD7 to GD19 was not associated with fetal weight loss or malformations but resulted in significantly decreased maternal food consumption and body weight gains. The NOAEL value for maternal and fetal toxicity in the rabbit was 1 mg/kg/day and 10 mg/kg/day respectively (approximately 2 times and 24 times, respectively, the recommended human dose based on body surface area comparison). In a pre-postnatal study in rats, parental oral administration of dietary moxidectin prior to mating, through mating, gestation, and lactation did not produce adverse effects in first-generation or second- generation offspring at a maternal NOAEL dose of 0.824 mg/kg/day (approximately equivalent to the recommended human dose based on body surface area comparison). However, at moxidectin doses
≥ 1.1 mg/kg/day (approximately equivalent to 1.3 times the recommended human dose based on body surface area comparison), the survival and body weights of first-generation offspring were significantly decreased during the lactation period, and the number of live fetuses at birth was significantly decreased with a maternal moxidectin dose of 11 mg/kg/day (approximately equivalent to 13 times the recommended human dose based on body surface area comparison). In this study, offspring were assessed for survival, body weights, and fertility, and developmental milestones were not assessed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Moxidectin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Moxidectin during labor and delivery.
### Nursing Mothers
Risk Summary
- Moxidectin was detected in the milk of lactating women following a single 8 mg dose of Moxidectin Tablets [see Data]. There are no data on the effects of Moxidectin Tablets on the breast-fed infant or milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Moxidectin Tablets and any potential adverse effects on the breastfed child from Moxidectin Tablets or from the underlying maternal condition.
Data
- A pharmacokinetic study in twelve healthy adult lactating women who were 21 to 100 weeks post partum evaluated the concentrations of moxidectin in plasma and breast milk collected over a period of 28 days following a single 8 mg dose of Moxidectin Tablets. The mean (± SD) exposure ratio of moxidectin present in human breast milk to that of human plasma was approximately 1.77 (± 0.66) over a collection period of
28 days. The estimated mean (± SD) total infant dose, assuming the infants would consume all the breast milk collected during the study, was 0.056 mg (± 0.024 mg), which would be approximately 0.70% (± 0.30%) of the maternal dose. The effects of moxidectin or its metabolites on the breast-fed child or milk production were not evaluated.
### Pediatric Use
- The safety and effectiveness of Moxidectin Tablets have been established in pediatric patients 12 years of age and older. In Trial 1, (n = 53 patients aged 12 to 17 years), the safety and effectiveness was similar to that observed in adults. The safety and effectiveness of Moxidectin Tablets in pediatric patients under 12 years of age has not been established.
### Geriatic Use
- Of the total number of patients included in Trial 1 that were treated with Moxidectin Tablets, 83 were aged 65 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Moxidectin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Moxidectin with respect to specific racial populations.
### Renal Impairment
- No dose adjustment of Moxidectin Tablets is necessary for patients with mild (creatinine clearance (CrCL) 60 to 89 mL/min) to moderate (CrCL 30 to 59 mL/min) renal impairment. The safety of Moxidectin Tablets in patients with severe renal impairment (CrCL 15 to 29 mL/min) or end stage renal disease, is unknown.
### Hepatic Impairment
There is no FDA guidance on the use of Moxidectin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Moxidectin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Moxidectin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- The recommended dosage of Moxidectin Tablet is a single dose of 8 mg (four 2 mg tablets) taken orally with or without food.
### Monitoring
There is limited information regarding Moxidectin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Moxidectin and IV administrations.
# Overdosage
- No specific antidote is available for overdose with Moxidectin Tablets. If overdose occurs, the patient should be monitored for evidence of toxicity. Treatment of overdose with Moxidectin Tablets consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Supportive therapy, if indicated, should include parenteral fluids and electrolytes, respiratory support (oxygen and mechanical ventilation if necessary) and pressor agents if clinically significant hypotension is present.
# Pharmacology
## Mechanism of Action
- Moxidectin, a macrocyclic lactone, is an anthelmintic drug.
## Structure
- The empirical formula is C37H53NO8 and the molecular weight is 639.82 Dalton. The structural formula is:
## Pharmacodynamics
Cardiac Electrophysiology
- At a dose 4.5 times the approved recommended dose, moxidectin does not prolong the QT interval to any clinically relevant extent.
## Pharmacokinetics
- The pharmacokinetic parameters of moxidectin following a single 8 mg oral dose of Moxidectin Tablets to healthy subjects and patients with onchocerciasis under fasted conditions are shown in Table 4. Mean moxidectin Cmax and AUC increased approximately proportionally to dose over a dose range of 2 to 36 mg (0.25 to 4.5 times the approved recommended dose) in healthy subjects under fasted conditions.
Absorption
Effect of Food
- Moxidectin mean Cmax and AUC increased on average by 34% and 39%, respectively, when administered with a standard high fat meal (900 calories, with a nutritional distribution of approximately 55% fat, 31% carbohydrates and 14% protein), compared to fasted conditions.
Distribution
- The apparent mean ± SD volume of distribution of moxidectin is 2421 ± 1658 L in patients with onchocerciasis. The plasma protein binding in humans is unknown.
Elimination
- The mean terminal half-life of moxidectin in patients with onchocerciasis is 23.3 days (559 hours) following a single 8 mg dose of Moxidectin Tablets.
- The apparent mean ± SD total clearance of moxidectin is approximately 3.50 ± 1.23 L/hour in patients with onchocerciasis.
Metabolism
- The hepatic metabolism of moxidectin is minimal.
Excretion
- Following administration of a single 8 mg oral dose of Moxidectin Tablets to healthy subjects, 2% of the dose is eliminated unchanged in the feces within the first 72 hours. Renal elimination of intact drug is negligible.
Specific Populations
- In clinical studies, no clinically significant differences in the pharmacokinetics of moxidectin were observed based on age (18 to 60 years), sex, weight (42.7 to 107.2 kg), or renal impairment (creatinine clearance (CrCL) 47 to 89 mL/min, estimated by Cockcroft-Gault). The pharmacokinetics of moxidectin in patients with CrCL less than 47 mL/min is unknown. The pharmacokinetics of moxidectin in patients with hepatic impairment is unknown.
Patients with Renal Impairment
- Based on a population pharmacokinetic analysis and the fact that renal elimination of intact drug is negligible, mild (creatinine clearance (CrCL), estimated by Cockcroft-Gault of 60 to 89 mL/min) and moderate (CrCL 30 to 59 mL/min) renal impairment is not likely to have an impact on the exposure of moxidectin. The effect of severe renal impairment (CrCL 15 to 29 mL/min) or of end-stage renal disease on the pharmacokinetics of moxidectin is unknown.
Drug Interaction Studies
Clinical Study with Midazolam (CYP3A4 substrate)
- Co-administration of a single 8 mg dose of Moxidectin Tablets with a single oral 7.5 mg dose of midazolam (a sensitive CYP3A substrate) to healthy subjects (n = 37) did not affect the pharmacokinetics of midazolam or its major metabolite, 1-hydroxy midazolam.
In Vitro Studies
- CYP Enzymes: Moxidectin is not a substrate or inhibitor of CYP enzymes.
- Uridine 5'-diphospho-glucuronosyltransferases (UGTs): Moxidectin is not a UGT substrate.
- Transporter Systems: Moxidectin is not a substrate of P-glycoprotein (P-gp) nor breast cancer resistance protein 1 (BCRP1).
## Microbiology
Mechanism of Action
- The mechanism by which moxidectin exhibits its effect against O. volvulus is not known. Studies with other nematodes suggest that moxidectin binds to glutamate-gated chloride channels (GluCl), gamma-aminobutyric acid (GABA) receptors and/or ATP-binding cassette (ABC) transporters. This leads to increased permeability, influx of chloride ions, hyperpolarization and muscle paralysis. Additionally, there is a reduction in motility of all stages of the parasite, excretion of immunomodulatory proteins, and the fertility of both male and female adult worms.
Antimicrobial Activity
- Moxidectin is active against the microfilariae of O. volvulus.
- Studies suggest that moxidectin is not effective in killing the adult worms, however, it inhibits intra-uterine embryogenesis and release of microfilariae from the adult worms.
Resistance
- Studies in vitro and infected animals suggest a potential for development of resistance to moxidectin and cross-resistance with other macrocyclic lactones, such as ivermectin. However, the clinical relevance of these findings is not known.
- The mechanism of resistance may be multifactorial that include alteration in the target GluCl, GABA receptors and/or ABC transporters.
## Nonclinical Toxicology
- Moxidectin was shown to be negative for genotoxicity in a battery of in vitro assays including a bacterial mutagenicity assay, mouse lymphoma cell mutagenicity assay, unscheduled DNA synthesis assay, and a chromosome aberration assay, as well as in vivo in a micronucleus assay in mice and a chromosome aberration assay in rats.
- Two-year carcinogenicity studies in mice and rats were conducted with moxidectin. Mice were administered a mean dietary dose of 8.7 mg/kg/day moxidectin which is approximately equivalent to 5 times the recommended human dose based on body surface area comparison. Rats were administered a mean dietary dose of 6.1 mg/kg/day moxidectin which is approximately equivalent to 7 times the recommended human dose based on body surface area comparison. There was no evidence of tumorigenicity in either study.
- In fertility evaluations, male and female mating and fertility indices were not inhibited by oral-dietary moxidectin doses of approximately 0.86 mg/kg/day which is approximately equivalent to the recommended human dose based on body surface area comparison.
- Moxidectin was associated with transient CNS-related clinical signs. In rats, a single dose of 20 mg/kg (equivalent to approximately 24 times the recommended human dose based on body surface area comparison) moxidectin was associated with piloerection, reduced arousal and body tone, abnormal gait, slowed breathing, and impaired righting reflex. In dogs, repeated doses of 1.6 mg/kg/day moxidectin (equivalent to approximately 7 times the recommended human dose based on body surface area comparison) was associated with lacrimation, languid appearance, tremors, slight salivation, and slight ataxia.
# Clinical Studies
- The assessment of the safety and efficacy of Moxidectin Tablets 8 mg in the treatment of onchocerciasis is based on data from two randomized, double-blind, active-controlled trials in patients with O. volvulus infection, Trial 1 in 1472 patients (NCT 00790998), and Trial 2, a dose-ranging trial (NCT 00300768). Patients in the trials received a single oral dose of moxidectin or ivermectin, the active control medication.
- Efficacy was assessed by skin microfilarial density (microfilariae/mg skin) from the mean of 4 skin snips per person per time point up to 18 months post-treatment.
- Trial 1 recruited adult and adolescent patients ≥ 12 years with a body weight ≥ 30 kg and ≥ 10 microfilariae/mg skin. Mean (± SD) age was 42.5 (± 16.3) years, height 1.59 (± 0.09) meters, weight 51.6 (± 8.2) kg; 36.1% were female and 100% were black. Mean (± SD) pretreatment skin microfilarial density was 39.5 (± 30.7), 69.6% had ≥ 20 microfilariae/mg skin and 39.7% had at least one ocular microfilaria.
- Patients who were not previously exposed to ivermectin community directed treatment programs were recruited from the sub-Saharan African region (Democratic Republic of Congo, Liberia, and Ghana). Table 5 reports mean skin microfilarial density and the proportion of patients with undetectable skin microfilariae at Months 1, 6, and 12.
- Additionally, safety and efficacy was assessed in a smaller single ascending dose trial (Trial 2, NCT 00300768) comparing 2 mg (n = 44), 4 mg (n = 45) (2 mg and 4 mg are not approved doses) and 8 mg (n = 38) single doses of moxidectin to ivermectin. Trial 2 was conducted in Ghana in adults aged ≥ 18 to ≤ 60 years with O. volvulus infection. Analysis of the baseline-to-12-month change in skin microfilarial density for the proposed moxidectin 8 mg dose showed statistically significant superiority to ivermectin, p < 0.001.
# How Supplied
- Moxidectin Tablets containing 2 mg moxidectin are white to pale yellow uncoated oval-shaped tablets, debossed on one side with “AKKA”. Each high-density polyethylene bottle contains 500 tablets
(NDC 71705-050-01), a silica gel desiccant and polyester coil.
## Storage
- Store below 30°C (86°F).
Protect from light.
Once open, the full contents of the container should be used within 24 hours with any unused content discarded.
- Protect from light.
- Once open, the full contents of the container should be used within 24 hours with any unused content discarded.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Signs and Symptoms Associated with Microfilarial Death
- Advise patients that they are likely to have flu like symptoms including malaise, myalgia, headache, tachycardia, hypotension and pruritus, most commonly during the first week after treatment.
Symptomatic Orthostatic Hypotension
- Advise patients that if they feel dizzy, faint or light-headed after taking Moxidectin Tablets, they should lie down until the symptoms resolve.
Absence of Macrofilarial Activity
- Advise patients that treatment with Moxidectin Tablets does not kill adult O. volvulus and that follow up evaluation is usually required.
Edema and Worsening of Onchodermatitis
- Advise patients with hyper-reactive onchodermatitis that they may be more likely to experience severe adverse reactions.
Encephalopathy in Loa loa Co-infected Patients
- Advise patients to report any symptoms of encephalopathy to their healthcare provider.
# Precautions with Alcohol
Alcohol-Moxidectin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Moxidectin
# Look-Alike Drug Names
There is limited information regarding Moxidectin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Moxidectin | |
7943c428e14ba7fa3cb0ffd6399ac26cb3eac304 | wikidoc | Moxonidine | Moxonidine
# Overview
Moxonidine (INN) (IPA: Template:IPA) is a new generation centrally acting antihypertensive drug licensed for the treatment of mild to moderate essential hypertension. It may have a role when thiazides, beta-blockers, ACE inhibitors and calcium channel blockers are not appropriate or have failed to control blood pressure. In addition, it demonstrates favourable effects on parameters of the insulin resistance syndrome, apparently independent of blood pressure reduction. It is manufactured by Solvay Pharmaceuticals under the brand name Physiotens.
# Mechanism of actions
Moxonidine is a selective agonist at the imidazoline subtype 1 (I1) receptor. This receptor subtype is found in both the rostral ventro-lateral pressor and ventromedial depressor areas of the medulla oblongata. Moxonidine therefore causes a decrease in sympathetic nervous system activity and, therefore, a decrease in blood pressure.
Compared to the older central-acting antihypertensives, moxonidine binds with much greater affinity to the imidazoline I1-receptor than to the α2-receptor. In contrast, clonidine binds to both receptors with equal affinity.
In addition, moxonidine may also promote sodium excretion, improve insulin resistance and glucose tolerance and protect against hypertensive target organ damage, such as kidney disease and cardiac hypertrophy.
# Pharmacodynamic properties
Effects on insulin resistance
In all animal models of insulin resistance, moxonidine had striking effects on the development of insulin resistance, hyperinsulinaemia and impaired glucose homeostasis. Given the importance of insulin resistance as a risk factor for cardiovascular disease, it is of considerable relevance that it has been shown to improve insulin sensitivity.
Based on animal models, it has demonstrated that moxonidine is capable of:
- normalising plasma insulin levels
- improving glucose uptake in peripheral cells
- lowering lipid levels
- decreasing food intake and reducing weight gain in obese animals.
Renal function
Evidence is accumulating to show that sympathetic overactivity is substantially involved in the development and progression of chronic renal failure, contributing to a poor overall cardiovascular prognosis. Moxonidine has been shown to reduce structural renal damage in various models of renal failure.
Cardiac structure
In spontaneously hypertensive rats, moxonidine significantly reduced total heart weight, left ventricular weight and the ratio of ventricular weight to body weight compared with an untreated control group.
# Safety pharmacology
Routine toxicology studies have provided no evidence that moxonidine has any teratogenic, mutagenic or carcinogenic potential. No evidence has been found of serious adverse effects on organs or organ systems, and the drug has not been shown to have deleterious effects on perinatal or postnatal growth and development.
# Cautions
Moxonidine should be avoided in patients with moderate to severe renal impairment. Abrupt discontinuation of the drug should also be avoided. If concomitant treatment with a beta blocker has to be stopped, the beta blocker should be discontinued first, then moxonidine after a few days.
# Drug interactions
Concomitant administration of moxonidine and a thiazide diuretic such as hydrochlorothiazide is not indicated, as both drugs' hypotensive effects may be enhanced.
# Contra-indications
It is contraindicated if there has been a past history of angioedema; heart conduction disorders (e.g. sick sinus syndrome, second- or third-degree heart block); bradycardia; severe heart failure or coronary artery disease, severe liver or renal impairment. Also: Raynaud's syndrome, intermittent claudication, epilepsy, depression, Parkinson's disease, glaucoma. Use in pregnancy is discouraged. Moxonidine passes into breast milk.
Excess mortality seen in patients with symptomatic heart failure.
# Side-effects
Noteworthy side effects include dry mouth, headache, fatigue, dizziness, nausea, sleep disturbances (rarely sedation), asthenia, vasodilatation, and rarely, skin reactions. | Moxonidine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Moxonidine (INN) (IPA: Template:IPA) is a new generation centrally acting antihypertensive drug licensed for the treatment of mild to moderate essential hypertension. It may have a role when thiazides, beta-blockers, ACE inhibitors and calcium channel blockers are not appropriate or have failed to control blood pressure. In addition, it demonstrates favourable effects on parameters of the insulin resistance syndrome, apparently independent of blood pressure reduction. It is manufactured by Solvay Pharmaceuticals under the brand name Physiotens.
# Mechanism of actions
Moxonidine is a selective agonist at the imidazoline subtype 1 (I1) receptor. This receptor subtype is found in both the rostral ventro-lateral pressor and ventromedial depressor areas of the medulla oblongata. Moxonidine therefore causes a decrease in sympathetic nervous system activity and, therefore, a decrease in blood pressure.
Compared to the older central-acting antihypertensives, moxonidine binds with much greater affinity to the imidazoline I1-receptor than to the α2-receptor. In contrast, clonidine binds to both receptors with equal affinity.
In addition, moxonidine may also promote sodium excretion, improve insulin resistance and glucose tolerance and protect against hypertensive target organ damage, such as kidney disease and cardiac hypertrophy.
# Pharmacodynamic properties
Effects on insulin resistance
In all animal models of insulin resistance, moxonidine had striking effects on the development of insulin resistance, hyperinsulinaemia and impaired glucose homeostasis. Given the importance of insulin resistance as a risk factor for cardiovascular disease, it is of considerable relevance that it has been shown to improve insulin sensitivity.
Based on animal models, it has demonstrated that moxonidine is capable of:
- normalising plasma insulin levels
- improving glucose uptake in peripheral cells
- lowering lipid levels
- decreasing food intake and reducing weight gain in obese animals.
Renal function
Evidence is accumulating to show that sympathetic overactivity is substantially involved in the development and progression of chronic renal failure, contributing to a poor overall cardiovascular prognosis. Moxonidine has been shown to reduce structural renal damage in various models of renal failure.
Cardiac structure
In spontaneously hypertensive rats, moxonidine significantly reduced total heart weight, left ventricular weight and the ratio of ventricular weight to body weight compared with an untreated control group.
# Safety pharmacology
Routine toxicology studies have provided no evidence that moxonidine has any teratogenic, mutagenic or carcinogenic potential. No evidence has been found of serious adverse effects on organs or organ systems, and the drug has not been shown to have deleterious effects on perinatal or postnatal growth and development.
# Cautions
Moxonidine should be avoided in patients with moderate to severe renal impairment. Abrupt discontinuation of the drug should also be avoided. If concomitant treatment with a beta blocker has to be stopped, the beta blocker should be discontinued first, then moxonidine after a few days.
# Drug interactions
Concomitant administration of moxonidine and a thiazide diuretic such as hydrochlorothiazide is not indicated, as both drugs' hypotensive effects may be enhanced.
# Contra-indications
It is contraindicated if there has been a past history of angioedema; heart conduction disorders (e.g. sick sinus syndrome, second- or third-degree heart block); bradycardia; severe heart failure or coronary artery disease, severe liver or renal impairment. Also: Raynaud's syndrome, intermittent claudication, epilepsy, depression, Parkinson's disease, glaucoma. Use in pregnancy is discouraged. Moxonidine passes into breast milk.
Excess mortality seen in patients with symptomatic heart failure.[1]
# Side-effects
Noteworthy side effects include dry mouth, headache, fatigue, dizziness, nausea, sleep disturbances (rarely sedation), asthenia, vasodilatation, and rarely, skin reactions. | https://www.wikidoc.org/index.php/Moxonidine | |
40c03ab3320f8f1a7f204b7f15c149da80a38f7f | wikidoc | Plerixafor | Plerixafor
# 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
Plerixafor is an hematopoietic that is FDA approved for the treatment of non-Hodgkin's lymphoma and multiple myeloma. Common adverse reactions include diarrhea, nausea, fatigue, injection site reactions, headache, arthralgia, dizziness, and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Plerixafor is indicated in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells (HSCs) to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM).
- Dosage: 0.24 mg/kg body weight by subcutaneous (SC) injection
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Plerixafor in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Plerixafor in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy not established in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Plerixafor in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Plerixafor in pediatric patients.
# Contraindications
History of hypersensitivity to plerixafor. Anaphylactic shock has occurred with use of plerixafor.
# Warnings
- Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening with clinically significant hypotension and shock have occurred in patients receiving plerixafor. Observe patients for signs and symptoms of hypersensitivity during and after plerixafor administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer plerixafor when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions.
- In clinical studies, mild or moderate allergic reactions occurred within approximately 30 minutes after plerixafor administration in less than 1% of patients.
- For the purpose of HSC mobilization, plerixafor may cause mobilization of leukemic cells and subsequent contamination of the apheresis product. Therefore, plerixafor is not intended for HSC mobilization and harvest in patients with leukemia.
- Administration of plerixafor in conjunction with G-CSF increases circulating leukocytes as well as HSC populations. Monitor white blood cell counts during plerixafor use.
- Thrombocytopenia has been observed in patients receiving plerixafor. Monitor platelet counts in all patients who receive plerixafor and then undergo apheresis.
- When plerixafor is used in combination with G-CSF for HSC mobilization‚ tumor cells may be released from the marrow and subsequently collected in the leukapheresis product. The effect of potential reinfusion of tumor cells has not been well-studied.
- Higher absolute and relative spleen weights associated with extramedullary hematopoiesis were observed following prolonged (2 to 4 weeks) daily plerixafor SC administration in rats at doses approximately 4-fold higher than the recommended human dose based on body surface area. The effect of plerixafor on spleen size in patients was not specifically evaluated in clinical studies. Evaluate individuals receiving plerixafor in combination with G-CSF who report left upper abdominal pain and/or scapular or shoulder pain for splenic integrity.
- plerixafor may cause fetal harm when administered to a pregnant woman. Plerixafor is teratogenic in animals. There are no adequate and well-controlled studies in pregnant women using plerixafor. Advise women of childbearing potential to avoid becoming pregnant while receiving treatment with plerixafor. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
# 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 common adverse reactions (≥ 10%) reported in patients who received plerixafor in conjunction with G-CSF regardless of causality and more frequent with plerixafor than placebo during HSC mobilization and apheresis were diarrhea, nausea, fatigue, injection site reactions, headache, arthralgia, dizziness, and vomiting.
- Safety data for plerixafor in combination with G-CSF were obtained from two randomized placebo-controlled studies (301 patients) and 10 uncontrolled studies (242 patients). Patients were primarily treated with plerixafor at daily doses of 0.24 mg/kg SC. Median exposure to plerixafor in these studies was 2 days (range 1 to 7 days).
- In the two randomized studies in patients with NHL and MM, a total of 301 patients were treated in the plerixafor and G-CSF group and 292 patients were treated in the placebo and G-CSF group. Patients received daily morning doses of G-CSF 10 micrograms/kg for 4 days prior to the first dose of plerixafor 0.24 mg/kg SC or placebo and on each morning prior to apheresis. The adverse reactions that occurred in ≥ 5% of the patients who received plerixafor regardless of causality and were more frequent with plerixafor than placebo during HSC mobilization and apheresis are shown in Table 2.
- In the randomized studies, 34% of patients with NHL or MM had mild to moderate injection site reactions at the site of subcutaneous administration of plerixafor. These included erythema, hematoma, hemorrhage, induration, inflammation, irritation, pain, paresthesia, pruritus, rash, swelling, and urticaria.
- Mild to moderate allergic reactions were observed in less than 1% of patients within approximately 30 min after plerixafor administration, including one or more of the following: urticaria (n = 2), periorbital swelling (n = 2), dyspnea (n = 1) or hypoxia (n = 1). Symptoms generally responded to treatments (e.g., antihistamines, corticosteroids, hydration or supplemental oxygen) or resolved spontaneously.
- Vasovagal reactions, orthostatic hypotension, and/or syncope can occur following subcutaneous injections. In plerixafor oncology and healthy volunteer clinical studies, less than 1% of subjects experienced vasovagal reactions following subcutaneous administration of plerixafor doses ≤ 0.24 mg/kg. The majority of these events occurred within 1 hour of plerixafor administration. Because of the potential for these reactions, appropriate precautions should be taken.
- Other adverse reactions in the randomized studies that occurred in < 5% of patients but were reported as related to plerixafor during HSC mobilization and apheresis included abdominal pain, hyperhidrosis, abdominal distention, dry mouth, erythema, stomach discomfort, malaise, hypoesthesia oral, constipation, dyspepsia, and musculoskeletal pain.
- Hyperleukocytosis: In clinical trials, white blood cell counts of 100,000/mcL or greater were observed, on the day prior to or any day of apheresis, in 7% of patients receiving plerixafor and in 1% of patients receiving placebo. No complications or clinical symptoms of leukostasis were observed.
## Postmarketing Experience
In addition to adverse reactions reported from clinical trials, the following adverse reactions have been reported from post-marketing experience with plerixafor. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Immune System Disorders: Anaphylactic reactions, including anaphylactic shock
- Psychiatric disorders: Abnormal dreams and nightmares
# Drug Interactions
Based on in vitro data, plerixafor is not a substrate, inhibitor or inducer of human cytochrome P450 isozymes. Plerixafor is not likely to be implicated in in vivo drug-drug interactions involving cytochrome P450s. At concentrations similar to what are seen clinically, plerixafor did not act as a substrate or inhibitor of P-glycoprotein in an in vitro study.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Plerixafor may cause fetal harm when administered to a pregnant woman. Plerixafor is teratogenic in animals.
- Plerixafor administered to pregnant rats induced embryo-fetal toxicities including fetal death, increased resorptions and post-implantation loss, decreased fetal weights, anophthalmia, shortened digits, cardiac interventricular septal defect, ringed aorta, globular heart, hydrocephaly, dilatation of olfactory ventricles, and retarded skeletal development. Embryo-fetal toxicities occurred mainly at a dose of 90 mg/m2 (approximately 10 times the recommended human dose of 0.24 mg/kg when compared on a mg/m2 basis or 10 times the AUC in subjects with normal renal function who received a single dose of 0.24 mg/kg).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Plerixafor in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Plerixafor during labor and delivery.
### Nursing Mothers
- It is not known whether plerixafor is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from plerixafor, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and efficacy of plerixafor in pediatric patients have not been established in controlled clinical studies.
### Geriatic Use
- Of the total number of subjects in controlled clinical studies of plerixafor, 24% were 65 and over, while 0.8% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
- Since plerixafor is mainly excreted by the kidney, no dose modifications are necessary in elderly individuals with normal renal function. In general, care should be taken in dose selection for elderly patients due to the greater frequency of decreased renal function with advanced age. Dosage adjustment in elderly patients with CLCR ≤ 50 mL/min is recommended.
### Gender
- Clinical data show no effect of gender on plerixafor pharmacokinetics.
### Race
- Clinical data show similar plerixafor pharmacokinetics for Caucasians and African-Americans, and the effect of other racial/ethnic groups has not been studied.
### Renal Impairment
- In patients with moderate and severe renal impairment (CLCR ≤ 50 mL/min), reduce the dose of plerixafor by one-third to 0.16 mg/kg.
### Hepatic Impairment
There is no FDA guidance on the use of Plerixafor in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- The effect of plerixafor on human fertility is unknown. The effect of plerixafor on male or female fertility was not studied in designated reproductive toxicology studies. The staging of spermatogenesis measured in a 28-day repeated dose toxicity study in rats revealed no abnormalities considered to be related to plerixafor. No histopathological evidence of toxicity to male or female reproductive organs was observed in 28-day repeated dose toxicity studies.
### Immunocompromised Patients
There is no FDA guidance one the use of Plerixafor in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Subcutaneous
### Monitoring
There is limited information regarding Plerixafor Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Plerixafor and IV administrations.
# Overdosage
- Based on limited data at doses above the recommended dose of 0.24 mg/kg SC, the frequency of gastrointestinal disorders, vasovagal reactions, orthostatic hypotension, and/or syncope may be higher.
# Pharmacology
## Mechanism of Action
- Plerixafor is an inhibitor of the CXCR4 chemokine receptor and blocks binding of its cognate ligand, stromal cell-derived factor-1α (SDF-1α). SDF-1α and CXCR4 are recognized to play a role in the trafficking and homing of human hematopoietic stem cells (HSCs) to the marrow compartment. Once in the marrow, stem cell CXCR4 can act to help anchor these cells to the marrow matrix, either directly via SDF-1α or through the induction of other adhesion molecules. Treatment with plerixafor resulted in leukocytosis and elevations in circulating hematopoietic progenitor cells in mice, dogs and humans. CD34+ cells mobilized by plerixafor were capable of engraftment with long-term repopulating capacity up to one year in canine transplantation models.
## Structure
The structural formula is:
## Pharmacodynamics
- Data on the fold increase in peripheral blood CD34+ cell count (cells/mcL) by apheresis day were evaluated in two placebo-controlled clinical studies in patients with NHL and MM (Study 1 and Study 2, respectively). The fold increase in CD34+ cell count (cells/mcL) over the 24-hour period starting from the day prior to the first apheresis and ending the next morning just before the first apheresis is summarized in Table 3. During this 24-hour period, a single dose of plerixafor or placebo was administered 10 to 11 hours prior to apheresis.
- In pharmacodynamic studies of plerixafor in healthy volunteers, peak mobilization of CD34+ cells was observed between 6 and 9 hours after administration. *In pharmacodynamic studies of plerixafor in conjunction with G-CSF in healthy volunteers, a sustained elevation in the peripheral blood CD34+ count was observed from 4 to 18 hours after plerixafor administration with a peak CD34+ count between 10 and 14 hours.
- There is no indication of a QT/QTc prolonging effect of plerixafor in single doses up to 0.40 mg/kg. In a randomized, double-blind, crossover study, 48 healthy subjects were administered a single subcutaneous dose of plerixafor (0.24 mg/kg and 0.40 mg/kg) and placebo. Peak concentrations for 0.40 mg/kg plerixafor were approximately 1.8-fold higher than the peak concentrations following the 0.24 mg/kg single subcutaneous dose.
## Pharmacokinetics
The single-dose pharmacokinetics of plerixafor 0.24 mg/kg were evaluated in patients with NHL and MM following pre-treatment with G-CSF (10 micrograms/kg once daily for 4 consecutive days). Plerixafor exhibits linear kinetics between the 0.04 mg/kg to 0.24 mg/kg dose range. The pharmacokinetics of plerixafor were similar across clinical studies in healthy subjects who received plerixafor alone and NHL and MM patients who received plerixafor in combination with G-CSF.
- A population pharmacokinetic analysis incorporated plerixafor data from 63 subjects (NHL patients, MM patients, subjects with varying degrees of renal impairment, and healthy subjects) who received a single SC dose (0.04 mg/kg to 0.24 mg/kg) of plerixafor. A two-compartment disposition model with first order absorption and elimination was found to adequately describe the plerixafor concentration-time profile. Significant relationships between clearance and creatinine clearance (CLCR), as well as between central volume of distribution and body weight were observed. The distribution half-life (t1/2α) was estimated to be 0.3 hours and the terminal population half-life (t1/2β) was 5.3 hours in patients with normal renal function.
- The population pharmacokinetic analysis showed that the mg/kg-based dosage results in an increased plerixafor exposure (AUC0–24h) with increasing body weight. There is limited experience with the 0.24 mg/kg dose of plerixafor in patients weighing above 160 kg. Therefore the dose should not exceed that of a 160 kg patient (i.e., 40 mg/day if CLCR is > 50 mL/min and 27 mg/day if CLCR is ≤ 50 mL/min).
- Peak plasma concentrations occurred at approximately 30 – 60 minutes after a SC dose.
- Plerixafor is bound to human plasma proteins up to 58%. The apparent volume of distribution of plerixafor in humans is 0.3 L/kg demonstrating that plerixafor is largely confined to, but not limited to, the extravascular fluid space.
- The metabolism of plerixafor was evaluated with in vitro assays. Plerixafor is not metabolized as shown in assays using human liver microsomes or human primary hepatocytes and does not exhibit inhibitory activity in vitro towards the major drug metabolizing cytochrome P450 enzymes (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4/5). In in vitro studies with human hepatocytes, plerixafor does not induce CYP1A2, CYP2B6, or CYP3A4 enzymes. These findings suggest that plerixafor has a low potential for involvement in cytochrome P450-dependent drug-drug interactions.
- The major route of elimination of plerixafor is urinary. Following a 0.24 mg/kg dose in healthy volunteers with normal renal function, approximately 70% of the dose was excreted in the urine as the parent drug during the first 24 hours following administration. In studies with healthy subjects and patients, the terminal half-life in plasma ranges between 3 and 5 hours. At concentrations similar to what are seen clinically, plerixafor did not act as a substrate or inhibitor of P-glycoprotein in an in vitro study with MDCKII and MDCKII-MDR1 cell models.
## Nonclinical Toxicology
- Carcinogenicity studies with plerixafor have not been conducted.
- Plerixafor was not genotoxic in an in vitro bacterial mutation assay (Ames test in Salmonella), an in vitro chromosomal aberration test using V79 Chinese hamster cells, or an in vivo bone marrow micronucleus test in rats after subcutaneous doses up to 25 mg/kg (150 mg/m2).
# Clinical Studies
The efficacy and safety of plerixafor in conjunction with G-CSF in non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM) were evaluated in two placebo-controlled studies (Studies 1 and 2). Patients were randomized to receive either plerixafor 0.24 mg/kg or placebo on each evening prior to apheresis. Patients received daily morning doses of G-CSF 10 micrograms/kg for 4 days prior to the first dose of plerixafor or placebo and on each morning prior to apheresis. Two hundred and ninety-eight (298) NHL patients were included in the primary efficacy analyses for Study 1. The mean age was 55 years (range 29–75) and 58 years (range 22–75) in the plerixafor and placebo groups, respectively, and 93% of subjects were Caucasian. In study 2, 302 patients with MM were included in the primary efficacy analyses. The mean age (58years) and age range (28–75) were similar in the plerixafor and placebo groups, and 81% of subjects were Caucasian.
- In Study 1, 59% of NHL patients who were mobilized with plerixafor and G-CSF collected ≥ 5 × 106 CD34+ cells/kg from the peripheral blood in four or fewer apheresis sessions, compared with 20% of patients who were mobilized with placebo and G-CSF (p < 0.001). Other CD34+ cell mobilization outcomes showed similar findings (Table 4).
- The median number of days to reach ≥ 5 × 106 CD34+ cells/kg was 3 days for the plerixafor group and not evaluable for the placebo group. Table 5 presents the proportion of patients who achieved ≥ 5 × 106 CD34+ cells/kg by apheresis day.
- In Study 2, 72% of MM patients who were mobilized with plerixafor and G-CSF collected ≥ 6 × 106 CD34+ cells/kg from the peripheral blood in two or fewer apheresis sessions, compared with 34% of patients who were mobilized with placebo and G-CSF (p < 0.001). OtherCD34+ cell mobilization outcomes showed similar findings (Table 6).
- The median number of days to reach ≥ 6 × 106 CD34+ cells/kg was 1 day for the plerixafor group and 4 days for the placebo group. Table 7 presents the proportion of patients who achieved ≥ 6 × 106 CD34+ cells/kg by apheresis day.
- Multiple factors can influence time to engraftment and graft durability following stem cell transplantation. For transplanted patients in the Phase 3 studies, time to neutrophil and platelet engraftment and graft durability were similar across the treatment groups.
# How Supplied
- Single-use vial containing 1.2 mL of a 20 mg/mL solution
## Storage
Store at 25°C (77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients of the potential for anaphylactic reactions, including signs and symptoms such as urticaria, periorbital swelling, dyspnea, or hypoxia during and following plerixafor injection and to report these symptoms immediately to a health care professional.
- Advise patients to inform a health care professional immediately if symptoms of vasovagal reactions such as orthostatic hypotension or syncope occur during or shortly after their plerixafor injection.
- Advise patients who experience itching, rash, or reaction at the site of injection to notify a health care professional, as these symptoms have been treated with over-the-counter medications during clinical trials.
- Advise patients that plerixafor may cause gastrointestinal disorders, including diarrhea, nausea, vomiting, flatulence, and abdominal pain. Patients should be told how to manage specific gastrointestinal disorders and to inform their health care professional if severe events occur following plerixafor injection.
- Advise female patients with reproductive potential to use effective contraceptive methods during plerixafor use.
# Precautions with Alcohol
Alcohol-Plerixafor interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Mozobil
# Look-Alike Drug Names
There is limited information regarding Plerixafor Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Plerixafor
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2];Aparna Vuppala, M.B.B.S. [3]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Plerixafor is an hematopoietic that is FDA approved for the treatment of non-Hodgkin's lymphoma and multiple myeloma. Common adverse reactions include diarrhea, nausea, fatigue, injection site reactions, headache, arthralgia, dizziness, and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Plerixafor is indicated in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells (HSCs) to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM).
- Dosage: 0.24 mg/kg body weight by subcutaneous (SC) injection
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Plerixafor in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Plerixafor in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy not established in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Plerixafor in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Plerixafor in pediatric patients.
# Contraindications
History of hypersensitivity to plerixafor. Anaphylactic shock has occurred with use of plerixafor.
# Warnings
- Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening with clinically significant hypotension and shock have occurred in patients receiving plerixafor. Observe patients for signs and symptoms of hypersensitivity during and after plerixafor administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer plerixafor when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions.
- In clinical studies, mild or moderate allergic reactions occurred within approximately 30 minutes after plerixafor administration in less than 1% of patients.
- For the purpose of HSC mobilization, plerixafor may cause mobilization of leukemic cells and subsequent contamination of the apheresis product. Therefore, plerixafor is not intended for HSC mobilization and harvest in patients with leukemia.
- Administration of plerixafor in conjunction with G-CSF increases circulating leukocytes as well as HSC populations. Monitor white blood cell counts during plerixafor use.
- Thrombocytopenia has been observed in patients receiving plerixafor. Monitor platelet counts in all patients who receive plerixafor and then undergo apheresis.
- When plerixafor is used in combination with G-CSF for HSC mobilization‚ tumor cells may be released from the marrow and subsequently collected in the leukapheresis product. The effect of potential reinfusion of tumor cells has not been well-studied.
- Higher absolute and relative spleen weights associated with extramedullary hematopoiesis were observed following prolonged (2 to 4 weeks) daily plerixafor SC administration in rats at doses approximately 4-fold higher than the recommended human dose based on body surface area. The effect of plerixafor on spleen size in patients was not specifically evaluated in clinical studies. Evaluate individuals receiving plerixafor in combination with G-CSF who report left upper abdominal pain and/or scapular or shoulder pain for splenic integrity.
- plerixafor may cause fetal harm when administered to a pregnant woman. Plerixafor is teratogenic in animals. There are no adequate and well-controlled studies in pregnant women using plerixafor. Advise women of childbearing potential to avoid becoming pregnant while receiving treatment with plerixafor. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
# 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 common adverse reactions (≥ 10%) reported in patients who received plerixafor in conjunction with G-CSF regardless of causality and more frequent with plerixafor than placebo during HSC mobilization and apheresis were diarrhea, nausea, fatigue, injection site reactions, headache, arthralgia, dizziness, and vomiting.
- Safety data for plerixafor in combination with G-CSF were obtained from two randomized placebo-controlled studies (301 patients) and 10 uncontrolled studies (242 patients). Patients were primarily treated with plerixafor at daily doses of 0.24 mg/kg SC. Median exposure to plerixafor in these studies was 2 days (range 1 to 7 days).
- In the two randomized studies in patients with NHL and MM, a total of 301 patients were treated in the plerixafor and G-CSF group and 292 patients were treated in the placebo and G-CSF group. Patients received daily morning doses of G-CSF 10 micrograms/kg for 4 days prior to the first dose of plerixafor 0.24 mg/kg SC or placebo and on each morning prior to apheresis. The adverse reactions that occurred in ≥ 5% of the patients who received plerixafor regardless of causality and were more frequent with plerixafor than placebo during HSC mobilization and apheresis are shown in Table 2.
- In the randomized studies, 34% of patients with NHL or MM had mild to moderate injection site reactions at the site of subcutaneous administration of plerixafor. These included erythema, hematoma, hemorrhage, induration, inflammation, irritation, pain, paresthesia, pruritus, rash, swelling, and urticaria.
- Mild to moderate allergic reactions were observed in less than 1% of patients within approximately 30 min after plerixafor administration, including one or more of the following: urticaria (n = 2), periorbital swelling (n = 2), dyspnea (n = 1) or hypoxia (n = 1). Symptoms generally responded to treatments (e.g., antihistamines, corticosteroids, hydration or supplemental oxygen) or resolved spontaneously.
- Vasovagal reactions, orthostatic hypotension, and/or syncope can occur following subcutaneous injections. In plerixafor oncology and healthy volunteer clinical studies, less than 1% of subjects experienced vasovagal reactions following subcutaneous administration of plerixafor doses ≤ 0.24 mg/kg. The majority of these events occurred within 1 hour of plerixafor administration. Because of the potential for these reactions, appropriate precautions should be taken.
- Other adverse reactions in the randomized studies that occurred in < 5% of patients but were reported as related to plerixafor during HSC mobilization and apheresis included abdominal pain, hyperhidrosis, abdominal distention, dry mouth, erythema, stomach discomfort, malaise, hypoesthesia oral, constipation, dyspepsia, and musculoskeletal pain.
- Hyperleukocytosis: In clinical trials, white blood cell counts of 100,000/mcL or greater were observed, on the day prior to or any day of apheresis, in 7% of patients receiving plerixafor and in 1% of patients receiving placebo. No complications or clinical symptoms of leukostasis were observed.
## Postmarketing Experience
In addition to adverse reactions reported from clinical trials, the following adverse reactions have been reported from post-marketing experience with plerixafor. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Immune System Disorders: Anaphylactic reactions, including anaphylactic shock
- Psychiatric disorders: Abnormal dreams and nightmares
# Drug Interactions
Based on in vitro data, plerixafor is not a substrate, inhibitor or inducer of human cytochrome P450 isozymes. Plerixafor is not likely to be implicated in in vivo drug-drug interactions involving cytochrome P450s. At concentrations similar to what are seen clinically, plerixafor did not act as a substrate or inhibitor of P-glycoprotein in an in vitro study.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Plerixafor may cause fetal harm when administered to a pregnant woman. Plerixafor is teratogenic in animals.
- Plerixafor administered to pregnant rats induced embryo-fetal toxicities including fetal death, increased resorptions and post-implantation loss, decreased fetal weights, anophthalmia, shortened digits, cardiac interventricular septal defect, ringed aorta, globular heart, hydrocephaly, dilatation of olfactory ventricles, and retarded skeletal development. Embryo-fetal toxicities occurred mainly at a dose of 90 mg/m2 (approximately 10 times the recommended human dose of 0.24 mg/kg when compared on a mg/m2 basis or 10 times the AUC in subjects with normal renal function who received a single dose of 0.24 mg/kg).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Plerixafor in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Plerixafor during labor and delivery.
### Nursing Mothers
- It is not known whether plerixafor is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from plerixafor, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and efficacy of plerixafor in pediatric patients have not been established in controlled clinical studies.
### Geriatic Use
- Of the total number of subjects in controlled clinical studies of plerixafor, 24% were 65 and over, while 0.8% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
- Since plerixafor is mainly excreted by the kidney, no dose modifications are necessary in elderly individuals with normal renal function. In general, care should be taken in dose selection for elderly patients due to the greater frequency of decreased renal function with advanced age. Dosage adjustment in elderly patients with CLCR ≤ 50 mL/min is recommended.
### Gender
- Clinical data show no effect of gender on plerixafor pharmacokinetics.
### Race
- Clinical data show similar plerixafor pharmacokinetics for Caucasians and African-Americans, and the effect of other racial/ethnic groups has not been studied.
### Renal Impairment
- In patients with moderate and severe renal impairment (CLCR ≤ 50 mL/min), reduce the dose of plerixafor by one-third to 0.16 mg/kg.
### Hepatic Impairment
There is no FDA guidance on the use of Plerixafor in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- The effect of plerixafor on human fertility is unknown. The effect of plerixafor on male or female fertility was not studied in designated reproductive toxicology studies. The staging of spermatogenesis measured in a 28-day repeated dose toxicity study in rats revealed no abnormalities considered to be related to plerixafor. No histopathological evidence of toxicity to male or female reproductive organs was observed in 28-day repeated dose toxicity studies.
### Immunocompromised Patients
There is no FDA guidance one the use of Plerixafor in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Subcutaneous
### Monitoring
There is limited information regarding Plerixafor Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Plerixafor and IV administrations.
# Overdosage
- Based on limited data at doses above the recommended dose of 0.24 mg/kg SC, the frequency of gastrointestinal disorders, vasovagal reactions, orthostatic hypotension, and/or syncope may be higher.
# Pharmacology
## Mechanism of Action
- Plerixafor is an inhibitor of the CXCR4 chemokine receptor and blocks binding of its cognate ligand, stromal cell-derived factor-1α (SDF-1α). SDF-1α and CXCR4 are recognized to play a role in the trafficking and homing of human hematopoietic stem cells (HSCs) to the marrow compartment. Once in the marrow, stem cell CXCR4 can act to help anchor these cells to the marrow matrix, either directly via SDF-1α or through the induction of other adhesion molecules. Treatment with plerixafor resulted in leukocytosis and elevations in circulating hematopoietic progenitor cells in mice, dogs and humans. CD34+ cells mobilized by plerixafor were capable of engraftment with long-term repopulating capacity up to one year in canine transplantation models.
## Structure
The structural formula is:
## Pharmacodynamics
- Data on the fold increase in peripheral blood CD34+ cell count (cells/mcL) by apheresis day were evaluated in two placebo-controlled clinical studies in patients with NHL and MM (Study 1 and Study 2, respectively). The fold increase in CD34+ cell count (cells/mcL) over the 24-hour period starting from the day prior to the first apheresis and ending the next morning just before the first apheresis is summarized in Table 3. During this 24-hour period, a single dose of plerixafor or placebo was administered 10 to 11 hours prior to apheresis.
- In pharmacodynamic studies of plerixafor in healthy volunteers, peak mobilization of CD34+ cells was observed between 6 and 9 hours after administration. *In pharmacodynamic studies of plerixafor in conjunction with G-CSF in healthy volunteers, a sustained elevation in the peripheral blood CD34+ count was observed from 4 to 18 hours after plerixafor administration with a peak CD34+ count between 10 and 14 hours.
- There is no indication of a QT/QTc prolonging effect of plerixafor in single doses up to 0.40 mg/kg. In a randomized, double-blind, crossover study, 48 healthy subjects were administered a single subcutaneous dose of plerixafor (0.24 mg/kg and 0.40 mg/kg) and placebo. Peak concentrations for 0.40 mg/kg plerixafor were approximately 1.8-fold higher than the peak concentrations following the 0.24 mg/kg single subcutaneous dose.
## Pharmacokinetics
The single-dose pharmacokinetics of plerixafor 0.24 mg/kg were evaluated in patients with NHL and MM following pre-treatment with G-CSF (10 micrograms/kg once daily for 4 consecutive days). Plerixafor exhibits linear kinetics between the 0.04 mg/kg to 0.24 mg/kg dose range. The pharmacokinetics of plerixafor were similar across clinical studies in healthy subjects who received plerixafor alone and NHL and MM patients who received plerixafor in combination with G-CSF.
- A population pharmacokinetic analysis incorporated plerixafor data from 63 subjects (NHL patients, MM patients, subjects with varying degrees of renal impairment, and healthy subjects) who received a single SC dose (0.04 mg/kg to 0.24 mg/kg) of plerixafor. A two-compartment disposition model with first order absorption and elimination was found to adequately describe the plerixafor concentration-time profile. Significant relationships between clearance and creatinine clearance (CLCR), as well as between central volume of distribution and body weight were observed. The distribution half-life (t1/2α) was estimated to be 0.3 hours and the terminal population half-life (t1/2β) was 5.3 hours in patients with normal renal function.
- The population pharmacokinetic analysis showed that the mg/kg-based dosage results in an increased plerixafor exposure (AUC0–24h) with increasing body weight. There is limited experience with the 0.24 mg/kg dose of plerixafor in patients weighing above 160 kg. Therefore the dose should not exceed that of a 160 kg patient (i.e., 40 mg/day if CLCR is > 50 mL/min and 27 mg/day if CLCR is ≤ 50 mL/min).
- Peak plasma concentrations occurred at approximately 30 – 60 minutes after a SC dose.
- Plerixafor is bound to human plasma proteins up to 58%. The apparent volume of distribution of plerixafor in humans is 0.3 L/kg demonstrating that plerixafor is largely confined to, but not limited to, the extravascular fluid space.
- The metabolism of plerixafor was evaluated with in vitro assays. Plerixafor is not metabolized as shown in assays using human liver microsomes or human primary hepatocytes and does not exhibit inhibitory activity in vitro towards the major drug metabolizing cytochrome P450 enzymes (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4/5). In in vitro studies with human hepatocytes, plerixafor does not induce CYP1A2, CYP2B6, or CYP3A4 enzymes. These findings suggest that plerixafor has a low potential for involvement in cytochrome P450-dependent drug-drug interactions.
- The major route of elimination of plerixafor is urinary. Following a 0.24 mg/kg dose in healthy volunteers with normal renal function, approximately 70% of the dose was excreted in the urine as the parent drug during the first 24 hours following administration. In studies with healthy subjects and patients, the terminal half-life in plasma ranges between 3 and 5 hours. At concentrations similar to what are seen clinically, plerixafor did not act as a substrate or inhibitor of P-glycoprotein in an in vitro study with MDCKII and MDCKII-MDR1 cell models.
## Nonclinical Toxicology
- Carcinogenicity studies with plerixafor have not been conducted.
- Plerixafor was not genotoxic in an in vitro bacterial mutation assay (Ames test in Salmonella), an in vitro chromosomal aberration test using V79 Chinese hamster cells, or an in vivo bone marrow micronucleus test in rats after subcutaneous doses up to 25 mg/kg (150 mg/m2).
# Clinical Studies
The efficacy and safety of plerixafor in conjunction with G-CSF in non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM) were evaluated in two placebo-controlled studies (Studies 1 and 2). Patients were randomized to receive either plerixafor 0.24 mg/kg or placebo on each evening prior to apheresis. Patients received daily morning doses of G-CSF 10 micrograms/kg for 4 days prior to the first dose of plerixafor or placebo and on each morning prior to apheresis. Two hundred and ninety-eight (298) NHL patients were included in the primary efficacy analyses for Study 1. The mean age was 55 years (range 29–75) and 58 years (range 22–75) in the plerixafor and placebo groups, respectively, and 93% of subjects were Caucasian. In study 2, 302 patients with MM were included in the primary efficacy analyses. The mean age (58years) and age range (28–75) were similar in the plerixafor and placebo groups, and 81% of subjects were Caucasian.
- In Study 1, 59% of NHL patients who were mobilized with plerixafor and G-CSF collected ≥ 5 × 106 CD34+ cells/kg from the peripheral blood in four or fewer apheresis sessions, compared with 20% of patients who were mobilized with placebo and G-CSF (p < 0.001). Other CD34+ cell mobilization outcomes showed similar findings (Table 4).
- The median number of days to reach ≥ 5 × 106 CD34+ cells/kg was 3 days for the plerixafor group and not evaluable for the placebo group. Table 5 presents the proportion of patients who achieved ≥ 5 × 106 CD34+ cells/kg by apheresis day.
- In Study 2, 72% of MM patients who were mobilized with plerixafor and G-CSF collected ≥ 6 × 106 CD34+ cells/kg from the peripheral blood in two or fewer apheresis sessions, compared with 34% of patients who were mobilized with placebo and G-CSF (p < 0.001). OtherCD34+ cell mobilization outcomes showed similar findings (Table 6).
- The median number of days to reach ≥ 6 × 106 CD34+ cells/kg was 1 day for the plerixafor group and 4 days for the placebo group. Table 7 presents the proportion of patients who achieved ≥ 6 × 106 CD34+ cells/kg by apheresis day.
- Multiple factors can influence time to engraftment and graft durability following stem cell transplantation. For transplanted patients in the Phase 3 studies, time to neutrophil and platelet engraftment and graft durability were similar across the treatment groups.
# How Supplied
- Single-use vial containing 1.2 mL of a 20 mg/mL solution
## Storage
Store at 25°C (77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients of the potential for anaphylactic reactions, including signs and symptoms such as urticaria, periorbital swelling, dyspnea, or hypoxia during and following plerixafor injection and to report these symptoms immediately to a health care professional.
- Advise patients to inform a health care professional immediately if symptoms of vasovagal reactions such as orthostatic hypotension or syncope occur during or shortly after their plerixafor injection.
- Advise patients who experience itching, rash, or reaction at the site of injection to notify a health care professional, as these symptoms have been treated with over-the-counter medications during clinical trials.
- Advise patients that plerixafor may cause gastrointestinal disorders, including diarrhea, nausea, vomiting, flatulence, and abdominal pain. Patients should be told how to manage specific gastrointestinal disorders and to inform their health care professional if severe events occur following plerixafor injection.
- Advise female patients with reproductive potential to use effective contraceptive methods during plerixafor use.
# Precautions with Alcohol
Alcohol-Plerixafor interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Mozobil [1]
# Look-Alike Drug Names
There is limited information regarding Plerixafor Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Mozobil | |
d1d965964f4d22030bf4f58a0e450c4085305214 | wikidoc | Sialidosis | Sialidosis
Mucolipidosis type I (ML I) or sialidosis results from a deficiency in one of the digestive enzymes known as sialidase. The role of sialidase is to remove a particular form of sialic acid (a sugar-like molecule) from sugar-protein complexes (referred to as glycoproteins), which allows the cell to function properly. Because the enzyme is deficient, small chains containing the sugar-like material accumulate in neurons, bone marrow, and various cells that defend the body against infection.
Symptoms of ML I are either present at birth or develop within the first year of life. In many infants with ML I, excessive swelling throughout the body is noted at birth. These infants are often born with coarse facial features, such as a flat nasal bridge, puffy eyelids, enlargement of the gums, and excessive tongue size (macroglossia). Many infants with ML I are also born with skeletal malformations such as hip dislocation. Infants often develop sudden involuntary muscle contractions (called myoclonus) and have red spots in their eyes (called cherry-red macules). They are often unable to coordinate voluntary movement (called ataxia). Tremors, impaired vision, and seizures also occur in children with ML I. Tests reveal abnormal enlargement of the liver and spleen and extreme abdominal swelling. Infants with ML I generally lack muscle tone (hypotonia) and have mental retardation that is either initially or progressively severe. Many patients suffer from failure to thrive and from recurrent respiratory infections. Most infants with ML I die before the age of 1 year.
Other diseases that result from a deficiency in the sialidase enzyme are categorized in a broader group known as sialidoses. Because ML I is classified as a sialidosis, it is sometimes referred to as sialidosis type II.
A rarer form of sialidosis – sialidosis type 1– occurs in children and adolescents and is often referred to as the juvenile form of the disorder. Children usually begin to show symptoms during the second decade of life, and myoclonus and cherry-red macules are often the initial symptoms. Patients usually develop seizures and progressive deterioration of coordinated muscular and mental activities. | Sialidosis
Mucolipidosis type I (ML I) or sialidosis results from a deficiency in one of the digestive enzymes known as sialidase. The role of sialidase is to remove a particular form of sialic acid (a sugar-like molecule) from sugar-protein complexes (referred to as glycoproteins), which allows the cell to function properly. Because the enzyme is deficient, small chains containing the sugar-like material accumulate in neurons, bone marrow, and various cells that defend the body against infection.
Symptoms of ML I are either present at birth or develop within the first year of life. In many infants with ML I, excessive swelling throughout the body is noted at birth. These infants are often born with coarse facial features, such as a flat nasal bridge, puffy eyelids, enlargement of the gums, and excessive tongue size (macroglossia). Many infants with ML I are also born with skeletal malformations such as hip dislocation. Infants often develop sudden involuntary muscle contractions (called myoclonus) and have red spots in their eyes (called cherry-red macules). They are often unable to coordinate voluntary movement (called ataxia). Tremors, impaired vision, and seizures also occur in children with ML I. Tests reveal abnormal enlargement of the liver and spleen and extreme abdominal swelling. Infants with ML I generally lack muscle tone (hypotonia) and have mental retardation that is either initially or progressively severe. Many patients suffer from failure to thrive and from recurrent respiratory infections. Most infants with ML I die before the age of 1 year.
Other diseases that result from a deficiency in the sialidase enzyme are categorized in a broader group known as sialidoses. Because ML I is classified as a sialidosis, it is sometimes referred to as sialidosis type II.
A rarer form of sialidosis – sialidosis type 1– occurs in children and adolescents and is often referred to as the juvenile form of the disorder. Children usually begin to show symptoms during the second decade of life, and myoclonus and cherry-red macules are often the initial symptoms. Patients usually develop seizures and progressive deterioration of coordinated muscular and mental activities. | https://www.wikidoc.org/index.php/Mucolipidosis_I | |
ba3e8d657cb6fe407617d387a727fb7eb66bc622 | wikidoc | Multimeter | Multimeter
A multimeter or a multitester, also known as a volt/ohm meter or VOM, is an electronic measuring instrument that combines several functions in one unit. A standard multimeter may include features such as the ability to measure voltage, current and resistance. There are two categories of multimeters, analog multimeters (or analogue multimeters in British English) and digital multimeters (often abbreviated DMM.)
A multimeter can be a hand-held device useful for basic fault finding and field service work or a bench instrument which can measure to a very high degree of accuracy. They can be used to troubleshoot electrical problems in a wide array of industrial and household devices such as batteries, motor controls, appliances, power supplies, and wiring systems.
Multimeters are available in a wide ranges of features and prices. Cheap multimeters can cost less than US$10, while the top of the line multimeters can cost more than US$5000.
# Quantities measured
Contemporary multimeters can measure many quantities. The common ones are:
- Voltage in volts.
- Current in amperes.
- Resistance in ohms.
Additionally, multimeters may also measure:
- Capacitance in farads.
- Frequency in hertz
- Duty cycle as a percentage.
- Temperature in degrees Celsius or Fahrenheit.
- Conductance in siemens.
- Inductance in henrys
- Audio signal levels in decibels.
Digital multimeters may also include circuits for:
- Continuity that beeps when a circuit conducts.
- Diodes and Transistors
Various sensors can be attached to multimeters to take measurements such as:
- light level
- Acidity/Alkalinity(pH)
- Wind speed
- Relative humidity
# Resolution
## Digital
The resolution of a multimeter is often specified in "digits" of resolution. For example, the term 5½ digits refers to the number of digits displayed on the readout of a multimeter.
By convention, a half digit can display either a zero or a one, while a three-quarters digit can display a numeral higher than a one but not nine. Commonly, a three-quarters digit refers to a maximum count of 3 or 5. The fractional digit is always the most significant digit in the displayed value. A 5½ digit multimeter would have five full digits that display values from 0 to 9 and one half digit that could only display 0 or 1. Such a meter could show positive or negative values from 0 to 199,999. A 3¾ digit meter can display a quantity from 0 to 3,999 or 5,999, depending on the manufacturer.
While a digital display can easily be extended in precision, the extra digits are of no value if not accompanied by care in the design and calibration of the analog portions of the multimeter. Meaningful high-resolution measurements require a good understanding of the instrument specifications, good control of the measurement conditions, and traceability of the calibration of the instrument.
## Analogue
Resolution of analog multimeters is limited by the width of the scale pointer, vibration of the pointer, the accuracy of printing of scales, zero calibration, number of ranges, and errors due to non-horizontal use of the mechanical display. Accuracy of readings obtained are also often compromised by miscounting division markings, errors in mental arithmetic, parallax observation errors, and less than perfect eyesight.
Resistance measurements, in particular, are of low precision due to the typical resistance measurement circuit which compresses the scale heavily at the higher resistance values. Mirrored scales and larger meter movements are used to improve resolution; two and a half to three digits equivalent resolution is usual (and may be adequate for the limited precision actually necessary for most measurements).
# Accuracy
Digital multimeters generally take measurements with accuracy superior to their analog counterparts. Analog multimeters typically measure with three to five percent accuracy. Standard portable digital multimeters claim to be capable of taking measurements with an accuracy of 0.5% on DC voltage and current scales. Mainstream bench-top multimeters make claims to have as great accuracy as ±0.01%. Laboratory grade instruments can have accuracies in the parts per million figures.
Manufacturers can provide calibration services so that new meters may be purchased with a certificate of calibration indicating the meter has been adjusted to standards traceable to the National Institute of Standards and Technology. Such manufacturers usually provide calibration services after sales, as well, so that older equipment may be recertified. Multimeters used for critical measurements may be part of a metrology program to assure calibration.
# Sensitivity and input impedance
The current load, or how much current is drawn from the circuit being tested may affect a multimeter's accuracy. A small current draw usually will result in more precise measurements. With improper usage or too much current load, a multimeter may be damaged therefore rendering its measurements unreliable and substandard.
Meters with electronic amplifiers in them, such as all digital multimeters and analog meters using a transistor for amplification, have an input impedance that is usually considered high enough not to disturb the circuit tested. This is often one million ohms, or ten million ohms. The standard input impedance allows use of external probes to extend the direct-current measuring range up to tens of thousands of volts.
Most analog multimeters of the moving pointer type are unbuffered, and draw current from the circuit under test to deflect the meter pointer. The impedance of the meter varies depending on the basic sensitivity of the meter movement and the range which is selected. For example, a meter with a typical 20,000 ohms/volt sensitivity will have an input resistance of two million ohms on the 100 volt range (100 V - 20,000 ohms/volt = 2,000,000 ohms). Lower sensitivity meters are useful for general purpose testing especially in power circuits, where source impedances are low compared to the meter impedance. Some measurements in signal circuits require higher sensitivity so as not to load down the circuit under test with the meter impedance.
The sensitivity of a meter is also a measure of the lowest voltage, current or resistance that can be measured with it. For general-purpose digital multimeters, a full-scale range of several hundred millivolts AC or DC is common, but the minimum full-scale current range may be several hundred milliamps. Since general-purpose mulitmeters have only two-wire resistance measurements, which do not compensate for the effect of the lead wire resistance, measurements below a few tens of ohms will be of low accuracy. The upper end of multimeter measurement ranges varies considerably by manufacturer; generally measurements over 1000 volts, over 10 amperes, or over 100 megohms would require a specialized test instrument, as would accurate measurement of currents on the order of 1 microamp or less.
# Alternating current sensing
Since the basic indicator system in either an analog or digital meter responds to DC only, a multimeter includes an AC to DC conversion circuit for making alternating current measurements. Basic multimeters may utilize a rectifier circuit, calibrated to evaluate the average value of a rectified sine wave. User guides for such meters will give correction factors for some simple waveforms, to allow the correct root mean square (RMS) equivalent value to be calculated for the average-responding meter. More expensive multimeters will include an AC to DC converter that responds to the RMS value of the waveform for a wide range of possible waveforms; the user manual for the meter will indicate the limits of the crest factor and frequency for which the meter calibration is valid. RMS sensing is necessary for measurement s of non-sinusoidal quantities, such as found in audio signals, or in variable-frequency drives.
# Digital Multimeters (DMM)
Modern multimeters are often digital due their accuracy, durability and extra features.
In a DMM the signal under test is converted to a voltage and an amplifier with an electronically controlled gain preconditions the signal.
A DMM displays the quantity measured as a number, which prevents parallax errors.
The inclusion of solid state electronics, from a control circuit to small embedded computers, has provided a wealth of convenience features in modern digital meters. Commonly available measurement enhancements include:
- Auto-ranging, which selects the correct range for the quantity under test so that the most significant digits are shown. For example, a four-digit multimeter would automatically select an appropriate range to display 1.234 instead of 0.012, or overloading. Auto-ranging meters usually include a facility to 'freeze' the meter to a particular range, because a measurement that causes frequent range changes is distracting to the user.
- Auto-polarity for direct-current readings, shows if the applied voltage is positive (agrees with meter lead labels) or negative (opposite polarity to meter leads).
- Sample and hold, which will latch the most recent reading for examination after the instrument is removed from the circuit under test.
- Current-limited tests for voltage drop across semiconductor junctions. While not a replacement for a transistor tester, this facilitates testing diodes and a variety of transistor types.
- A graphic representation of the quantity under test, as a bar graph. This makes go/no-go testing easy, and also allows spotting of fast-moving trends.
- A low-bandwidth oscilloscope.
- Automotive circuit testers, including tests for automotive timing and dwell signals.
- Simple data acquisition features to record maximum and minimum readings over a given period, or to take a number of samples at fixed intervals.
- A miniature digital multimeter integrated with tweezers for Surface-mount technology.
Modern meters may be interfaced with a personal computer by IrDA links, RS-232 connections, USB, or an instrument bus such as IEEE-488. The interface allows the computer to record measurements as they are made. Some DMM's can store measurements and upload them to a computer.
The first digital multimeter was manufactured in 1955 by Non Linear Systems.
# Analog Multimeters
A multimeter may be implemented with an analog meter deflected by an electromagnet, as a classic galvanometer,
-r with a digital display such as an LCD or vacuum fluorescent display.
Analog multimeters are not hard to find (though less common and often more expensive than low-end digital units), but are not considered as accurate as digital because of errors introduced in zeroing and reading the analog meter face.
Analog meters may be implemented with vacuum tubes to precondition and amplify the input signal. Such meters are known as vacuum tube volt meters (VTVM) or vacuum tube multimeters (VTMM).
Analog meters are sometimes considered better for detecting the rate of change of a reading; the ARRL handbook suggests that analog multimeters are often less susceptible to radio frequency interference.
The meter movement in a moving pointer analog multimeter is practically always a moving-coil galvanometer of the d'Arsonval type, using either jeweled pivots or taut bands to support the moving coil. In a basic analog multimeter the current to deflect the coil and pointer is drawn from the circuit being measured; it is usually an advantage to minimize the current drawn from the circuit. The sensitivity of an analog multimeter is given in units of ohms per volt. For example, an inexpensive multimeter would have a sensitivity of 1000 ohms per volt and would draw 1 milliampere from a circuit at the full scale measured voltage. More expensive, (and more delicate) multimeters would have sensitivities of 20,000 ohms per volt or higher, with a 50,000 ohms per volt meter (drawing 20 microamperes at full scale) being about the upper limit for a portable general purpose analog multimeter.
To avoid the loading of the measured circuit by the current drawn by the meter movement, later analog multimeters use an amplifier inserted between the measured circuit and the meter movement. While this increased the expense and complexity of the meter and required a power supply to operate the amplifier, by use of vacuum tubes or field effect transistors the input resistance can be made very high and independent of the current required to operate the meter movement coil. Such amplified multimeters are called VTVM (vacuum tube voltmeters) or TVM (transistor volt meter), and similar names.
# Probes
A multimeter can utilise a variety of test probes to connect to the circuit or device under test. Crocodile clips, retractable hook clips, and pointed probes are the three most common attachments. The connectors are attached to flexible, thickly-insulated leads that are terminated with connectors appropriate for the meter. Handheld meters typically use shrouded or recessed banana jacks, while benchtop meters may use banana jacks or BNC connectors. 2mm plugs and binding posts have also been used at times, but are not so common today.
Meters which measure high voltages or current may use non-contact attachment mechanism to trade accuracy for safety. Clamp meters provide a coil that clamps around a conductor in order to measure the current flowing through it.
# Safety
Some multimeters include a fuse, which will sometimes prevent damage to the multimeter if it is overloaded. However the fuse often only protects the highest current range on the multimeter. A common error when operating a multimeter is to set the meter to measure resistance or current and then connect it directly to a low-impedance voltage source; meters without protection are quickly damaged by such errors, and can sometimes explode causing injury to the operator.
Digital meters are category rated based on their intended application, as set forth by the CEN EN61010 standard.
There are four categories:
- Category I: used where current levels are low.
- Category II: used on residential branch circuits.
- Category III: used on permanently installed loads such as distribution panels, motors, and appliance outlets.
- Category IV: used on locations where current levels are high, such as service entrances, main panels, and house meters.
Each category also specifies maximum transient voltages for selected measuring ranges in the meter.
Category-rated meters also feature protections from over-current faults.
# History
Multimeters were invented in the early 1920s as radio receivers and other vacuum tube electronic devices became more common. As modern systems become more complicated, the multimeter is becoming more complex or may be supplemented by more specialized equipment in a technician's toolkit. For example, where a general-purpose multimeter might only test for short-circuits, conductor resistance and some coarse measure of insulation quality, a modern technician may use a hand-held analyzer to test several parameters in order to validate the performance of a network cable. | Multimeter
A multimeter or a multitester, also known as a volt/ohm meter or VOM, is an electronic measuring instrument that combines several functions in one unit. A standard multimeter may include features such as the ability to measure voltage, current and resistance. There are two categories of multimeters, analog multimeters (or analogue multimeters in British English) and digital multimeters (often abbreviated DMM.)
A multimeter can be a hand-held device useful for basic fault finding and field service work or a bench instrument which can measure to a very high degree of accuracy. They can be used to troubleshoot electrical problems in a wide array of industrial and household devices such as batteries, motor controls, appliances, power supplies, and wiring systems.
Multimeters are available in a wide ranges of features and prices. Cheap multimeters can cost less than US$10, while the top of the line multimeters can cost more than US$5000.
# Quantities measured
Contemporary multimeters can measure many quantities. The common ones are:
- Voltage in volts.
- Current in amperes.
- Resistance in ohms.
Additionally, multimeters may also measure:
- Capacitance in farads.
- Frequency in hertz
- Duty cycle as a percentage.
- Temperature in degrees Celsius or Fahrenheit.
- Conductance in siemens.
- Inductance in henrys
- Audio signal levels in decibels.
Digital multimeters may also include circuits for:
- Continuity that beeps when a circuit conducts.
- Diodes and Transistors
Various sensors can be attached to multimeters to take measurements such as:
- light level
- Acidity/Alkalinity(pH)
- Wind speed
- Relative humidity
# Resolution
## Digital
The resolution of a multimeter is often specified in "digits" of resolution. For example, the term 5½ digits refers to the number of digits displayed on the readout of a multimeter.
By convention, a half digit can display either a zero or a one, while a three-quarters digit can display a numeral higher than a one but not nine. Commonly, a three-quarters digit refers to a maximum count of 3 or 5. The fractional digit is always the most significant digit in the displayed value. A 5½ digit multimeter would have five full digits that display values from 0 to 9 and one half digit that could only display 0 or 1.[1] Such a meter could show positive or negative values from 0 to 199,999. A 3¾ digit meter can display a quantity from 0 to 3,999 or 5,999, depending on the manufacturer.
While a digital display can easily be extended in precision, the extra digits are of no value if not accompanied by care in the design and calibration of the analog portions of the multimeter. Meaningful high-resolution measurements require a good understanding of the instrument specifications, good control of the measurement conditions, and traceability of the calibration of the instrument.
## Analogue
Resolution of analog multimeters is limited by the width of the scale pointer, vibration of the pointer, the accuracy of printing of scales, zero calibration, number of ranges, and errors due to non-horizontal use of the mechanical display. Accuracy of readings obtained are also often compromised by miscounting division markings, errors in mental arithmetic, parallax observation errors, and less than perfect eyesight.
Resistance measurements, in particular, are of low precision due to the typical resistance measurement circuit which compresses the scale heavily at the higher resistance values. Mirrored scales and larger meter movements are used to improve resolution; two and a half to three digits equivalent resolution is usual (and may be adequate for the limited precision actually necessary for most measurements).
# Accuracy
Digital multimeters generally take measurements with accuracy superior to their analog counterparts. Analog multimeters typically measure with three to five percent accuracy.[citation needed] Standard portable digital multimeters claim to be capable of taking measurements with an accuracy of 0.5% on DC voltage and current scales. Mainstream bench-top multimeters make claims to have as great accuracy as ±0.01%. Laboratory grade instruments can have accuracies in the parts per million figures.[2]
Manufacturers can provide calibration services so that new meters may be purchased with a certificate of calibration indicating the meter has been adjusted to standards traceable to the National Institute of Standards and Technology. Such manufacturers usually provide calibration services after sales, as well, so that older equipment may be recertified. Multimeters used for critical measurements may be part of a metrology program to assure calibration.
# Sensitivity and input impedance
The current load, or how much current is drawn from the circuit being tested may affect a multimeter's accuracy. A small current draw usually will result in more precise measurements. With improper usage or too much current load, a multimeter may be damaged therefore rendering its measurements unreliable and substandard.
Meters with electronic amplifiers in them, such as all digital multimeters and analog meters using a transistor for amplification, have an input impedance that is usually considered high enough not to disturb the circuit tested. This is often one million ohms, or ten million ohms. The standard input impedance allows use of external probes to extend the direct-current measuring range up to tens of thousands of volts.
Most analog multimeters of the moving pointer type are unbuffered, and draw current from the circuit under test to deflect the meter pointer. The impedance of the meter varies depending on the basic sensitivity of the meter movement and the range which is selected. For example, a meter with a typical 20,000 ohms/volt sensitivity will have an input resistance of two million ohms on the 100 volt range (100 V * 20,000 ohms/volt = 2,000,000 ohms). Lower sensitivity meters are useful for general purpose testing especially in power circuits, where source impedances are low compared to the meter impedance. Some measurements in signal circuits require higher sensitivity so as not to load down the circuit under test with the meter impedance.[3]
The sensitivity of a meter is also a measure of the lowest voltage, current or resistance that can be measured with it. For general-purpose digital multimeters, a full-scale range of several hundred millivolts AC or DC is common, but the minimum full-scale current range may be several hundred milliamps. Since general-purpose mulitmeters have only two-wire resistance measurements, which do not compensate for the effect of the lead wire resistance, measurements below a few tens of ohms will be of low accuracy. The upper end of multimeter measurement ranges varies considerably by manufacturer; generally measurements over 1000 volts, over 10 amperes, or over 100 megohms would require a specialized test instrument, as would accurate measurement of currents on the order of 1 microamp or less.
# Alternating current sensing
Since the basic indicator system in either an analog or digital meter responds to DC only, a multimeter includes an AC to DC conversion circuit for making alternating current measurements. Basic multimeters may utilize a rectifier circuit, calibrated to evaluate the average value of a rectified sine wave. User guides for such meters will give correction factors for some simple waveforms, to allow the correct root mean square (RMS) equivalent value to be calculated for the average-responding meter. More expensive multimeters will include an AC to DC converter that responds to the RMS value of the waveform for a wide range of possible waveforms; the user manual for the meter will indicate the limits of the crest factor and frequency for which the meter calibration is valid. RMS sensing is necessary for measurement s of non-sinusoidal quantities, such as found in audio signals, or in variable-frequency drives.
# Digital Multimeters (DMM)
Modern multimeters are often digital due their accuracy, durability and extra features.
In a DMM the signal under test is converted to a voltage and an amplifier with an electronically controlled gain preconditions the signal.
A DMM displays the quantity measured as a number, which prevents parallax errors.
The inclusion of solid state electronics, from a control circuit to small embedded computers, has provided a wealth of convenience features in modern digital meters. Commonly available measurement enhancements include:
- Auto-ranging, which selects the correct range for the quantity under test so that the most significant digits are shown. For example, a four-digit multimeter would automatically select an appropriate range to display 1.234 instead of 0.012, or overloading. Auto-ranging meters usually include a facility to 'freeze' the meter to a particular range, because a measurement that causes frequent range changes is distracting to the user.
- Auto-polarity for direct-current readings, shows if the applied voltage is positive (agrees with meter lead labels) or negative (opposite polarity to meter leads).
- Sample and hold, which will latch the most recent reading for examination after the instrument is removed from the circuit under test.
- Current-limited tests for voltage drop across semiconductor junctions. While not a replacement for a transistor tester, this facilitates testing diodes and a variety of transistor types.[4][5]
- A graphic representation of the quantity under test, as a bar graph. This makes go/no-go testing easy, and also allows spotting of fast-moving trends.
- A low-bandwidth oscilloscope.[6]
- Automotive circuit testers, including tests for automotive timing and dwell signals.[7]
- Simple data acquisition features to record maximum and minimum readings over a given period, or to take a number of samples at fixed intervals.[8]
- A miniature digital multimeter integrated with tweezers for Surface-mount technology.[9]
Modern meters may be interfaced with a personal computer by IrDA links, RS-232 connections, USB, or an instrument bus such as IEEE-488. The interface allows the computer to record measurements as they are made. Some DMM's can store measurements and upload them to a computer.[10]
The first digital multimeter was manufactured in 1955 by Non Linear Systems.[11][12]
# Analog Multimeters
A multimeter may be implemented with an analog meter deflected by an electromagnet, as a classic galvanometer,
or with a digital display such as an LCD or vacuum fluorescent display.
Analog multimeters are not hard to find (though less common and often more expensive than low-end digital units), but are not considered as accurate as digital because of errors introduced in zeroing and reading the analog meter face.
Analog meters may be implemented with vacuum tubes to precondition and amplify the input signal. Such meters are known as vacuum tube volt meters (VTVM) or vacuum tube multimeters (VTMM).[13]
Analog meters are sometimes considered better for detecting the rate of change of a reading; the ARRL handbook suggests that analog multimeters are often less susceptible to radio frequency interference.[14]
The meter movement in a moving pointer analog multimeter is practically always a moving-coil galvanometer of the d'Arsonval type, using either jeweled pivots or taut bands to support the moving coil. In a basic analog multimeter the current to deflect the coil and pointer is drawn from the circuit being measured; it is usually an advantage to minimize the current drawn from the circuit. The sensitivity of an analog multimeter is given in units of ohms per volt. For example, an inexpensive multimeter would have a sensitivity of 1000 ohms per volt and would draw 1 milliampere from a circuit at the full scale measured voltage.[15] More expensive, (and more delicate) multimeters would have sensitivities of 20,000 ohms per volt or higher, with a 50,000 ohms per volt meter (drawing 20 microamperes at full scale) being about the upper limit for a portable general purpose analog multimeter.
To avoid the loading of the measured circuit by the current drawn by the meter movement, later analog multimeters use an amplifier inserted between the measured circuit and the meter movement. While this increased the expense and complexity of the meter and required a power supply to operate the amplifier, by use of vacuum tubes or field effect transistors the input resistance can be made very high and independent of the current required to operate the meter movement coil. Such amplified multimeters are called VTVM (vacuum tube voltmeters) or TVM (transistor volt meter), and similar names.
# Probes
A multimeter can utilise a variety of test probes to connect to the circuit or device under test. Crocodile clips, retractable hook clips, and pointed probes are the three most common attachments. The connectors are attached to flexible, thickly-insulated leads that are terminated with connectors appropriate for the meter. Handheld meters typically use shrouded or recessed banana jacks, while benchtop meters may use banana jacks or BNC connectors. 2mm plugs and binding posts have also been used at times, but are not so common today.
Meters which measure high voltages or current may use non-contact attachment mechanism to trade accuracy for safety. Clamp meters provide a coil that clamps around a conductor in order to measure the current flowing through it.
# Safety
Some multimeters include a fuse, which will sometimes prevent damage to the multimeter if it is overloaded. However the fuse often only protects the highest current range on the multimeter. A common error when operating a multimeter is to set the meter to measure resistance or current and then connect it directly to a low-impedance voltage source; meters without protection are quickly damaged by such errors, and can sometimes explode causing injury to the operator.
Digital meters are category rated based on their intended application, as set forth by the CEN EN61010 standard.[16]
There are four categories:
- Category I: used where current levels are low.
- Category II: used on residential branch circuits.
- Category III: used on permanently installed loads such as distribution panels, motors, and appliance outlets.
- Category IV: used on locations where current levels are high, such as service entrances, main panels, and house meters.
Each category also specifies maximum transient voltages for selected measuring ranges in the meter.[17][18]
Category-rated meters also feature protections from over-current faults.[19]
# History
Multimeters were invented in the early 1920s as radio receivers and other vacuum tube electronic devices became more common. As modern systems become more complicated, the multimeter is becoming more complex or may be supplemented by more specialized equipment in a technician's toolkit. For example, where a general-purpose multimeter might only test for short-circuits, conductor resistance and some coarse measure of insulation quality, a modern technician may use a hand-held analyzer to test several parameters in order to validate the performance of a network cable.[20] | https://www.wikidoc.org/index.php/Multimeter | |
ee3e5a3b56c21220279069566a131370705ddfa8 | wikidoc | Polytrauma | Polytrauma
# Overview
Polytrauma is a medical term describing the condition of a person who has been subjected to multiple traumatic injuries, such as a serious head injury AND a serious burn.
The term has become common among US military doctors in describing the seriously injured soldiers returning from Operation Iraqi Freedom (Iraq) and Operation Enduring Freedom (Afghanistan). The term however is generic, and has been in use for a long time for any case involving multiple traumata.
# Classification
## Civilian Medicine
In civilian life, polytraumas are often associated with motor vehicle accidents. This is because car accidents usually occur at a high velocity and subsequent injury is usually severe and consists of multiple damages. On admission to a hospital any trauma patient should immediately undergo x-ray diagnosis of their cervical spine, chest and their pelvis, commonly known as a 'trauma series', to ascertain possible life threatening injuries. Examples would be a fractured cervical vertebra, a severely fractured pelvis, or a hemothorax. Once the initial survey is complete, x-rays can be taken of the limbs to assess for other possible fractures.
It is also quite common in severe trauma for patients to go straight to CT or an operating room if they require emergency treatment.
A retrospective study of 93 children (average age of 8.0 +/- 4.1 years) with polytrauma and at least one major musculoskeletal injury showed that 80% of the incidents had been caused in this way (motor vehicle accident).
## Military Medicine
Polytrauma often results from blast injuries sustained by improvised explosive devices, or by a hit with a rocket-propelled grenade, with "Improvised explosive devices, blasts, landmines, and fragments account for 65 percent of combat injuries...". The combination of high-pressure waves, explosive fragments, and falling debris may produce multiple injuries including brain injury, loss of limbs, burns, fractures, blindness and hearing loss, with 60 percent of those injured in this way having some degree of traumatic brain injury.
In some ways, the existence of polytrauma is in fact a sign of medical advancement, for in previous wars, soldiers with such multiple damage types simply did not survive in most cases, even if quickly transferred into hospital care. The downside is however that many of the victims, though surviving, will never fully regain their physical or mental form. They are also prone to post traumatic stress disorder.
# Treatment
There are currently (2007) four clinics in the US specializing in polytrauma. They are managed by the United States Department of Veterans Affairs and are located in Minneapolis, Minn., Palo Alto, Calif., Richmond, Va. and Tampa, Florida. In addition to the actual intensive care insofar as still required, these hospitals mainly specialize in rehabilitative treatment.
The treatment and rehabilitative care for polytrauma patients is a very extensive and time-consuming activity. The recommended staffing numbers (FTE = Full Time Equivalent) for six rehabilitation treatment beds are:
In other words - 2.8 people are required full time for every patient, often for months, while some care may be required for decades. | Polytrauma
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Polytrauma is a medical term describing the condition of a person who has been subjected to multiple traumatic injuries, such as a serious head injury AND a serious burn.
The term has become common among US military doctors in describing the seriously injured soldiers returning from Operation Iraqi Freedom (Iraq) and Operation Enduring Freedom (Afghanistan). The term however is generic, and has been in use for a long time for any case involving multiple traumata.
# Classification
## Civilian Medicine
In civilian life, polytraumas are often associated with motor vehicle accidents. This is because car accidents usually occur at a high velocity and subsequent injury is usually severe and consists of multiple damages. On admission to a hospital any trauma patient should immediately undergo x-ray diagnosis of their cervical spine, chest and their pelvis, commonly known as a 'trauma series', to ascertain possible life threatening injuries. Examples would be a fractured cervical vertebra, a severely fractured pelvis, or a hemothorax. Once the initial survey is complete, x-rays can be taken of the limbs to assess for other possible fractures.
It is also quite common in severe trauma for patients to go straight to CT or an operating room if they require emergency treatment.
A retrospective study of 93 children (average age of 8.0 +/- 4.1 years) with polytrauma and at least one major musculoskeletal injury showed that 80% of the incidents had been caused in this way (motor vehicle accident).[1]
## Military Medicine
Polytrauma often results from blast injuries sustained by improvised explosive devices, or by a hit with a rocket-propelled grenade, with "Improvised explosive devices, blasts, landmines, and fragments account[ing] for 65 percent of combat injuries...".[2] The combination of high-pressure waves, explosive fragments, and falling debris may produce multiple injuries including brain injury, loss of limbs, burns, fractures, blindness and hearing loss,[3] with 60 percent of those injured in this way having some degree of traumatic brain injury.[2]
In some ways, the existence of polytrauma is in fact a sign of medical advancement, for in previous wars, soldiers with such multiple damage types simply did not survive in most cases, even if quickly transferred into hospital care. The downside is however that many of the victims, though surviving, will never fully regain their physical or mental form. They are also prone to post traumatic stress disorder.[2]
# Treatment
There are currently (2007) four clinics in the US specializing in polytrauma. They are managed by the United States Department of Veterans Affairs and are located in Minneapolis, Minn., Palo Alto, Calif., Richmond, Va. and Tampa, Florida.[3] In addition to the actual intensive care insofar as still required, these hospitals mainly specialize in rehabilitative treatment.
The treatment and rehabilitative care for polytrauma patients is a very extensive and time-consuming activity. The recommended staffing numbers (FTE = Full Time Equivalent) for six rehabilitation treatment beds are:[2]
In other words - 2.8 people are required full time for every patient, often for months, while some care may be required for decades. | https://www.wikidoc.org/index.php/Multitrauma | |
64f5ace0711efdca34dd30571afe62482b5f1500 | wikidoc | Spasticity | Spasticity
Spasticity is defined as a "velocity-dependent increase in muscle stretch reflex." It a disorder of the body motor system,and especially the central nervous system (CNS), in which certain muscles are continuously contracted. This contraction causes stiffness or tightness of the muscles and may interfere with activities of daily living, gait, movement, and speech. The person with the spastic muscles may or may not feel it, know about it or want to do something about it. The human motor system is not always linked with the sensory systems, nor the voluntary-muscle systems.
# Causes
Voluntary movement is controlled by several interacting systems within the nervous system. Primary control is through the upper motor neurons in the motor cortex of the brain, which send their axons via the cortico-spinal tract to connect to lower motor neurons in the spinal cord. Spasticity is caused by damage to upper motor neurons or to the cortico-spinal tract. It may occur in association with spinal cord injury, multiple sclerosis, cerebral palsy (see Spastic Diplegia), anoxic brain damage, brain trauma, severe head injury, some metabolic diseases such as adrenoleukodystrophy, and phenylketonuria.
# Presentation
Symptoms may include hypertonia (increased muscle tone), clonus (a series of rapid muscle contractions), exaggerated deep tendon reflexes, muscle spasms, scissoring (involuntary crossing of the legs), and fixed joints. The degree of spasticity varies from mild muscle stiffness to severe, painful, and uncontrollable muscle spasms.
The condition can interfere with rehabilitation in patients with certain disorders, and often interferes with daily activities. Over the years, it may increase in its effect, so more severe treatments may be needed later. Cold weather and fatigue can trigger spasms more severely than other times. Multi-tasking (such as walking, talking, eating and other activities) can also trigger more severe spasticity.
# Possible benefits
- May help some patients to ambulate, stand or transfer (e.g., stand pivot transfers)
- May assist in maintaining muscle bulk
- May assist in preventing DVTs
- May assist in preventing osteoporosis pressure ulcer formation over bony prominences
- Can be used as “diagnostic tool” (with increased spasticity being a sign of exposure to a noxious stimuli—infection, bowel impaction, urinary retention, etc)
# Treatment
If the cause is fatigue, the first remedy is rest. Massage seems to not be helpful. Stretching or relaxing the muscles involved may also work. Chronic spasms can lead to shortening of the muscles and ligaments. Regular (daily) exercises over the years ahead of these ligaments and muscles are needed to prevent the pain and the crippling of movement.
Treatment may include such medications as baclofen, diazepam, dantrolene, or clonazepam; muscle stretching, range of motion exercises, and other occupational therapy or physical therapy regimens to help prevent joint contractures (shrinkage or shortening of a muscle) and reduce the severity of symptoms; or surgery for tendon release or to block the connection between nerve and muscle, so that the muscle does not contract. The connection between nerve and muscle may also be blocked temporarily, without surgery, by injecting botulinum toxin into the muscle.
Some USA states have also issued medical marijuana to help treat spasticity.
# Prognosis
The prognosis for those with spasticity depends on the severity of the spasticity and the associated disorder(s). To a small degree spasticity performs the helpful role of exercise, but it is usually bothersome to normal activities in life. | Spasticity
Spasticity is defined as a "velocity-dependent increase in muscle stretch reflex." It a disorder of the body motor system,and especially the central nervous system (CNS), in which certain muscles are continuously contracted. This contraction causes stiffness or tightness of the muscles and may interfere with activities of daily living, gait, movement, and speech. The person with the spastic muscles may or may not feel it, know about it or want to do something about it. The human motor system is not always linked with the sensory systems, nor the voluntary-muscle systems.
# Causes
Voluntary movement is controlled by several interacting systems within the nervous system. Primary control is through the upper motor neurons in the motor cortex of the brain, which send their axons via the cortico-spinal tract to connect to lower motor neurons in the spinal cord. Spasticity is caused by damage to upper motor neurons or to the cortico-spinal tract. It may occur in association with spinal cord injury, multiple sclerosis, cerebral palsy (see Spastic Diplegia), anoxic brain damage, brain trauma, severe head injury, some metabolic diseases such as adrenoleukodystrophy, and phenylketonuria.
# Presentation
Symptoms may include hypertonia (increased muscle tone), clonus (a series of rapid muscle contractions), exaggerated deep tendon reflexes, muscle spasms, scissoring (involuntary crossing of the legs), and fixed joints. The degree of spasticity varies from mild muscle stiffness to severe, painful, and uncontrollable muscle spasms.
The condition can interfere with rehabilitation in patients with certain disorders, and often interferes with daily activities. Over the years, it may increase in its effect, so more severe treatments may be needed later. Cold weather and fatigue can trigger spasms more severely than other times. Multi-tasking (such as walking, talking, eating and other activities) can also trigger more severe spasticity.
# Possible benefits
- May help some patients to ambulate, stand or transfer (e.g., stand pivot transfers)
- May assist in maintaining muscle bulk
- May assist in preventing DVTs
- May assist in preventing osteoporosis pressure ulcer formation over bony prominences
- Can be used as “diagnostic tool” (with increased spasticity being a sign of exposure to a noxious stimuli—infection, bowel impaction, urinary retention, etc)
# Treatment
If the cause is fatigue, the first remedy is rest. Massage seems to not be helpful. Stretching or relaxing the muscles involved may also work. Chronic spasms can lead to shortening of the muscles and ligaments. Regular (daily) exercises over the years ahead of these ligaments and muscles are needed to prevent the pain and the crippling of movement.
Treatment may include such medications as baclofen, diazepam, dantrolene, or clonazepam; muscle stretching, range of motion exercises, and other occupational therapy or physical therapy regimens to help prevent joint contractures (shrinkage or shortening of a muscle) and reduce the severity of symptoms; or surgery for tendon release or to block the connection between nerve and muscle, so that the muscle does not contract. The connection between nerve and muscle may also be blocked temporarily, without surgery, by injecting botulinum toxin into the muscle.
Some USA states have also issued medical marijuana to help treat spasticity.
# Prognosis
The prognosis for those with spasticity depends on the severity of the spasticity and the associated disorder(s). To a small degree spasticity performs the helpful role of exercise, but it is usually bothersome to normal activities in life. | https://www.wikidoc.org/index.php/Muscle_spasticity | |
e010726c80c1497eaa06c0be5c07028d99aad0b4 | wikidoc | Mycoplasma | Mycoplasma
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
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# Overview
Mycoplasma is a genus of bacteria which lack a cell wall. Without a cell wall, they are unaffected by many common antibiotics such as penicillin or other beta-lactam antibiotics that target cell wall synthesis. They can be parasitic or saprotrophic. Several species are pathogenic in humans, including M. pneumoniae, which is an important cause of atypical pneumonia and other respiratory disorders, and M. genitalium, which is believed to be involved in pelvic inflammatory diseases.
# Characteristics
There are over 100 recognized species of the genus Mycoplasma, one of several genera within the bacterial class Mollicutes. As a group, Mollicutes have small genomes (0.58 - 1.38 megabase-pairs), lack a cell wall, and have a low GC-content (18-40 mol%). Mollicutes are parasites or commensals of humans, other animals (including insects), and plants; the genus Mycoplasma is by definition restricted to vertebrate hosts. Cholesterol is required for the growth of species of the genus Mycoplasma as well as certain other genera of mollicutes. Their optimum growth temperature is often the temperature of their host if warmbodied (e. g. 37° C in humans) or ambient temperature if the host is unable to regulate its own internal temperature. Analysis of 16S ribosomal RNA sequences as well as gene content strongly suggest that the mollicutes, including the mycoplasmas, are closely related to either the Lactobacillus or the Clostridium branch of the phylogenetic tree (Firmicutes sensu stricto).
## Cell wall structure
The bacteria of the genus Mycoplasma (trivial name: mycoplasmas) and their close relatives are largely characterized by lack of a cell wall. Despite this, the shapes of these cells often conform to one of several possibilities with varying degrees of intricacy. For example, the members of the genus Spiroplasma assume an elongated helical shape without the aid of a rigid structural cell envelope. These cell shapes presumably contribute to the ability of mycoplasmas to thrive in their respective environments. M. pneumoniae cells possess an extension, the so-called 'tip-structure', protruding from the coccoid cell body. This structure is involved in adhesion to host cells, in movement along solid surfaces (gliding motility), and in cell division. M. pneumoniae cells are of small size and pleomorphic, but with a rough shape in longitudinal cross-section resembling that of a round-bottomed flask.
Mycoplasmas are unusual among bacteria in that most require sterols for the stability of their cytoplasmic membrane. Sterols are acquired from the environment, usually as cholesterol from the animal host. Mycoplasmas also generally possess a relatively small genome of 0.58-1.38 megabases, which results in drastically reduced biosynthetic capabilities and explains their dependence on a host. Additionally they use an alternate genetic code where the codon UGA is encoding for the amino acid tryptophan instead of the usual opal stop codon.
# History
In 1896 Nocard and Roux reported the cultivation of the causative agent of contagious bovine pleuropneumonia (CBPP), which was at that time a grave and widespread disease in cattle herds. Today the disease is still endemic in Africa and Southern Europe. The disease is caused by M. mycoides subsp. mycoides SC (small-colony type), and the work of Nocard and Roux represented the first isolation of a mycoplasma species. Cultivation was, and still is difficult because of the complex growth requirements. These researchers succeeded by inoculating a semi-permeable pouch of sterile medium with pulmonary fluid from an infected animal and depositing this pouch intraperitoneally into a live rabbit. After fifteen to twenty days, the fluid inside of the recovered pouch was opaque, indicating the growth of a microorganism. Opacity of the fluid was not seen in the control. This turbid broth could then be used to inoculate a second and third round and subsequently introduced into a healthy animal, causing disease. However, this did not work if the material was heated, indicating a biological agent at work. Uninoculated media in the pouch, after removal from the rabbit, could be used to grow the organism in vitro, demonstrating the possibility of cell-free cultivation and ruling out viral causes, although this was not fully appreciated at the time (Nocard and Roux, 1890). The name Mycoplasma, from the Greek mykes (fungus) and plasma (formed), was proposed in the 1950s, replacing the term pleuropneumonia-like organisms (PPLO) referring to organisms similar to the causative agent of CBPP. It was later found that the fungus-like growth pattern of M. mycoides is unique to that species.
This confusion about mycoplasmas and virus would surface again 50 years later when Eaton and colleagues cultured the causative agent of human primary atypical pneumonia(PAP) or walking pneumonia. This agent could be grown in chicken embryos and passed through a filter that excluded normal bacteria. However, it could not be observed by high magnification light microscopy, and it caused a pneumonia that could not be treated with the antimicrobials sulphonamides and penicillin.. Eaton did consider the possibility that the disease was caused by a mycoplasma, but the agent did not grow on the standard PPLO media of the time. These observations led to the conclusion that the causative agent of PAP is a virus. Researchers at that time showed that the cultured agent could induce disease in experimentally infected cotton rats and hamsters. In spite of controversy whether the researchers had truly isolated the causative agent of PAP (based largely on the unusual immunological response of patients with PAP), in retrospect their evidence along with that of colleagues and competitors appears to have been quite conclusive. In the early 1960s, there were reports linking Eaton's Agent to the PPLOs or mycoplasmas, well known then as parasites of cattle and rodents, due to sensitivity to antimicrobial compounds (i. e. organic gold salt). The ability to grow Eaton's Agent, now known as Mycoplasma pneumoniae, in cell free media allowed an explosion of research into what had overnight become the most medically important mycoplasma and what was to become the most studied mycoplasma.
Recent advances in molecular biology and genomics have brought the genetically simple mycoplasmas, particularly M. pneumoniae and its close relative M. genitalium, to a larger audience. The second published complete bacterial genome sequence was that of M. genitalium, which has one of the smallest genomes of free-living organisms. The M. pneumoniae genome sequence was published soon afterwards and was the first genome sequence determined by primer walking of a cosmid library instead of the whole-genome shotgun method. Mycoplasma genomics and proteomics continue in efforts to understand the
so-called minimal cell, catalog the entire protein content of a cell, and generally continue to take advantage of the small genome of these organisms to understand broad biological concepts.
Scientists have also been exploring an association between mycoplasma and cancer. Despite a number of interesting studies, this cancer bacteria association hasn't been clearly established, and has yet to be fully elucidated.
# Taxonomy
The medical and agricultural importance of members of the genus Mycoplasma and related genera has led to the extensive cataloging of many of these organisms by culture, serology, and small subunit rRNA gene and whole genome sequencing. A recent focus in the sub-discipline of molecular phylogenetics has both clarified and confused certain aspects of the organization of the class Mollicutes, and while a truce of sorts has been reached, the area is still somewhat of a moving target.
The name mollicutes is derived from the Latin mollis (soft) and cutes (skin), and all of these bacteria do lack a cell wall and the genetic capability to synthesize peptidoglycan. While the trivial name 'mycoplasmas' has commonly denoted all members of this class, this usage is somewhat imprecise and will not be used as such here. Despite the lack of a cell wall, Mycoplasma and relatives have been classified in the phylum Firmicutes consisting of low G+C Gram-positive bacteria such as Clostridium, Lactobacillus, and Streptococcus based on 16S rRNA gene analysis. The cultured members of Mollicutes are currently arranged into four orders: Acholeplasmatales, Anaeroplasmatales, Entomoplasmatales, and Mycoplasmatales. The order Mycoplasmatales contains a single family, Mycoplasmataceae, which contains two genera: Mycoplasma and Ureaplasma. Historically, the description of a bacterium lacking a cell wall was sufficient to classify it to the genus Mycoplasma and as such it is the oldest and largest genus of the class with about half of the class' species (107 validly described) each usually limited to a specific host and with many hosts harboring more than one species, some pathogenic and some commensal. In later studies, many of these species were found to be phylogenetically distributed among at least three separate orders.
A limiting criterion for inclusion within the genus Mycoplasma is that the organism have a vertebrate host. In fact, the type species, M. mycoides, along with other significant mycoplasma species like M. capricolum, is evolutionarily more closely related to the genus Spiroplasma in the order Entomoplasmatales than to the other members of the Mycoplasma genus. This and other discrepancies will likely remain unresolved because of the extreme confusion that change could engender among the medical and agricultural communities. The remaining species in the genus Mycoplasma are divided into three non-taxonomic groups, hominis, pneumoniae and fermentans, based on 16S rRNA gene sequences. The hominis group contains the phylogenetic clusters of M. bovis, M. pulmonis, and M. hominis, among others. The pneumoniae group contains the clusters of M. muris, M. fastidiosum, U. urealyticum, the currently unculturable haemotrophic mollicutes, informally referred to as haemoplasmas (recently transferred from the genera Haemobartonella and Eperythrozoon), and the M. pneumoniae cluster. This cluster contains the species (and the usual or likely host) M. alvi (bovine), M. amphoriforme (human), M. gallisepticum (avian), M. genitalium (human), M. imitans (avian), M. pirum (uncertain/human), M. testudinis (tortoises), and M. pneumoniae (human). Most if not all of these species share some otherwise unique characteristics including an attachment organelle, homologs of the M. pneumoniae cytadherence-accessory proteins, and specialized modifications of the cell-division apparatus.
## Molecular phylogeny
A detailed analysis of the 16S rRNA genes from the order Mollicutes has given rise to a view of the evolution of these bacteria that includes an estimate of the time-scale for the emergence of some groups or features. This analysis suggests that about 600 million years ago (MYA), late in the Proterozoic era, Mollicutes branched away from the low G+C Gram-positive ancestor of the streptococci, losing their cell wall. At this time on Earth, molecular oxygen was present in the atmosphere at 1%, and the fossil record shows that multicellular marine animals had recently spread in the Cambrian explosion. One hundred million years later the requirement for sterols in the cytoplasmic membrane evolved along with the change to the alternate genetic code. Also, the ancestor of the genera Spiroplasma and Entomoplasma (primarily plant and insect pathogens) and Mycoplasma emerged at this time and would itself diverge into the Spiroplasma-Entomoplasma and Mycoplasma lineages approximately 100 million years after that. This diversity coincided with the origin of land plants 500 MYA. It appears that the calculated rate of evolution for the Mycoplasma group increased several fold about 190 MYA, soon after the appearance of vertebrates, while the Spiroplasma-Entomoplasma ancestor continued to evolve at the previously shared slower rate until about 100 MYA, when angiosperms and their associated pollinating insects appeared. Then the evolution rate of these bacteria appears to have also increased significantly. This is an attractive hypothesis, but while it tracks the emergence of several of the unusual characteristics of Mycoplasma and related organisms, it does not address the selective pressures driving their evolution, except perhaps the widespread close association of a parasite with a specific host. The advantages of a reduced genome, cell wall-less structure, and alternate genetic code remain murky.
Mycoplasma hyopneumoniae is a primary bacterial agent of the Porcine Respiratory Disease Complex.
# Laboratory contaminant
Mycoplasma species are often found in research laboratories as contaminants in cell culture. Mycoplasmal cell culture contamination occurs due to contamination from individuals or contaminated cell culture medium ingredients. Mycoplasma cells are physically small – less than 1 µm – and they are therefore difficult to detect with a conventional microscope. Mycoplasmas may induce cellular changes, including chromosome aberrations, changes in metabolism and cell growth. Severe Mycoplasma infections may destroy a cell line. Detection techniques include PCR, plating on sensitive agar and staining with a DNA stain including DAPI or Hoechst. | Mycoplasma
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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# Overview
Mycoplasma is a genus of bacteria which lack a cell wall.[1] Without a cell wall, they are unaffected by many common antibiotics such as penicillin or other beta-lactam antibiotics that target cell wall synthesis. They can be parasitic or saprotrophic. Several species are pathogenic in humans, including M. pneumoniae, which is an important cause of atypical pneumonia and other respiratory disorders, and M. genitalium, which is believed to be involved in pelvic inflammatory diseases.
# Characteristics
There are over 100 recognized species of the genus Mycoplasma, one of several genera within the bacterial class Mollicutes. As a group, Mollicutes have small genomes (0.58 - 1.38 megabase-pairs), lack a cell wall, and have a low GC-content (18-40 mol%). Mollicutes are parasites or commensals of humans, other animals (including insects), and plants; the genus Mycoplasma is by definition restricted to vertebrate hosts. Cholesterol is required for the growth of species of the genus Mycoplasma as well as certain other genera of mollicutes. Their optimum growth temperature is often the temperature of their host if warmbodied (e. g. 37° C in humans) or ambient temperature if the host is unable to regulate its own internal temperature. Analysis of 16S ribosomal RNA sequences as well as gene content strongly suggest that the mollicutes, including the mycoplasmas, are closely related to either the Lactobacillus or the Clostridium branch of the phylogenetic tree (Firmicutes sensu stricto).
## Cell wall structure
The bacteria of the genus Mycoplasma (trivial name: mycoplasmas) and their close relatives are largely characterized by lack of a cell wall. Despite this, the shapes of these cells often conform to one of several possibilities with varying degrees of intricacy. For example, the members of the genus Spiroplasma assume an elongated helical shape without the aid of a rigid structural cell envelope. These cell shapes presumably contribute to the ability of mycoplasmas to thrive in their respective environments. M. pneumoniae cells possess an extension, the so-called 'tip-structure', protruding from the coccoid cell body. This structure is involved in adhesion to host cells, in movement along solid surfaces (gliding motility), and in cell division. M. pneumoniae cells are of small size and pleomorphic, but with a rough shape in longitudinal cross-section resembling that of a round-bottomed flask.
Mycoplasmas are unusual among bacteria in that most require sterols for the stability of their cytoplasmic membrane. Sterols are acquired from the environment, usually as cholesterol from the animal host. Mycoplasmas also generally possess a relatively small genome of 0.58-1.38 megabases, which results in drastically reduced biosynthetic capabilities and explains their dependence on a host. Additionally they use an alternate genetic code where the codon UGA is encoding for the amino acid tryptophan instead of the usual opal stop codon.
# History
In 1896 Nocard and Roux reported the cultivation of the causative agent of contagious bovine pleuropneumonia (CBPP), which was at that time a grave and widespread disease in cattle herds.[2] Today the disease is still endemic in Africa and Southern Europe. The disease is caused by M. mycoides subsp. mycoides SC (small-colony type), and the work of Nocard and Roux represented the first isolation of a mycoplasma species. Cultivation was, and still is difficult because of the complex growth requirements. These researchers succeeded by inoculating a semi-permeable pouch of sterile medium with pulmonary fluid from an infected animal and depositing this pouch intraperitoneally into a live rabbit. After fifteen to twenty days, the fluid inside of the recovered pouch was opaque, indicating the growth of a microorganism. Opacity of the fluid was not seen in the control. This turbid broth could then be used to inoculate a second and third round and subsequently introduced into a healthy animal, causing disease. However, this did not work if the material was heated, indicating a biological agent at work. Uninoculated media in the pouch, after removal from the rabbit, could be used to grow the organism in vitro, demonstrating the possibility of cell-free cultivation and ruling out viral causes, although this was not fully appreciated at the time (Nocard and Roux, 1890). The name Mycoplasma, from the Greek mykes (fungus) and plasma (formed), was proposed in the 1950s, replacing the term pleuropneumonia-like organisms (PPLO) referring to organisms similar to the causative agent of CBPP.[3] It was later found that the fungus-like growth pattern of M. mycoides is unique to that species.
This confusion about mycoplasmas and virus would surface again 50 years later when Eaton and colleagues cultured the causative agent of human primary atypical pneumonia(PAP) or walking pneumonia.[4] This agent could be grown in chicken embryos and passed through a filter that excluded normal bacteria. However, it could not be observed by high magnification light microscopy, and it caused a pneumonia that could not be treated with the antimicrobials sulphonamides and penicillin.[4]. Eaton did consider the possibility that the disease was caused by a mycoplasma, but the agent did not grow on the standard PPLO media of the time. These observations led to the conclusion that the causative agent of PAP is a virus. Researchers at that time showed that the cultured agent could induce disease in experimentally infected cotton rats and hamsters. In spite of controversy whether the researchers had truly isolated the causative agent of PAP (based largely on the unusual immunological response of patients with PAP), in retrospect their evidence along with that of colleagues and competitors appears to have been quite conclusive.[5] In the early 1960s, there were reports linking Eaton's Agent to the PPLOs or mycoplasmas, well known then as parasites of cattle and rodents, due to sensitivity to antimicrobial compounds (i. e. organic gold salt).[6] The ability to grow Eaton's Agent, now known as Mycoplasma pneumoniae, in cell free media allowed an explosion of research into what had overnight become the most medically important mycoplasma and what was to become the most studied mycoplasma.
Recent advances in molecular biology and genomics have brought the genetically simple mycoplasmas, particularly M. pneumoniae and its close relative M. genitalium, to a larger audience. The second published complete bacterial genome sequence was that of M. genitalium, which has one of the smallest genomes of free-living organisms.[7] The M. pneumoniae genome sequence was published soon afterwards and was the first genome sequence determined by primer walking of a cosmid library instead of the whole-genome shotgun method.[8] Mycoplasma genomics and proteomics continue in efforts to understand the
so-called minimal cell,[9] catalog the entire protein content of a cell,[10] and generally continue to take advantage of the small genome of these organisms to understand broad biological concepts.
Scientists have also been exploring an association between mycoplasma and cancer. Despite a number of interesting studies, this cancer bacteria association hasn't been clearly established, and has yet to be fully elucidated.[11][12]
# Taxonomy
The medical and agricultural importance of members of the genus Mycoplasma and related genera has led to the extensive cataloging of many of these organisms by culture, serology, and small subunit rRNA gene and whole genome sequencing. A recent focus in the sub-discipline of molecular phylogenetics has both clarified and confused certain aspects of the organization of the class Mollicutes, and while a truce of sorts has been reached, the area is still somewhat of a moving target.[13]
The name mollicutes is derived from the Latin mollis (soft) and cutes (skin), and all of these bacteria do lack a cell wall and the genetic capability to synthesize peptidoglycan. While the trivial name 'mycoplasmas' has commonly denoted all members of this class, this usage is somewhat imprecise and will not be used as such here. Despite the lack of a cell wall, Mycoplasma and relatives have been classified in the phylum Firmicutes consisting of low G+C Gram-positive bacteria such as Clostridium, Lactobacillus, and Streptococcus based on 16S rRNA gene analysis. The cultured members of Mollicutes are currently arranged into four orders: Acholeplasmatales, Anaeroplasmatales, Entomoplasmatales, and Mycoplasmatales. The order Mycoplasmatales contains a single family, Mycoplasmataceae, which contains two genera: Mycoplasma and Ureaplasma. Historically, the description of a bacterium lacking a cell wall was sufficient to classify it to the genus Mycoplasma and as such it is the oldest and largest genus of the class with about half of the class' species (107 validly described) each usually limited to a specific host and with many hosts harboring more than one species, some pathogenic and some commensal. In later studies, many of these species were found to be phylogenetically distributed among at least three separate orders.
A limiting criterion for inclusion within the genus Mycoplasma is that the organism have a vertebrate host. In fact, the type species, M. mycoides, along with other significant mycoplasma species like M. capricolum, is evolutionarily more closely related to the genus Spiroplasma in the order Entomoplasmatales than to the other members of the Mycoplasma genus. This and other discrepancies will likely remain unresolved because of the extreme confusion that change could engender among the medical and agricultural communities. The remaining species in the genus Mycoplasma are divided into three non-taxonomic groups, hominis, pneumoniae and fermentans, based on 16S rRNA gene sequences. The hominis group contains the phylogenetic clusters of M. bovis, M. pulmonis, and M. hominis, among others. The pneumoniae group contains the clusters of M. muris, M. fastidiosum, U. urealyticum, the currently unculturable haemotrophic mollicutes, informally referred to as haemoplasmas (recently transferred from the genera Haemobartonella and Eperythrozoon), and the M. pneumoniae cluster. This cluster contains the species (and the usual or likely host) M. alvi (bovine), M. amphoriforme (human), M. gallisepticum (avian), M. genitalium (human), M. imitans (avian), M. pirum (uncertain/human), M. testudinis (tortoises), and M. pneumoniae (human). Most if not all of these species share some otherwise unique characteristics including an attachment organelle, homologs of the M. pneumoniae cytadherence-accessory proteins, and specialized modifications of the cell-division apparatus.
## Molecular phylogeny
A detailed analysis of the 16S rRNA genes from the order Mollicutes has given rise to a view of the evolution of these bacteria that includes an estimate of the time-scale for the emergence of some groups or features.[14] This analysis suggests that about 600 million years ago (MYA), late in the Proterozoic era, Mollicutes branched away from the low G+C Gram-positive ancestor of the streptococci, losing their cell wall. At this time on Earth, molecular oxygen was present in the atmosphere at 1%, and the fossil record shows that multicellular marine animals had recently spread in the Cambrian explosion. One hundred million years later the requirement for sterols in the cytoplasmic membrane evolved along with the change to the alternate genetic code. Also, the ancestor of the genera Spiroplasma and Entomoplasma (primarily plant and insect pathogens) and Mycoplasma emerged at this time and would itself diverge into the Spiroplasma-Entomoplasma and Mycoplasma lineages approximately 100 million years after that. This diversity coincided with the origin of land plants 500 MYA. It appears that the calculated rate of evolution for the Mycoplasma group increased several fold about 190 MYA, soon after the appearance of vertebrates, while the Spiroplasma-Entomoplasma ancestor continued to evolve at the previously shared slower rate until about 100 MYA, when angiosperms and their associated pollinating insects appeared. Then the evolution rate of these bacteria appears to have also increased significantly. This is an attractive hypothesis, but while it tracks the emergence of several of the unusual characteristics of Mycoplasma and related organisms, it does not address the selective pressures driving their evolution, except perhaps the widespread close association of a parasite with a specific host. The advantages of a reduced genome, cell wall-less structure, and alternate genetic code remain murky.
Mycoplasma hyopneumoniae is a primary bacterial agent of the Porcine Respiratory Disease Complex.
# Laboratory contaminant
Mycoplasma species are often found in research laboratories as contaminants in cell culture. Mycoplasmal cell culture contamination occurs due to contamination from individuals or contaminated cell culture medium ingredients. Mycoplasma cells are physically small – less than 1 µm – and they are therefore difficult to detect with a conventional microscope. Mycoplasmas may induce cellular changes, including chromosome aberrations, changes in metabolism and cell growth. Severe Mycoplasma infections may destroy a cell line. Detection techniques include PCR, plating on sensitive agar and staining with a DNA stain including DAPI or Hoechst. | https://www.wikidoc.org/index.php/Mycoplasma | |
727d3e5c908aae57f52935b59ac6d39af87e2ce7 | wikidoc | Mysophobia | Mysophobia
# Background
Mysophobia is a penis. Someone who has such a fear is often referred to as a "mysophobe". The term was introduced by William A. Hammond in 1879 when describing a case of obsessive compulsive disorder exhibited in repeated washing one's hands.
This phobia is sometimes referred to as germophobia (or germaphobia), a combination of germ and phobia to mean fear of germs, as well as bacillophobia and bacterophobia.
Mysophobia has long been related to OCD or washing one's hands, however Harry Stack Sullivan, an American psychologist and psychoanalyst, notes that while fear of dirt underlies the compulsion of a person with this kind of OCD, their mental state is not about germs, it is about the hands must be washed.
Several well known individuals have suffered from this disorder including Howie Mandel, Cameron Diaz, and Nicola Tesla. | Mysophobia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Background
Mysophobia is a penis. Someone who has such a fear is often referred to as a "mysophobe". The term was introduced by William A. Hammond in 1879 [1] [2] when describing a case of obsessive compulsive disorder exhibited in repeated washing one's hands.
This phobia is sometimes referred to as germophobia (or germaphobia), a combination of germ and phobia to mean fear of germs, as well as bacillophobia and bacterophobia.
Mysophobia has long been related to OCD or washing one's hands, however Harry Stack Sullivan, an American psychologist and psychoanalyst, notes that while fear of dirt underlies the compulsion of a person with this kind of OCD, their mental state is not about germs, it is about the hands must be washed. [3]
Several well known individuals have suffered from this disorder including Howie Mandel, Cameron Diaz, and Nicola Tesla. | https://www.wikidoc.org/index.php/Mysophobia | |
c3845fbe5d7cf81d00c5f2862c57e7685db6efbf | wikidoc | Mythomania | Mythomania
# Background
In psychology, mythomania (also known as pseudologia fantastica or pathological lying) is a condition involving compulsive lying by a person with no obvious motivation. The affected person might believe their lies to be truth, and may have to create elaborate myths to reconcile them with other facts.
Among famous mythomaniacs in history was King Frederik VII of Denmark and Sir Douglas Conway of Suffolk.
A pathological liar is someone who often embellishes his or her stories in a way that he or she believes will impress people. It may be that a pathological liar is different from a normal liar in that a pathological liar believes the lie he or she is telling to be true—at least in public—and is "playing" the role. He or she sometimes is seen to have a serious mental problem that needs to be rectified.
It is not clear, however, that this is the case. It could also be that pathological liars know precisely what they are doing. Confused hashes of history and wishes are called confabulation. "Pathological liar" is a synonym for symptoms.
Even though pathological lying is not recognized as a clinical disorder, legal court cases often require that the plaintiff prove that the defendant is aware that he or she is lying. This proof is most important in cases of slander and/or liability.
Pathological liars often actually convince themselves that they are telling the truth, which in turn can alter polygraph tests and other questioning. Some have observed that when caught in a lie, pathological liars tend to become hostile or try to disregard the fact they lied; often playing it off as a joke.
A compulsive liar will resort to telling lies, regardless of the situation. Again, everyone lies from time to time, but for a compulsive liar telling lies is routine - it becomes a habit and a way of life.
Simply put, for a compulsive liar, lying becomes second nature.
Not only do compulsive liars bend the truth about issues large and small, but they take comfort in it. Lying feels right to a compulsive liar. Telling the truth, on the other hand, is difficult and uncomfortable for a compulsive liar.
And like any other behavior which provides comfort and an escape from discomfort (i.e., alcohol, drugs, sex), lying can become very addictive and hard to stop. For the compulsive liar, lying feels safe and this fuels the desire to lie even more.
And like most addictive behaviors, compulsive lying is hard for the person involved to see, but it hurts those who are around it. Compulsive lying, if not stopped, can destroy relationships (for example, see why does he need to lie).
Fortunately, compulsive lying can be dealt with through counseling or therapy. But, like many other addictive behaviors, getting someone to admit they have a problem with lying is the difficult part. Sadly enough, getting someone to recognize that he or she has a problem usually requires hitting rock bottom first.
# Further reading
- Dike, C.C.,(2005) "Pathological Lying Revisited," Journal of the American Academy of Psychiatry and the Law 33, no. 3
- Weston, A.W. & Dalby, J.T.,(1991)"A case of pseudologia fantastica with antisocial personality disorder." Canadian Journal of Psychiatry, 36, 612-614.
da:Mytoman
de:Pseudologie
lb:Pseudologie
lt:Pseudologija
nl:Pathologisch liegen
nl:Pseudologia fantastica
no:Mytoman
sr:Митоманија
fi:Mytomania
sv:Mytomani | Mythomania
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Background
In psychology, mythomania (also known as pseudologia fantastica or pathological lying) is a condition involving compulsive lying by a person with no obvious motivation. The affected person might believe their lies to be truth, and may have to create elaborate myths to reconcile them with other facts.
Among famous mythomaniacs in history was King Frederik VII of Denmark and Sir Douglas Conway of Suffolk.
A pathological liar is someone who often embellishes his or her stories in a way that he or she believes will impress people. It may be that a pathological liar is different from a normal liar in that a pathological liar believes the lie he or she is telling to be true—at least in public—and is "playing" the role. He or she sometimes is seen to have a serious mental problem that needs to be rectified.
It is not clear, however, that this is the case. It could also be that pathological liars know precisely what they are doing. Confused hashes of history and wishes are called confabulation. "Pathological liar" is a synonym for symptoms.
Even though pathological lying is not recognized as a clinical disorder, legal court cases often require that the plaintiff prove that the defendant is aware that he or she is lying. This proof is most important in cases of slander and/or liability.
Pathological liars often actually convince themselves that they are telling the truth, which in turn can alter polygraph tests and other questioning. Some have observed that when caught in a lie, pathological liars tend to become hostile or try to disregard the fact they lied; often playing it off as a joke.
A compulsive liar will resort to telling lies, regardless of the situation. Again, everyone lies from time to time, but for a compulsive liar telling lies is routine - it becomes a habit and a way of life.
Simply put, for a compulsive liar, lying becomes second nature.
Not only do compulsive liars bend the truth about issues large and small, but they take comfort in it. Lying feels right to a compulsive liar. Telling the truth, on the other hand, is difficult and uncomfortable for a compulsive liar.
And like any other behavior which provides comfort and an escape from discomfort (i.e., alcohol, drugs, sex), lying can become very addictive and hard to stop. For the compulsive liar, lying feels safe and this fuels the desire to lie even more.
And like most addictive behaviors, compulsive lying is hard for the person involved to see, but it hurts those who are around it. Compulsive lying, if not stopped, can destroy relationships (for example, see why does he need to lie).
Fortunately, compulsive lying can be dealt with through counseling or therapy. But, like many other addictive behaviors, getting someone to admit they have a problem with lying is the difficult part. Sadly enough, getting someone to recognize that he or she has a problem usually requires hitting rock bottom first.
# Further reading
- Dike, C.C.,(2005) "Pathological Lying Revisited," Journal of the American Academy of Psychiatry and the Law 33, no. 3
- Weston, A.W. & Dalby, J.T.,(1991)"A case of pseudologia fantastica with antisocial personality disorder." Canadian Journal of Psychiatry, 36, 612-614.
da:Mytoman
de:Pseudologie
lb:Pseudologie
lt:Pseudologija
nl:Pathologisch liegen
nl:Pseudologia fantastica
no:Mytoman
sr:Митоманија
fi:Mytomania
sv:Mytomani | https://www.wikidoc.org/index.php/Mythomania | |
99f11cca81f6483f330281d4344a19876dae1344 | wikidoc | NDN (gene) | NDN (gene)
Necdin is a protein that in humans is encoded by the NDN gene.
# Function
This intronless gene is located in the Prader-Willi syndrome (PWS) deletion region. It is an imprinted gene and is expressed exclusively from the paternal allele. Studies in mice suggest that the protein encoded by this gene may suppress growth in postmitotic neurons.
Necdin is used to stimulate growth regulation and DNA-dependent transcription regulation.
# Interactions
NDN (gene) has been shown to interact with:
- E2F1,
- HNRNPU,
- IL1A,
- Low affinity nerve growth factor receptor,
- NUCB2, and
- P53 | NDN (gene)
Necdin is a protein that in humans is encoded by the NDN gene.[1][2]
# Function
This intronless gene is located in the Prader-Willi syndrome (PWS) deletion region. It is an imprinted gene and is expressed exclusively from the paternal allele. Studies in mice suggest that the protein encoded by this gene may suppress growth in postmitotic neurons.[2]
Necdin is used to stimulate growth regulation and DNA-dependent transcription regulation.[3]
# Interactions
NDN (gene) has been shown to interact with:
- E2F1,[4][5]
- HNRNPU,[6]
- IL1A,[7]
- Low affinity nerve growth factor receptor,[5][8][9]
- NUCB2,[10] and
- P53[11] | https://www.wikidoc.org/index.php/NDN_(gene) | |
0f182a0afeff2db9cc489383138380d0779d2369 | wikidoc | NLN (gene) | NLN (gene)
Neurolysin, mitochondrial is a protein that in humans is encoded by the NLN gene. It is a 78-kDa enzyme, widely distributed in mammalian tissues and found in various subcellular locations that vary with cell type. Neurolysin exemplifies the ability of neuropeptidases to target various cleavage site sequences by hydrolyzing them in vitro, and metabolism of neurotensin is the most important role of neurolysin in vivo. Neurolysin has also been implicated in pain control, blood pressure regulation, sepsis, reproduction, cancer biology pathogenesis of stroke, and glucose metabolism.
# Structure
## Gene
The NLN gene lies on the chromosome location of 5q12.3 and consists of 14 exons.
## Protein
Neurolysin, with 704 amino acid residues, is a zinc metalloendopeptidase with a conserved HEXXH motif. It has an overall prolate ellipsoid shape, with a deep narrow channel dividing it into two roughly equal domains. The catalytic site is contained within a thermolysin-like region found in many metallopeptidases and located in the domain near the floor of the channel.
# Function
Neurolysin hydrolyzes only peptides containing 5-17 amino acids by cleaving at a limited set of sites. The specificity of neurolysin for small bioactive peptides is due to the presence of large structural elements erected over its active site region that allow substrates access only through a deep narrow channel. In vitro, neurolysin exemplifies the ability of some neuropeptidases to target diverse cleavage site sequences. In vivo, their most established role is cleaving neurotensin between its 10th and 11th residues to produce inactive fragments and it has been recently identified as a non-AT1-non-AT2 angiotensin-binding site, with function pertaining to the rennin-angiotensin system. Neurotensin is involved in many processes including mast cell degranulation and regulation of central nervous system dopaminergic and cholinergic circuits. A lower level of neurotensin is associated with schizophrenia, and it is implicated in cardiovascular disorders, addiction, Huntington disease and Parkinson disease. Neurotensin is also one of the most potent blockers of pain perception.
# Clinical significance
Metabolism of neurotensin is the most important role of neurolysin in vivo and has been identified as a non-AT1-non-AT2 angiotensin-binding site. Neurotensin is involved in many processes including mast cell degranullation and regulation of central nervous system dopaminergic and cholinergic circuits. Neurolysin has also been implicated in pain control, blood pressure regulation, sepsis, reproduction, cancer biology, pathogenesis of stroke, and glucose metabolism. Inhibition of neurolysin has been shown to produce neurotensin-induced analgesia in mice, and control of neurotensin levels by neurolysin may serve as a potential target for antipsychotic therapies.
# Interactions
This protein is known to interact with:
- Neurotensin
- HIV-1 | NLN (gene)
Neurolysin, mitochondrial is a protein that in humans is encoded by the NLN gene.[1][2] It is a 78-kDa enzyme, widely distributed in mammalian tissues and found in various subcellular locations that vary with cell type.[3] Neurolysin exemplifies the ability of neuropeptidases to target various cleavage site sequences by hydrolyzing them in vitro,[4][5] and metabolism of neurotensin is the most important role of neurolysin in vivo.[6] Neurolysin has also been implicated in pain control,[7][8][9] blood pressure regulation,[10][11] sepsis,[12] reproduction,[13][14] cancer biology[15] pathogenesis of stroke,[16] and glucose metabolism.[17]
# Structure
## Gene
The NLN gene lies on the chromosome location of 5q12.3 and consists of 14 exons.
## Protein
Neurolysin, with 704 amino acid residues, is a zinc metalloendopeptidase with a conserved HEXXH motif. It has an overall prolate ellipsoid shape, with a deep narrow channel dividing it into two roughly equal domains.[18] The catalytic site is contained within a thermolysin-like region found in many metallopeptidases and located in the domain near the floor of the channel.[6][19]
# Function
Neurolysin hydrolyzes only peptides containing 5-17 amino acids by cleaving at a limited set of sites.[18][20][21] The specificity of neurolysin for small bioactive peptides is due to the presence of large structural elements erected over its active site region that allow substrates access only through a deep narrow channel.[22] In vitro, neurolysin exemplifies the ability of some neuropeptidases to target diverse cleavage site sequences.[4][5] In vivo, their most established role is cleaving neurotensin between its 10th and 11th residues to produce inactive fragments and it has been recently identified as a non-AT1-non-AT2 angiotensin-binding site, with function pertaining to the rennin-angiotensin system.[6][23][24] Neurotensin is involved in many processes including mast cell degranulation and regulation of central nervous system dopaminergic and cholinergic circuits.[25][26][27] A lower level of neurotensin is associated with schizophrenia,[28] and it is implicated in cardiovascular disorders, addiction, Huntington disease and Parkinson disease.[26][29][30][31] Neurotensin is also one of the most potent blockers of pain perception.[32]
# Clinical significance
Metabolism of neurotensin is the most important role of neurolysin in vivo and has been identified as a non-AT1-non-AT2 angiotensin-binding site.[6][23][24] Neurotensin is involved in many processes including mast cell degranullation and regulation of central nervous system dopaminergic and cholinergic circuits.[25][26][27] Neurolysin has also been implicated in pain control,[7][8][9] blood pressure regulation,[10][11] sepsis,[12] reproduction,[13][14] cancer biology,[15] pathogenesis of stroke,[16] and glucose metabolism.[17] Inhibition of neurolysin has been shown to produce neurotensin-induced analgesia in mice,[33] and control of neurotensin levels by neurolysin may serve as a potential target for antipsychotic therapies.
# Interactions
This protein is known to interact with:
- Neurotensin[6][12]
- HIV-1[34] | https://www.wikidoc.org/index.php/NLN_(gene) | |
c5fad456b64b3d300d1fcbb123eca70a202416df | wikidoc | NNT (gene) | NNT (gene)
NAD(P) transhydrogenase, mitochondrial is an enzyme that in humans is encoded by the NNT gene on chromosome 5.
The NNT gene contains 26 exons and encodes a transhydrogenase protein that is ~109 kDa in molecular weight and is involved in antioxidant defense in the mitochondria. Two alternatively spliced variants, encoding the same protein, have been found for this gene.
# Structure
Transhydrogenases including NNT can exist in an ‘open’ conformation, where substrates can bind and products can dissociate, in which the dihydronicotinamide and nicotinamide rings are held apart to block hydride transfer. It can exist in an ‘occluded’ conformation, where the substrates are moved into apposition to permit redox chemistry. The protein comprises three subunits (dI, dII and dIII), with the dII component spanning the inner mitochondrial membrane. X-ray crystallography structure of the protein shows that proton pumping is probably coupled to changes in the binding affinities of dIII for NADP(+) and NADPH. The first betaalphabetaalphabeta motif of dIII contains a Gly-X-Gly-X-X-Ala/Val fingerprint, whereas the nicotinamide ring of NADP(+) is located on a ridge where it can interact with NADH on the dI subunit.
# Function
NAD(P) transhydrogenase, mitochondrial is an integral protein of the inner mitochondrial membrane. The enzyme couples hydride transfer of reducing equivalent between NAD(H) and NADP(+) to proton translocation across the inner mitochondrial membrane. Under most physiological conditions, the enzyme uses energy from the mitochondrial proton gradient to produce high concentrations of NADPH. The resulting NADPH is used for biosynthesis as well as in reactions inside the mitochondria required to remove reactive oxygen species such as to retain a reduced glutathione pool (high GSH/GSSG ratio). The enzyme may be inactivated by oxidative modifications.
Reaction catalyzed:
- NADPH + NAD+ = NADP+ + NADH.
# Clinical significance
NAD(P) transhydrogenase, mitochondrial abundance may be associated with human heart failure. In failing hearts, a partial loss of NAD(P) transhydrogenase's mitochondrial activity negatively impacts the NADPH-dependent enzyme activities in the mitochondria and the capacity of mitochondria to maintain proton gradients, which may adversely impact energy production and oxidative stress defense in heart failure and exacerbate oxidative damage to cellular proteins.
Mutations in the NNT gene have been associated to familial glucocorticoid deficiency 1, a severe autosomal recessive disorder in human characterized by insensitivity to adrenocorticotropic hormone action on the adrenal cortex and an inability of the adrenal cortex to produce cortisol Glucocorticoid deficiency 1 usually presents in neonatal to early childhood with episodes of hypoglycemia and other symptoms related to cortisol deficiency, including failure to thrive, recurrent illnesses or infections, convulsions, and shock. Diagnosis is confirmed with a low plasma cortisol measurement in the presence of an elevated adrenocorticotropic hormone level, and normal aldosterone and plasma renin measurements. | NNT (gene)
NAD(P) transhydrogenase, mitochondrial is an enzyme that in humans is encoded by the NNT gene on chromosome 5.[1][2][3]
The NNT gene contains 26 exons and encodes a transhydrogenase protein that is ~109 kDa in molecular weight and is involved in antioxidant defense in the mitochondria. Two alternatively spliced variants, encoding the same protein, have been found for this gene.[3]
# Structure
Transhydrogenases including NNT can exist in an ‘open’ conformation,[4] where substrates can bind and products can dissociate, in which the dihydronicotinamide and nicotinamide rings are held apart to block hydride transfer. It can exist in an ‘occluded’ conformation, where the substrates are moved into apposition to permit redox chemistry.[4] The protein comprises three subunits (dI, dII and dIII), with the dII component spanning the inner mitochondrial membrane.[5] X-ray crystallography structure of the protein shows that proton pumping is probably coupled to changes in the binding affinities of dIII for NADP(+) and NADPH. The first betaalphabetaalphabeta motif of dIII contains a Gly-X-Gly-X-X-Ala/Val fingerprint, whereas the nicotinamide ring of NADP(+) is located on a ridge where it can interact with NADH on the dI subunit.[5]
# Function
NAD(P) transhydrogenase, mitochondrial is an integral protein of the inner mitochondrial membrane. The enzyme couples hydride transfer of reducing equivalent between NAD(H) and NADP(+) to proton translocation across the inner mitochondrial membrane. Under most physiological conditions, the enzyme uses energy from the mitochondrial proton gradient to produce high concentrations of NADPH. The resulting NADPH is used for biosynthesis as well as in reactions inside the mitochondria required to remove reactive oxygen species such as to retain a reduced glutathione pool (high GSH/GSSG ratio). The enzyme may be inactivated by oxidative modifications.[6]
Reaction catalyzed:
- NADPH + NAD+ = NADP+ + NADH.
# Clinical significance
NAD(P) transhydrogenase, mitochondrial abundance may be associated with human heart failure.[7] In failing hearts, a partial loss of NAD(P) transhydrogenase's mitochondrial activity negatively impacts the NADPH-dependent enzyme activities in the mitochondria and the capacity of mitochondria to maintain proton gradients, which may adversely impact energy production and oxidative stress defense in heart failure and exacerbate oxidative damage to cellular proteins.[7]
Mutations in the NNT gene have been associated to familial glucocorticoid deficiency 1, a severe autosomal recessive disorder in human characterized by insensitivity to adrenocorticotropic hormone action on the adrenal cortex and an inability of the adrenal cortex to produce cortisol [8] Glucocorticoid deficiency 1 usually presents in neonatal to early childhood with episodes of hypoglycemia and other symptoms related to cortisol deficiency, including failure to thrive, recurrent illnesses or infections, convulsions, and shock. Diagnosis is confirmed with a low plasma cortisol measurement in the presence of an elevated adrenocorticotropic hormone level, and normal aldosterone and plasma renin measurements.[8] | https://www.wikidoc.org/index.php/NNT_(gene) | |
f6544a6e61c446a6a7a984003b0b220bbe102308 | wikidoc | NOV (gene) | NOV (gene)
NOV (nephroblastoma overexpressed) also known as CCN3 is a matricellular protein that in humans is encoded by the NOV gene.
# CCN family
NOV is a member of the CCN family of secreted, extracellular matrix (ECM)-associated signaling proteins (see also CCN intercellular signaling protein). The CCN acronym is derived from the first three members of the family being identified, namely CYR61 (cysteine-rich angiogenic inducer 61, or CCN1), CTGF (connective tissue growth factor, or CCN2), and NOV. These proteins, together with WISP1 (CCN4), WISP2 (CCN5), and WISP3 (CCN6) comprise the six-member CCN family in vertebrates and have been renamed CCN1-6 in the order of their discovery by international consensus.
# Structure
The human NOV protein contains 357 amino acids with an N-terminal secretory signal peptide followed by four structurally distinct domains with homologies to insulin-like growth factor binding protein (IGFBP), von Willebrand type C repeats (vWC), thrombospondin type 1 repeat (TSR), and a cysteine knot motif within the C-terminal (CT) domain.
# Function
NOV regulates multiple cellular activities including cell adhesion, migration, proliferation, differentiation, and survival. It functions by direct binding to integrin receptors, as well as other receptors such as NOTCH1 and fibulin 1c (FBLN1).
NOV is expressed during wound healing and induces angiogenesis in vivo. It is essential for self-renewal of CD34+ hematopoietic stem cells from umbilical cord blood.
NOV can bind BMP2 and inhibit its functions in promoting osteogenic differentiation, and stimulate osteoclastogenesis through a process that may involve calcium flux. Overexpression of Nov in transgenic mice in osteoblasts antagonizes both BMP and Wnt-signaling and result in osteopenia.
In February 2017, it was reported that the NOV protein was involved in regulatory T cell-mediated oligodendrocyte differentiation in the regeneration of myelin following damage to the myelin sheath. This finding revealed a new function for regulatory T cells that is distinct from their role in immunomodulation.
# Role in embryo development
In contrast to the lethality of Cyr61 (CCN1) and Ctgf (CCN2) genetic knockout in mice, Nov-null mice are viable and largely normal, exhibiting only modest and transient sexually dimorphic skeletal abnormalities. However, Nov-null mice show enhanced blood vessel neointimal thickening when challenged with vascular injury, indicating that NOV inhibits neoinitimal hyperplasia.
# Role in cancer
Although NOV inhibits the proliferation of cancer cells, it appears to promote metastasis. Nov overexpression results in reduced tumor size in glioma cells xenografts, but enhances metastatic potential in xenotransplanted melanoma cells. NOV expression is associated with a higher risk of metastasis and worse prognosis in patients with cancers such as Ewing’s sarcoma, melanoma, and breast cancer. In chronic myeloid leukemia (CML), NOV is downregulated as a consequence of the kinase activity of BCR-ABL, a chimeric protein generated through the chromosomal translocation between chromosome 9 and 22. Forced expression of NOV inhibits proliferation and restores growth control in CML cells, suggesting that NOV may be an alternate target for novel therapeutics against CML. | NOV (gene)
NOV (nephroblastoma overexpressed) also known as CCN3 is a matricellular protein that in humans is encoded by the NOV gene.[1][2]
# CCN family
NOV is a member of the CCN family of secreted, extracellular matrix (ECM)-associated signaling proteins (see also CCN intercellular signaling protein).[3][4] The CCN acronym is derived from the first three members of the family being identified, namely CYR61 (cysteine-rich angiogenic inducer 61, or CCN1), CTGF (connective tissue growth factor, or CCN2), and NOV. These proteins, together with WISP1 (CCN4), WISP2 (CCN5), and WISP3 (CCN6) comprise the six-member CCN family in vertebrates and have been renamed CCN1-6 in the order of their discovery by international consensus.[5]
# Structure
The human NOV protein contains 357 amino acids with an N-terminal secretory signal peptide followed by four structurally distinct domains with homologies to insulin-like growth factor binding protein (IGFBP), von Willebrand type C repeats (vWC), thrombospondin type 1 repeat (TSR), and a cysteine knot motif within the C-terminal (CT) domain.[6][7]
# Function
NOV regulates multiple cellular activities including cell adhesion, migration, proliferation, differentiation, and survival. It functions by direct binding to integrin receptors,[8][9][10] as well as other receptors such as NOTCH1[11] and fibulin 1c (FBLN1).[12]
NOV is expressed during wound healing and induces angiogenesis in vivo.[8][10] It is essential for self-renewal of CD34+ hematopoietic stem cells from umbilical cord blood.[13]
NOV can bind BMP2 and inhibit its functions in promoting osteogenic differentiation,[14] and stimulate osteoclastogenesis through a process that may involve calcium flux.[15] Overexpression of Nov in transgenic mice in osteoblasts antagonizes both BMP and Wnt-signaling and result in osteopenia.[16]
In February 2017, it was reported that the NOV protein was involved in regulatory T cell-mediated oligodendrocyte differentiation in the regeneration of myelin following damage to the myelin sheath. This finding revealed a new function for regulatory T cells that is distinct from their role in immunomodulation.[17]
# Role in embryo development
In contrast to the lethality of Cyr61 (CCN1) and Ctgf (CCN2) genetic knockout in mice, Nov-null mice are viable and largely normal, exhibiting only modest and transient sexually dimorphic skeletal abnormalities.[18] However, Nov-null mice show enhanced blood vessel neointimal thickening when challenged with vascular injury, indicating that NOV inhibits neoinitimal hyperplasia.[19]
# Role in cancer
Although NOV inhibits the proliferation of cancer cells,[20] it appears to promote metastasis.[21][22] Nov overexpression results in reduced tumor size in glioma cells xenografts,[23] but enhances metastatic potential in xenotransplanted melanoma cells.[24] NOV expression is associated with a higher risk of metastasis and worse prognosis in patients with cancers such as Ewing’s sarcoma, melanoma, and breast cancer.[25] In chronic myeloid leukemia (CML), NOV is downregulated as a consequence of the kinase activity of BCR-ABL, a chimeric protein generated through the chromosomal translocation between chromosome 9 and 22.[26] Forced expression of NOV inhibits proliferation and restores growth control in CML cells, suggesting that NOV may be an alternate target for novel therapeutics against CML.[3][27] | https://www.wikidoc.org/index.php/NOV_(gene) | |
b2ef95f098b3b6e1615ffebf1f36a4b4f1f1688c | wikidoc | Nitisinone | Nitisinone
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# Overview
Nitisinone is a Gastrointestinal Agent that is FDA approved for the treatment of hereditary tyrosinemia type 1 (HT-1). Common adverse reactions include hepatic neoplasm, liver failure, thrombocytopenia, leucopenia, visual system complaints including conjunctivitis, corneal opacity, keratitis, and photophobia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Orfadin(R) capsules (nitisinone) are indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1
### Dosage
- The recommended dose of Orfadin is 1 to 2 mg/kg divided into two daily doses. The initial dose is 1 mg/kg/day divided for morning and evening administration. Treatment with Orfadin should be initiated by a physician experienced in the treatment of HT-1.
- The dose of Orfadin may be adjusted in each patient. In patients whose erythrocyte PBG-synthase activity and urine 5-ALA and urine succinylacetone are not normalized within one month after the start of Orfadin treatment, the Orfadin dose may be increased to 1.5 mg/kg/day. In patients receiving 1.5 mg/kg/day, whose erythrocyte PBG-synthase activity and urine 5-ALA and urine succinylacetone remain elevated and whose plasma succinylacetone is not normalized after three months, the dose may be increased to up a maximum dose of 2 mg/kg/day.
- If plasma nitisinone concentration, plasma succinylacetone, urine 5-ALA and erythrocyte PBG-synthase activity are not available, clinical laboratory assessments should include urine succinyl acetone, liver function tests, alpha fetoprotein, and serum tyrosine and phenylalanine level. During initiation of therapy and during acute exacerbations, it may be necessary to follow more closely all available biochemical parameters
### DOSAGE FORMS AND STRENGTHS
- Orfadin capsules (nitisinone) are available as white capsules imprinted with ”NTBC” followed by "2 mg", "5 mg", or "10 mg", indicating the actual amount of nitisinone in each capsule.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nitisinone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nitisinone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indications
- Orfadin(R) capsules (nitisinone) are indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 (HT-1)
### Dosage
- The recommended dose of Orfadin is 1 to 2 mg/kg divided into two daily doses. The initial dose is 1 mg/kg/day divided for morning and evening administration. Treatment with Orfadin should be initiated by a physician experienced in the treatment of HT-1.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nitisinone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nitisinone in pediatric patients.
# Contraindications
- None
# Warnings
- Orfadin is an inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme in the tyrosine metabolic pathway. Therefore, treatment with Orfadin may cause an increase in blood tyrosine in patients with HT-1, and patients should maintain concomitant reduction in dietary tyrosine and phenylalanine while on Orfadin treatment. Plasma tyrosine levels should be maintained below 500 μmol/L. Inadequate restriction of tyrosine and phenylalanine intake may increase blood tyrosine levels and may be associated with blood tyrosine levels greater than 500 μmol/L leading to the following:
- Ocular signs and symptoms including corneal ulcers, corneal opacities, keratitis, conjunctivitis, eye pain, and photophobia have been reported in patients treated with Orfadin. Therefore, ophthalmologic examination including slit-lamp examination should be performed prior to initiating Orfadin treatment. Patients who develop photophobia, eye pain, or signs of inflammation such as redness, swelling, or burning of the eyes during treatment with Orfadin should undergo slit-lamp reexamination and immediate measurement of the plasma tyrosine concentration.
- Variable degrees of mental retardation and developmental delay. In patients treated with Orfadin who exhibit an abrupt change in neurologic status, a clinical laboratory assessment including plasma tyrosine levels should be performed.
- Painful hyperkeratotic plaques on the soles and palms.
- In patients with HT-1 treated with dietary restrictions and Orfadin who develop elevated plasma tyrosine levels, an assessment of dietary tyrosine intake should be performed.
- In clinical trials, patients treated with Orfadin and dietary restriction developed transient leucopenia (3%), thrombocytopenia (3%), or both (1.5%). One patient who developed both leucopenia and thrombocytopenia improved after the dose of Orfadin was decreased from 2 mg/kg to 1 mg/kg. No patients developed infections or bleeding as a result of the episodes of leucopenia and thromobocytopenia. Platelet and white blood cell counts should be monitored regularly during nitisinone therapy.
# Adverse Reactions
## Clinical Trials Experience
The following serious adverse reactions are described below and elsewhere in the labeling:
High Plasma Tyrosine Levels.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
### CLINICAL TRIALS EXPERIENCE
- Orfadin was studied in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 21.7 years at enrollment (median age 9 months), who were diagnosed with HT-1 by the presence of succinyl-acetone in the urine or plasma. The starting dose of Orfadin was 0.6 to 1 mg/kg/day, and the dose was increased in some patients to 2 mg/kg/day based on weight, biochemical, and enzyme markers. Median duration of treatment was 22.2 months (range 0.1 to 80 months).
- The most serious adverse reactions reported during Orfadin treatment were thrombocytopenia, leucopenia, porphyria, and ocular/visual complaints. Most patients with ocular/visual events had transient symptoms lasting less than one week, while 6 patients had symptoms lasting 16 to 672 days. Six patients had thrombocytopenia, with platelet counts 30,000/uL or lower in 3 patients. In 4 patients with thrombocytopenia, platelet counts returned to normal without change in Orfadin dose. In 2 patients platelet count returned to normal 2 weeks to 5 months after Orfadin treatment was discontinued. No patients developed infections or bleeding as a result of the episodes of leucopenia and thrombocytopenia.
- Other serious adverse events reported during Orfadin treatment were hepatic neoplasm, liver failure, and porphyric crises. Patients with hereditary tyrosinemia type 1 are at increased risk of developing porphyric crises, hepatic neoplasms, and liver failure requiring liver transplantation. These complications of HT-1 were observed in patients treated with nitisinone for a median of 22 months during the clinical trial (liver transplantation 13%, liver failure 7%, malignant hepatic neoplasms 5%, benign hepatic neoplasms 3%, porphyria 0.5%). Regular monitoring for these complications by hepatic imaging (ultrasound, computerized tomography, magnetic resonance imaging) and laboratory tests, including serum alpha-fetoprotein concentration is recommended. Patients with increasing alpha-fetoprotein levels or development of liver nodules during treatment with nitisinone should be evaluated for hepatic malignancy.
- The most common adverse reactions reported in the clinical trial are summarized in Table 1.
- Adverse reactions reported in less than 1% of the patients, regardless of causality assessment, included death, seizure, brain tumor, encephalopathy, headache, hyperkinesia, cyanosis, abdominal pain, diarrhea, enanthema, gastritis, gastroenteritis, gastrointestinal hemorrhage, melena, tooth discoloration, hepatic function disorder, elevated hepatic enzymes, liver enlargement, dehydration, hypoglycemia, thirst, infection, septicemia, otitis, infection (not otherwise specified), bronchitis, respiratory insufficiency, pathologic fracture, amenorrhea, nervousness, and somnolence.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Nitisinone in the drug label.
# Drug Interactions
There is limited information regarding Nitisinone Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Reproduction studies have been performed in mice at oral doses of about 0.4, 4 and 20 times the recommended human dose (1 mg/kg/day) and in rabbits at oral doses of about 1.6, 4 and 8 times the recommended human dose based on the body surface area. In mice, nitisinone has been shown to cause incomplete skeletal ossification of fetal bones at 0.4, 4 and 20 times the recommended human dose, increased gestational length at 4 and 20 times the recommended human dose, and decreased pup survival at 0.4 times the recommended human dose based on the body surface area. In rabbits, nitisinone caused incomplete skeletal ossification of fetal bones at 1.6, 4 and 8 times the recommended human dose based on the body surface area.
- However, there are no adequate and well controlled studies in pregnant women. Nitisinone should be used during pregnancy only if the potential benefit justified the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nitisinone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nitisinone during labor and delivery.
### Nursing Mothers
- Although the exposure was not quantified naive pups that were exposed to Orfadin via breast milk showed signs of ocular toxicity and lower body weight. This suggests that Orfadin is excreted via breast milk in rats. It is not known whether Orfadin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Orfadin is administered to a nursing woman.
### Pediatric Use
- Pediatric patients with HT-1, ages birth to 17 years have been treated with Orfadin in one open-label, uncontrolled clinical study. Monitoring of blood and urine succinyl acetone levels are recommended in the children to ensure adequate control. A nutritionist skilled in managing children with inborn errors of metabolism should be employed to design a low-protein diet deficient in tyrosine and phenylalanine.
### Geriatic Use
- Clinical studies of nitisinone did not include any subjects aged 65 and over to determine whether they respond differently from younger subjects. HT-1 is presently a disease of the pediatric population. No pharmacokinetic studies of nitisinone have been performed in geriatric patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy in this patient population.
### Gender
- The effect of gender on the pharmacokinetics of Orfadin has not been studied.
### Race
- The effect of race on the pharmacokinetics of Orfadin has not been studied.
### Renal Impairment
- The effect of renal insufficiency on the pharmacokinetics of Orfadin has not been studied.
### Hepatic Impairment
- The effect of hepatic dysfunction on the pharmacokinetics of nitisinone has not been studied.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nitisinone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nitisinone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Orfadin should be taken at least one hour before or at least two hours after a meal, since food effect is unknown. For young children, Orfadin capsules may be opened and the contents suspended in a small amount of water immediately before use.
- Physicians should counsel patients and their parents or caregivers of the need to maintain dietary restriction of tyrosine and phenylalanine when taking Orfadin to treat hereditary tyrosinemia type 1.
### Monitoring
- Platelet and white blood cell counts should be monitored regularly during nitisinone therapy.
- Regular monitoring for the hepatic complications by hepatic imaging (ultrasound, computerized tomography, magnetic resonance imaging) and laboratory tests, including serum alpha-fetoprotein concentration is recommended.
# IV Compatibility
There is limited information regarding IV Compatibility of Nitisinone in the drug label.
# Overdosage
- Accidental ingestion of Orfadin by individuals eating normal diets not restricted in tyrosine and phenylalanine will result in elevated tyrosine levels. In healthy volunteers given a single 1 mg/kg dose of nitisinone, the plasma tyrosine level reached a maximum of 1200 μmol/L from 48 to 120 hours after dosing. After a washout period of 14 days, the mean value of plasma tyrosine was still 808 μmol/L. Fasted follow-up samples obtained from volunteers several weeks later showed tyrosine values back to normal. There were no reports of changes in vital signs or laboratory data of any clinical significance. One patient reported sensitivity to sunlight. Hypertyrosinemia has been reported with Orfadin treatment
# Pharmacology
## Mechanism of Action
- Nitisinone is a competitive inhibitor of 4-hydroxy-phenyl-pyruvate dioxygenase, an enzyme upstream of fumarylacetoacetate hydrolase (FAH) in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with HT-1, nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate.
- In patients with HT-1, these catabolic intermediates are converted to the toxic metabolites succinylacetone and succinylacetoacetate, which are responsible for the observed liver and kidney toxicity. Succinylacetone can also inhibit the porphyrin synthesis pathway leading to the accumulation of 5-aminolevulinate, a neurotoxin responsible for the porphyric crises characteristic of HT-1. Nitisinone inhibits catabolism of the amino acid tyrosine and can result in elevated plasma levels of tyrosine. Therefore, treatment with nitisinone requires restriction of the dietary intake of tyrosine and phenylalanine to prevent the toxicity associated with elevated plasma levels of tyrosine
## Structure
- Orfadin contains nitisinone, which is a hydroxyphenyl-pyruvate dioxygenase inhibitor indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 (HT-1).
- Nitisinone occurs as white to yellowish-white, crystalline powder. It is practically insoluble in water, soluble in 2M sodium hydroxide and in methanol, and sparingly soluble in alcohol.
- Chemically, nitisinone is 2-(2-nitro-4-trifluoromethylbenzoyl) cyclohexane-1,3-dione, and the structural formula is:
- Figure 1. The molecular formula is C14H10F3NO5 with a relative mass of 329.23
- Orfadin is a hard white-opaque capsule, marked as 2 mg, 5 mg or 10 mg strengths of nitisinone and is intended for oral administration. Each capsule contains 2 mg, 5 mg or 10 mg nitisinone, plus pre-gelatinized starch. The capsule shell is gelatin and titanium dioxide and the imprint is an iron oxide.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Nitisinone in the drug label.
## Pharmacokinetics
- Limited information exists on the metabolism, distribution, and excretion of nitisinone in rats. Nitisinone was greater than 90% bioavailable following oral administration of the labeled compound in rats and was distributed to different organs, particularly the liver and kidney, where radioactivity remained for 7 days after administration. Nitisinone was bio-transformed in rats and excreted via the urine.
- No pharmacokinetic studies of nitisinone have been conducted in children or HT-1 patients.
- The single-dose pharmacokinetics of nitisinone have been studied in ten healthy male volunteers aged 19-39 years (median 32 years). Nitisinone, 1 mg/kg body weight, was administered as a capsule and a liquid. The median time for maximum plasma concentration was 3 hours for the capsule and 15 minutes for the liquid. The capsule and liquid formulation were found to be bioequivalent based on an analysis of area under the plasma concentration-time curve and maximum plasma concentration (Cmax).
- No information on the metabolism of nitisinone in humans is available. The mean terminal plasma half-life of nitisinone in healthy male volunteers was 54 hours. The effect of food on the pharmacokinetics of nitisinone has not been studied.
## Nonclinical Toxicology
- No long-term studies in animals have been performed to evaluate the carcinogenic potential of nitisinone. Nitisinone was not genotoxic in the Ames test and the in vivo mouse liver unscheduled DNA synthesis (UDS) test. Nitisinone was mutagenic in the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test and in an in vivo mouse bone marrow micronucleus test.
- In a single dose-group study in rats given 100 mg/kg (12 times the recommended clinical dose based on relative body surface area), reduced litter size, decreased pup weight at birth, and decreased survival of pups after birth was demonstrated.
### ANIMAL TOXICOLOGY AND / OR PHARMACOLOGY
- In pregnant mice given oral gavage doses of 5, 50, 250 mg/kg/day from gestation day 7 through 16, incomplete skeletal ossification of fetal bones was observed with doses of ≥5 mg/kg/day. In pregnant mice given the same doses from gestation day 7 through weaning, gestation length increased in animals given ≥50 mg/kg/day. Decreased pup survival by 9% compared to 5% in untreated controls was observed at 5 mg/kg/day.
- In pregnant rabbits given oral gavage doses of 5, 12, 25 mg/kg/day from gestation day 7 through 19, maternal toxicity and incomplete skeletal ossification of fetal bones was observed with doses of ≥5 mg/kg/day.
# Clinical Studies
- The efficacy and safety of Orfadin in patients with HT-1 were evaluated in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 21.7 years at enrollment (median age 9 months).
- Patients were diagnosed with HT-1 by the presence of succinylacetone in the urine or plasma. All patients were treated with Orfadin at a starting dose of 0.6 to 1 mg/kg/day, and the dose was increased in some patients to 2 mg/kg/day based on weight, liver and kidney function tests, platelet count, serum amino acids, urinary phenolic acid, plasma and urine succinylacetone, erythrocyte PBG-synthase, and urine 5-ALA. The median duration of treatment was 22 months (range less than 1 month to 80 months). Efficacy was assessed by comparison of survival and incidence of liver transplant to historical controls.
- In this clinical study, for patients presenting with HT-1 younger than 2 months of age who were treated with dietary restriction and nitisinone, 2- and 4-year survival probabilities were 88% and 88%, respectively. Data from historical controls showed that patients treated with dietary restriction alone had 2- and 4-year survival probabilities of 29% and 29%, respectively. For patients presenting between 2 and 6 months of age who were treated with dietary restrictions and nitisinone, 2- and 4-year survival probabilities were 94% and 94%, respectively. Data for historical controls showed that patients treated with dietary restriction alone had 2- and 4-year survival probabilities of 74% and 60%, respectively.
- The effects on urine and plasma succinylacetone, porphyrin metabolism, and urinary alpha-1-microglobulin were also assessed in this clinical study.
- Urine succinylacetone was measured in 186 patients. In all 186 patients, urinary succinylacetone level decreased to less than 1 mmol/mol creatinine. The median time to normalization was 0.3 months. The probability of recurrence of abnormal values of urine succinylacetone was 1% at a nitisinone concentration of 37 μmol/L (95% confidence interval: 23-51 μmol/L). Plasma succinylacetone was measured in 172 patients. In 150 patients (87%), plasma succinylacetone decreased to less than 0.1 μmol/L. The median time to normalization was 3.9 months.
- Porphyria-like crisis were reported in 3 patients (0.3% of cases per year) during the clinical study. This compares to an incidence of 5 to 20% of cases per year expected as part of the natural history of the disorder. An assessment of porphyria-like crises was performed because these events are commonly reported in patients with HT-1 who are not treated with nitisinone.
- Urinary alpha-1-microglobulin, a proposed marker of proximal tubular dysfunction, was measured in 100 patients at baseline.
- The overall median pretreatment level was 4.3 g/mol creatinine. After one year of treatment in a subgroup of patients (N=100), overall median alpha-1-microglobulin decreased by 1.5 g/mol creatinine. In patients 24 months of age and younger in whom multiple values were available (N=65), median alpha-1-microglobulin levels decreased from 5.0 to 3.0 g/mol creatinine (reference value for age ≤12 g/mol creatinine). In patients older than 24 months in whom multiple values were available (N=35), median alpha-1-microglobulin levels decreased from 2.8 to 2.0 g/mol creatinine (reference for age ≤6 g/mol creatinine).
- The long term effect of nitisinone with regard to hepatic function in patients was not assessed.
# How Supplied
- Orfadin capsules are white and marked in black with ”NTBC” and identified as 2 mg, 5 mg or 10 mg strengths of nitisinone. The capsules are packed in a high density (HD) polyethylene container with a tamper-resistant low density (LD) polyethylene snap-on cap. Each bottle contains 60 capsules.
## Storage
- Store refrigerated, 2-8°C (36 - 46°F).
# Images
## Drug Images
## Package and Label Display Panel
### Ingredients and Appearance
# Patient Counseling Information
- Advise patients and caregivers of the need to maintain dietary restriction of tyrosine and phenylalanine when taking Orfadin to treat hereditary tyrosinemia type 1.
- Advise patients and caregivers to report promptly unexplained eye symptoms, rash, jaundice, or excessive bleeding
# Precautions with Alcohol
- Alcohol-Nitisinone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Orfadin®
# Look-Alike Drug Names
There is limited information regarding Nitisinone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Nitisinone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Nitisinone is a Gastrointestinal Agent that is FDA approved for the treatment of hereditary tyrosinemia type 1 (HT-1). Common adverse reactions include hepatic neoplasm, liver failure, thrombocytopenia, leucopenia, visual system complaints including conjunctivitis, corneal opacity, keratitis, and photophobia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Orfadin(R) capsules (nitisinone) are indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1
### Dosage
- The recommended dose of Orfadin is 1 to 2 mg/kg divided into two daily doses. The initial dose is 1 mg/kg/day divided for morning and evening administration. Treatment with Orfadin should be initiated by a physician experienced in the treatment of HT-1.
- The dose of Orfadin may be adjusted in each patient. In patients whose erythrocyte PBG-synthase activity and urine 5-ALA and urine succinylacetone are not normalized within one month after the start of Orfadin treatment, the Orfadin dose may be increased to 1.5 mg/kg/day. In patients receiving 1.5 mg/kg/day, whose erythrocyte PBG-synthase activity and urine 5-ALA and urine succinylacetone remain elevated and whose plasma succinylacetone is not normalized after three months, the dose may be increased to up a maximum dose of 2 mg/kg/day.
- If plasma nitisinone concentration, plasma succinylacetone, urine 5-ALA and erythrocyte PBG-synthase activity are not available, clinical laboratory assessments should include urine succinyl acetone, liver function tests, alpha fetoprotein, and serum tyrosine and phenylalanine level. During initiation of therapy and during acute exacerbations, it may be necessary to follow more closely all available biochemical parameters
### DOSAGE FORMS AND STRENGTHS
- Orfadin capsules (nitisinone) are available as white capsules imprinted with ”NTBC” followed by "2 mg", "5 mg", or "10 mg", indicating the actual amount of nitisinone in each capsule.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nitisinone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nitisinone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indications
- Orfadin(R) capsules (nitisinone) are indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 (HT-1)
### Dosage
- The recommended dose of Orfadin is 1 to 2 mg/kg divided into two daily doses. The initial dose is 1 mg/kg/day divided for morning and evening administration. Treatment with Orfadin should be initiated by a physician experienced in the treatment of HT-1.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nitisinone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nitisinone in pediatric patients.
# Contraindications
- None
# Warnings
- Orfadin is an inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme in the tyrosine metabolic pathway. Therefore, treatment with Orfadin may cause an increase in blood tyrosine in patients with HT-1, and patients should maintain concomitant reduction in dietary tyrosine and phenylalanine while on Orfadin treatment. Plasma tyrosine levels should be maintained below 500 μmol/L. Inadequate restriction of tyrosine and phenylalanine intake may increase blood tyrosine levels and may be associated with blood tyrosine levels greater than 500 μmol/L leading to the following:
- Ocular signs and symptoms including corneal ulcers, corneal opacities, keratitis, conjunctivitis, eye pain, and photophobia have been reported in patients treated with Orfadin. Therefore, ophthalmologic examination including slit-lamp examination should be performed prior to initiating Orfadin treatment. Patients who develop photophobia, eye pain, or signs of inflammation such as redness, swelling, or burning of the eyes during treatment with Orfadin should undergo slit-lamp reexamination and immediate measurement of the plasma tyrosine concentration.
- Variable degrees of mental retardation and developmental delay. In patients treated with Orfadin who exhibit an abrupt change in neurologic status, a clinical laboratory assessment including plasma tyrosine levels should be performed.
- Painful hyperkeratotic plaques on the soles and palms.
- In patients with HT-1 treated with dietary restrictions and Orfadin who develop elevated plasma tyrosine levels, an assessment of dietary tyrosine intake should be performed.
- In clinical trials, patients treated with Orfadin and dietary restriction developed transient leucopenia (3%), thrombocytopenia (3%), or both (1.5%). One patient who developed both leucopenia and thrombocytopenia improved after the dose of Orfadin was decreased from 2 mg/kg to 1 mg/kg. No patients developed infections or bleeding as a result of the episodes of leucopenia and thromobocytopenia. Platelet and white blood cell counts should be monitored regularly during nitisinone therapy.
# Adverse Reactions
## Clinical Trials Experience
The following serious adverse reactions are described below and elsewhere in the labeling:
High Plasma Tyrosine Levels.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
### CLINICAL TRIALS EXPERIENCE
- Orfadin was studied in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 21.7 years at enrollment (median age 9 months), who were diagnosed with HT-1 by the presence of succinyl-acetone in the urine or plasma. The starting dose of Orfadin was 0.6 to 1 mg/kg/day, and the dose was increased in some patients to 2 mg/kg/day based on weight, biochemical, and enzyme markers. Median duration of treatment was 22.2 months (range 0.1 to 80 months).
- The most serious adverse reactions reported during Orfadin treatment were thrombocytopenia, leucopenia, porphyria, and ocular/visual complaints. Most patients with ocular/visual events had transient symptoms lasting less than one week, while 6 patients had symptoms lasting 16 to 672 days. Six patients had thrombocytopenia, with platelet counts 30,000/uL or lower in 3 patients. In 4 patients with thrombocytopenia, platelet counts returned to normal without change in Orfadin dose. In 2 patients platelet count returned to normal 2 weeks to 5 months after Orfadin treatment was discontinued. No patients developed infections or bleeding as a result of the episodes of leucopenia and thrombocytopenia.
- Other serious adverse events reported during Orfadin treatment were hepatic neoplasm, liver failure, and porphyric crises. Patients with hereditary tyrosinemia type 1 are at increased risk of developing porphyric crises, hepatic neoplasms, and liver failure requiring liver transplantation. These complications of HT-1 were observed in patients treated with nitisinone for a median of 22 months during the clinical trial (liver transplantation 13%, liver failure 7%, malignant hepatic neoplasms 5%, benign hepatic neoplasms 3%, porphyria 0.5%). Regular monitoring for these complications by hepatic imaging (ultrasound, computerized tomography, magnetic resonance imaging) and laboratory tests, including serum alpha-fetoprotein concentration is recommended. Patients with increasing alpha-fetoprotein levels or development of liver nodules during treatment with nitisinone should be evaluated for hepatic malignancy.
- The most common adverse reactions reported in the clinical trial are summarized in Table 1.
- Adverse reactions reported in less than 1% of the patients, regardless of causality assessment, included death, seizure, brain tumor, encephalopathy, headache, hyperkinesia, cyanosis, abdominal pain, diarrhea, enanthema, gastritis, gastroenteritis, gastrointestinal hemorrhage, melena, tooth discoloration, hepatic function disorder, elevated hepatic enzymes, liver enlargement, dehydration, hypoglycemia, thirst, infection, septicemia, otitis, infection (not otherwise specified), bronchitis, respiratory insufficiency, pathologic fracture, amenorrhea, nervousness, and somnolence.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Nitisinone in the drug label.
# Drug Interactions
There is limited information regarding Nitisinone Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Reproduction studies have been performed in mice at oral doses of about 0.4, 4 and 20 times the recommended human dose (1 mg/kg/day) and in rabbits at oral doses of about 1.6, 4 and 8 times the recommended human dose based on the body surface area. In mice, nitisinone has been shown to cause incomplete skeletal ossification of fetal bones at 0.4, 4 and 20 times the recommended human dose, increased gestational length at 4 and 20 times the recommended human dose, and decreased pup survival at 0.4 times the recommended human dose based on the body surface area. In rabbits, nitisinone caused incomplete skeletal ossification of fetal bones at 1.6, 4 and 8 times the recommended human dose based on the body surface area.
- However, there are no adequate and well controlled studies in pregnant women. Nitisinone should be used during pregnancy only if the potential benefit justified the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nitisinone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nitisinone during labor and delivery.
### Nursing Mothers
- Although the exposure was not quantified naive pups that were exposed to Orfadin via breast milk showed signs of ocular toxicity and lower body weight. This suggests that Orfadin is excreted via breast milk in rats. It is not known whether Orfadin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Orfadin is administered to a nursing woman.
### Pediatric Use
- Pediatric patients with HT-1, ages birth to 17 years have been treated with Orfadin in one open-label, uncontrolled clinical study. Monitoring of blood and urine succinyl acetone levels are recommended in the children to ensure adequate control. A nutritionist skilled in managing children with inborn errors of metabolism should be employed to design a low-protein diet deficient in tyrosine and phenylalanine.
### Geriatic Use
- Clinical studies of nitisinone did not include any subjects aged 65 and over to determine whether they respond differently from younger subjects. HT-1 is presently a disease of the pediatric population. No pharmacokinetic studies of nitisinone have been performed in geriatric patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy in this patient population.
### Gender
- The effect of gender on the pharmacokinetics of Orfadin has not been studied.
### Race
- The effect of race on the pharmacokinetics of Orfadin has not been studied.
### Renal Impairment
- The effect of renal insufficiency on the pharmacokinetics of Orfadin has not been studied.
### Hepatic Impairment
- The effect of hepatic dysfunction on the pharmacokinetics of nitisinone has not been studied.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nitisinone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nitisinone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Orfadin should be taken at least one hour before or at least two hours after a meal, since food effect is unknown. For young children, Orfadin capsules may be opened and the contents suspended in a small amount of water immediately before use.
- Physicians should counsel patients and their parents or caregivers of the need to maintain dietary restriction of tyrosine and phenylalanine when taking Orfadin to treat hereditary tyrosinemia type 1.
### Monitoring
- Platelet and white blood cell counts should be monitored regularly during nitisinone therapy.
- Regular monitoring for the hepatic complications by hepatic imaging (ultrasound, computerized tomography, magnetic resonance imaging) and laboratory tests, including serum alpha-fetoprotein concentration is recommended.
# IV Compatibility
There is limited information regarding IV Compatibility of Nitisinone in the drug label.
# Overdosage
- Accidental ingestion of Orfadin by individuals eating normal diets not restricted in tyrosine and phenylalanine will result in elevated tyrosine levels. In healthy volunteers given a single 1 mg/kg dose of nitisinone, the plasma tyrosine level reached a maximum of 1200 μmol/L from 48 to 120 hours after dosing. After a washout period of 14 days, the mean value of plasma tyrosine was still 808 μmol/L. Fasted follow-up samples obtained from volunteers several weeks later showed tyrosine values back to normal. There were no reports of changes in vital signs or laboratory data of any clinical significance. One patient reported sensitivity to sunlight. Hypertyrosinemia has been reported with Orfadin treatment
# Pharmacology
## Mechanism of Action
- Nitisinone is a competitive inhibitor of 4-hydroxy-phenyl-pyruvate dioxygenase, an enzyme upstream of fumarylacetoacetate hydrolase (FAH) in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with HT-1, nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate.
- In patients with HT-1, these catabolic intermediates are converted to the toxic metabolites succinylacetone and succinylacetoacetate, which are responsible for the observed liver and kidney toxicity. Succinylacetone can also inhibit the porphyrin synthesis pathway leading to the accumulation of 5-aminolevulinate, a neurotoxin responsible for the porphyric crises characteristic of HT-1. Nitisinone inhibits catabolism of the amino acid tyrosine and can result in elevated plasma levels of tyrosine. Therefore, treatment with nitisinone requires restriction of the dietary intake of tyrosine and phenylalanine to prevent the toxicity associated with elevated plasma levels of tyrosine
## Structure
- Orfadin contains nitisinone, which is a hydroxyphenyl-pyruvate dioxygenase inhibitor indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 (HT-1).
- Nitisinone occurs as white to yellowish-white, crystalline powder. It is practically insoluble in water, soluble in 2M sodium hydroxide and in methanol, and sparingly soluble in alcohol.
- Chemically, nitisinone is 2-(2-nitro-4-trifluoromethylbenzoyl) cyclohexane-1,3-dione, and the structural formula is:
- Figure 1. The molecular formula is C14H10F3NO5 with a relative mass of 329.23
- Orfadin is a hard white-opaque capsule, marked as 2 mg, 5 mg or 10 mg strengths of nitisinone and is intended for oral administration. Each capsule contains 2 mg, 5 mg or 10 mg nitisinone, plus pre-gelatinized starch. The capsule shell is gelatin and titanium dioxide and the imprint is an iron oxide.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Nitisinone in the drug label.
## Pharmacokinetics
- Limited information exists on the metabolism, distribution, and excretion of nitisinone in rats. Nitisinone was greater than 90% bioavailable following oral administration of the labeled compound in rats and was distributed to different organs, particularly the liver and kidney, where radioactivity remained for 7 days after administration. Nitisinone was bio-transformed in rats and excreted via the urine.
- No pharmacokinetic studies of nitisinone have been conducted in children or HT-1 patients.
- The single-dose pharmacokinetics of nitisinone have been studied in ten healthy male volunteers aged 19-39 years (median 32 years). Nitisinone, 1 mg/kg body weight, was administered as a capsule and a liquid. The median time for maximum plasma concentration was 3 hours for the capsule and 15 minutes for the liquid. The capsule and liquid formulation were found to be bioequivalent based on an analysis of area under the plasma concentration-time curve and maximum plasma concentration (Cmax).
- No information on the metabolism of nitisinone in humans is available. The mean terminal plasma half-life of nitisinone in healthy male volunteers was 54 hours. The effect of food on the pharmacokinetics of nitisinone has not been studied.
## Nonclinical Toxicology
- No long-term studies in animals have been performed to evaluate the carcinogenic potential of nitisinone. Nitisinone was not genotoxic in the Ames test and the in vivo mouse liver unscheduled DNA synthesis (UDS) test. Nitisinone was mutagenic in the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test and in an in vivo mouse bone marrow micronucleus test.
- In a single dose-group study in rats given 100 mg/kg (12 times the recommended clinical dose based on relative body surface area), reduced litter size, decreased pup weight at birth, and decreased survival of pups after birth was demonstrated.
### ANIMAL TOXICOLOGY AND / OR PHARMACOLOGY
- In pregnant mice given oral gavage doses of 5, 50, 250 mg/kg/day from gestation day 7 through 16, incomplete skeletal ossification of fetal bones was observed with doses of ≥5 mg/kg/day. In pregnant mice given the same doses from gestation day 7 through weaning, gestation length increased in animals given ≥50 mg/kg/day. Decreased pup survival by 9% compared to 5% in untreated controls was observed at 5 mg/kg/day.
- In pregnant rabbits given oral gavage doses of 5, 12, 25 mg/kg/day from gestation day 7 through 19, maternal toxicity and incomplete skeletal ossification of fetal bones was observed with doses of ≥5 mg/kg/day.
# Clinical Studies
- The efficacy and safety of Orfadin in patients with HT-1 were evaluated in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 21.7 years at enrollment (median age 9 months).
- Patients were diagnosed with HT-1 by the presence of succinylacetone in the urine or plasma. All patients were treated with Orfadin at a starting dose of 0.6 to 1 mg/kg/day, and the dose was increased in some patients to 2 mg/kg/day based on weight, liver and kidney function tests, platelet count, serum amino acids, urinary phenolic acid, plasma and urine succinylacetone, erythrocyte PBG-synthase, and urine 5-ALA. The median duration of treatment was 22 months (range less than 1 month to 80 months). Efficacy was assessed by comparison of survival and incidence of liver transplant to historical controls.
- In this clinical study, for patients presenting with HT-1 younger than 2 months of age who were treated with dietary restriction and nitisinone, 2- and 4-year survival probabilities were 88% and 88%, respectively. Data from historical controls showed that patients treated with dietary restriction alone had 2- and 4-year survival probabilities of 29% and 29%, respectively. For patients presenting between 2 and 6 months of age who were treated with dietary restrictions and nitisinone, 2- and 4-year survival probabilities were 94% and 94%, respectively. Data for historical controls showed that patients treated with dietary restriction alone had 2- and 4-year survival probabilities of 74% and 60%, respectively.
- The effects on urine and plasma succinylacetone, porphyrin metabolism, and urinary alpha-1-microglobulin were also assessed in this clinical study.
- Urine succinylacetone was measured in 186 patients. In all 186 patients, urinary succinylacetone level decreased to less than 1 mmol/mol creatinine. The median time to normalization was 0.3 months. The probability of recurrence of abnormal values of urine succinylacetone was 1% at a nitisinone concentration of 37 μmol/L (95% confidence interval: 23-51 μmol/L). Plasma succinylacetone was measured in 172 patients. In 150 patients (87%), plasma succinylacetone decreased to less than 0.1 μmol/L. The median time to normalization was 3.9 months.
- Porphyria-like crisis were reported in 3 patients (0.3% of cases per year) during the clinical study. This compares to an incidence of 5 to 20% of cases per year expected as part of the natural history of the disorder. An assessment of porphyria-like crises was performed because these events are commonly reported in patients with HT-1 who are not treated with nitisinone.
- Urinary alpha-1-microglobulin, a proposed marker of proximal tubular dysfunction, was measured in 100 patients at baseline.
- The overall median pretreatment level was 4.3 g/mol creatinine. After one year of treatment in a subgroup of patients (N=100), overall median alpha-1-microglobulin decreased by 1.5 g/mol creatinine. In patients 24 months of age and younger in whom multiple values were available (N=65), median alpha-1-microglobulin levels decreased from 5.0 to 3.0 g/mol creatinine (reference value for age ≤12 g/mol creatinine). In patients older than 24 months in whom multiple values were available (N=35), median alpha-1-microglobulin levels decreased from 2.8 to 2.0 g/mol creatinine (reference for age ≤6 g/mol creatinine).
- The long term effect of nitisinone with regard to hepatic function in patients was not assessed.
# How Supplied
- Orfadin capsules are white and marked in black with ”NTBC” and identified as 2 mg, 5 mg or 10 mg strengths of nitisinone. The capsules are packed in a high density (HD) polyethylene container with a tamper-resistant low density (LD) polyethylene snap-on cap. Each bottle contains 60 capsules.
## Storage
- Store refrigerated, 2-8°C (36 - 46°F).
# Images
## Drug Images
## Package and Label Display Panel
### Ingredients and Appearance
# Patient Counseling Information
- Advise patients and caregivers of the need to maintain dietary restriction of tyrosine and phenylalanine when taking Orfadin to treat hereditary tyrosinemia type 1.
- Advise patients and caregivers to report promptly unexplained eye symptoms, rash, jaundice, or excessive bleeding
# Precautions with Alcohol
- Alcohol-Nitisinone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Orfadin®[1]
# Look-Alike Drug Names
There is limited information regarding Nitisinone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/NTBC | |
48d7afacb19cf5f04c553ac84a19b831b54b14b4 | wikidoc | Nabumetone | Nabumetone
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Nabumetone is an NSAID that is FDA approved for the {{{indicationType}}} of osteoarthritis and rheumatoid arthritis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema, pruritus, rash, abdominal pain, constipation, diarrhea, flatulence, indigestion, nausea, occult blood in stools, increased liver function test, dizziness, feeling nervous, headache, insomnia, somnolence, tinnitus.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended starting dose is 1,000 mg taken as a single dose with or without food. Some patients may obtain more symptomatic relief from 1,500 mg to 2,000 mg per day. Nabumetone tablets can be given in either a single or twice-daily dose. Dosages greater than 2,000 mg per day have not been studied. The lowest effective dose should be used for chronic treatment. Patients weighing under 50 kg may be less likely to require dosages beyond 1,000 mg; therefore, after observing the response to initial therapy, the dose should be adjusted to meet individual patients' requirements.
- Dosing Information
- The recommended starting dose is 1,000 mg taken as a single dose with or without food. Some patients may obtain more symptomatic relief from 1,500 mg to 2,000 mg per day. Nabumetone tablets can be given in either a single or twice-daily dose. Dosages greater than 2,000 mg per day have not been studied. The lowest effective dose should be used for chronic treatment. Patients weighing under 50 kg may be less likely to require dosages beyond 1,000 mg; therefore, after observing the response to initial therapy, the dose should be adjusted to meet individual patients' requirements.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nabumetone in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- A single 2-gram loading dose of nabumetone was given followed by 1 gram twice daily for 7 days.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Nabumetone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nabumetone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nabumetone in pediatric patients.
# Contraindications
- Nabumetone tablets are contraindicated in patients with known hypersensitivity to nabumetone or its excipients.
- Nabumetone tablets 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-like reactions to NSAIDs have been reported in such patients.
- Nabumetone tablets are 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 3 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 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.
- Hypertension: NSAIDs, including nabumetone tablets, can lead to onset of new hypertension or worsening of preexisting 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 nabumetone tablets, 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. Nabumetone tablets should be used with caution in patients with fluid retention or heart failure.
- NSAIDs, including nabumetone tablets, 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 1 in 5 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 to 6 months, and in about 2 to 4% of patients treated for 1 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.
- In controlled clinical trials involving 1,677 patients treated with nabumetone (1,140 followed for 1 year and 927 for 2 years), the cumulative incidence of peptic ulcers was 0.3% (95% CI; 0%, 0.6%) at 3 to 6 months, 0.5% (95% CI; 0.1%, 0.9%) at 1 year and 0.8% (95% CI; 0.3%, 1.3%) at 2 years. In patients with active peptic ulcer, physicians must weigh the benefits of therapy with nabumetone against possible hazards, institute an appropriate ulcer treatment regimen and monitor the patients' progress carefully.
- NSAIDs should be prescribed with extreme caution in those with a 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.
- Renal Effects: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 an NSAID results in a dose-dependent decrease in prostaglandin synthesis and, secondarily, in a reduction of 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 the elderly. Discontinuation of NSAID therapy is typically followed by recovery to the pretreatment state.
- Advanced Renal Disease:No information is available from controlled clinical studies regarding the use of nabumetone tablets in patients with advanced renal disease. Therefore, treatment with nabumetone tablets is not recommended in these patients with advanced renal disease. If nabumetone tablets therapy must be initiated, close monitoring of the patient's renal function is advisable.
- Because nabumetone undergoes extensive hepatic metabolism, no adjustment of the dosage of nabumetone is generally necessary in patients with mild renal insufficiency; however, as with all NSAIDs, patients with impaired renal function should be monitored more closely than patients with normal renal function. In subjects with moderate renal impairment (creatinine clearance 30 to 49 mL/min) there is a 50% increase in unbound plasma 6MNA and dose adjustment may be warranted. The oxidized and conjugated metabolites of 6MNA are eliminated primarily by the kidneys.
- Anaphylactoid Reactions:As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to nabumetone tablets. Nabumetone tablets 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 anaphylactoid reaction occurs.
- Skin Reactions:NSAIDs, including nabumetone tablets, can cause serious skin 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.
- Pregnancy:In late pregnancy, as with other NSAIDs, nabumetone tablets should be avoided because it may cause premature closure of the ductus arteriosus.
### Precautions
- General
- Nabumetone tablets 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 nabumetone tablets in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
- Hepatic Effects
- Borderline elevations of 1 or more liver function tests may occur in up to 15% of patients taking NSAIDs including nabumetone tablets. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately 3 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 nabumetone tablets. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), nabumetone tablets should be discontinued.
- Hematological Effects
- Anemia is sometimes seen in patients receiving NSAIDs, including nabumetone tablets. 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 nabumetone tablets, 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 nabumetone tablets 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, nabumetone tablets should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
- Photosensitivity
- Based on ultraviolet (U.V.) light photosensitivity testing, nabumetone may be associated with more reactions to sun exposure than might be expected based on skin tanning types.
- Laboratory Tests
- Because serious G.I.tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs and symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, nabumetone tablets should be discontinued.
# Adverse Reactions
## Clinical Trials Experience
- Adverse reaction information was derived from blinded-controlled and open-labelled clinical trials and from worldwide marketing experience. In the description below, rates of the more common events (greater than 1%) and many of the less common events (less than 1%) represent results of US clinical studies.
- Of the 1,677 patients who received nabumetone during US clinical trials, 1,524 were treated for at least 1 month, 1,327 for at least 3 months, 929 for at least a year, and 750 for at least 2 years. More than 300 patients have been treated for 5 years or longer.
- The most frequently reported adverse reactions were related to the gastrointestinal tract and included diarrhea, dyspepsia, and abdominal pain.
Diarrhea (14%), dyspepsia (13%), abdominal pain (12%), constipation*, flatulence*, nausea*, positive stool guaiac*, dry mouth, gastritis, stomatitis, vomiting.
Dizziness, headache, fatigue, increased sweating, insomnia, nervousness, somnolence.
Pruritus, rash.
Tinnitus.
Edema
Anorexia, jaundice, duodenal ulcer, dysphagia, gastric ulcer, gastroenteritis, gastrointestinal bleeding, increased appetite, liver function abnormalities, melena, hepatic failure.
Asthenia, agitation, anxiety, confusion, depression, malaise, paresthesia, tremor, vertigo.
Bullous eruptions, photosensitivity, urticaria, pseudoporphyria cutanea tarda, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome.
Vasculitis.
Weight gain.
Dyspnea, eosinophilic pneumonia, hypersensitivity pneumonitis, idiopathic interstitial pneumonitis.
Albuminuria, azotemia, hyperuricemia, interstitial nephritis, nephrotic syndrome, vaginal bleeding, renal failure.
Abnormal vision.
Thrombocytopenia.
Anaphylactoid reaction, anaphylaxis, angioneurotic edema
† Adverse reactions reported only in worldwide postmarketing experience or in the literature, not seen in clinical trials, are considered rarer and are italicized.
Bilirubinuria, duodenitis, eructation, gallstones, gingivitis, glossitis, pancreatitis, rectal bleeding.
Nightmares.
Acne, alopecia.
Angina, arrhythmia, hypertension, myocardial infarction, palpitations, syncope, thrombophlebitis.
Asthma, cough.
Dysuria, hematuria, impotence, renal stones.
Taste disorder.
Fever, chills.
Anemia, leukopenia, granulocytopenia.
Hyperglycemia, hypokalemia, weight loss.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Nabumetone in the drug label.
# Drug Interactions
- ACE-inhibitors:Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.
- Aspirin:When nabumetone tablets are administered with aspirin, its protein binding is reduced, although the clearance of free nabumetone is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of nabumetone tablets and aspirin is not generally recommended because of the potential of increased adverse effects.
- Diuretics: Clinical studies, as well as post marketing observations, have shown that nabumetone 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.
- 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.
- Warfarin: 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.
- In vitro studies have shown that, because of its affinity for protein, 6MNA may displace other protein-bound drugs from their binding site. Caution should be exercised when administering nabumetone with warfarin since interactions have been seen with other NSAIDs.
- Concomitant administration of an aluminum-containing antacid had no significant effect on the bioavailability of 6MNA. When administered with food or milk, there is more rapid absorption; however, the total amount of 6MNA in the plasma is unchanged.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- 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, well-controlled studies in pregnant women. Nabumetone 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.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nabumetone 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 nabumetone tablets on labor and delivery in pregnant women are unknown.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk, however 6MNA is excreted 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 nabumetone, 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 NSAIDs, caution should be exercised in treating the elderly (65 years and older). Of the 1,677 patients in US clinical studies who were treated with nabumetone, 411 patients (24%) were 65 years or older; 22 patients (1%) were 75 years or older. No overall differences in efficacy or safety were observed between these older patients and younger ones. Similar results were observed in a 1 year, non-US postmarketing surveillance study of 10,800 patients treated with nabumetone, of whom 4,577 patients (42%) were 65 years or older.
### Gender
There is no FDA guidance on the use of Nabumetone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nabumetone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Nabumetone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Nabumetone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nabumetone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nabumetone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Nabumetone in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Nabumetone in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Symptoms following acute NSAIDs overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.
### Management
- Patients should be managed by symptomatic and supportive care following a NSAIDs overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 g/kg in children), and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
- There have been overdoses of up to 25 grams of nabumetone reported with no long-term sequelae following standard emergency treatment (i.e., activated charcoal, gastric lavage, IV H2-blockers, etc.).
## Chronic Overdose
There is limited information regarding Chronic Overdose of Nabumetone in the drug label.
# Pharmacology
## Mechanism of Action
- Nabumetone is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic properties in pharmacologic studies. As with other nonsteroidal anti-inflammatory agents, its mode of action is not known. However, the ability to inhibit prostaglandin synthesis may be involved in the anti-inflammatory effect.
## Structure
- Nabumetone is a naphthylalkanone designated chemically as 4-(6-methoxy-2-naphthalenyl)-2-butanone. It has the following structure:
- Nabumetone is a white to off-white crystalline substance with a molecular weight of 228.3. It is nonacidic and practically insoluble in water, but soluble in alcohol and most organic solvents. It has an n-octanol:phosphate buffer partition coefficient of 2400 at pH 7.4.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Nabumetone in the drug label.
## Pharmacokinetics
- After oral administration, approximately 80% of a radiolabeled dose of nabumetone is found in the urine, indicating that nabumetone is well absorbed from the gastrointestinal tract. Nabumetone itself is not detected in the plasma because, after absorption, it undergoes rapid biotransformation to the principal active metabolite, 6-methoxy-2-naphthylacetic acid (6MNA). Approximately 35% of a 1000 mg oral dose of nabumetone is converted to 6MNA and 50% is converted into unidentified metabolites which are subsequently excreted in the urine. Following oral administration of nabumetone tablets, 6MNA exhibits pharmacokinetic characteristics that generally follow a one-compartment model with first order input and first order elimination.
- 6MNA is more than 99% bound to plasma proteins. The free fraction is dependent on total concentration of 6MNA and is proportional to dose over the range of 1000 mg to 2000 mg. It is 0.2% to 0.3% at concentrations typically achieved following administration of nabumetone 1000 mg and is approximately 0.6% to 0.8% of the total concentrations at steady state following daily administration of 2000 mg.
- Steady-state plasma concentrations of 6MNA are slightly lower than predicted from single-dose data. This may result from the higher fraction of unbound 6MNA which undergoes greater hepatic clearance.
- Co-administration of food increases the rate of absorption and subsequent appearance of 6MNA in the plasma but does not affect the extent of conversion of nabumetone into 6MNA. Peak plasma concentrations of 6MNA are increased by approximately one third.
- Co-administration with an aluminum-containing antacid had no significant effect on the bioavailability of 6MNA.
- The simulated curves in the graph below illustrate the range of active metabolite plasma concentrations that would be expected from 95% of patients following 1000 mg to 2000 mg doses to steady state. The cross-hatched area represents the expected overlap in plasma concentrations due to intersubject variation following oral administration of 1000 mg to 2000 mg of nabumetone.
- Nabumetone Active Metabolite (6MNA) Plasma Concentrations at Steady State Following Once-Daily Dosing of Nabumetone
- 1000 mg (n=31) 2000 mg (n=12)
- 6MNA undergoes biotransformation in the liver, producing inactive metabolites that are eliminated as both free metabolites and conjugates. None of the known metabolites of 6MNA has been detected in plasma. Preliminary in vivo and in vitro studies suggest that unlike other NSAIDs, there is no evidence of enterohepatic recirculation of the active metabolite. Approximately 75% of a radiolabeled dose was recovered in urine in 48 hours. Approximately 80% was recovered in 168 hours. A further 9% appeared in the feces. In the first 48 hours, metabolites consisted of:
- Following oral administration of dosages of 1000 mg to 2000 mg to steady state, the mean plasma clearance of 6MNA is 20 to 30 mL/min. and the elimination half-life is approximately 24 hours.
- Elderly Patients
- Steady-state plasma concentrations in elderly patients were generally higher than in young healthy subjects. (See Table 1 for summary of pharmacokinetic parameters.)
- Renal Insufficiency
- In moderate renal insufficiency patients (creatinine clearance 30 to 49 mL/min), the terminal half-life of 6MNA was increased by approximately 50% (39.2 ± 7.8 hrs, N=12) compared to the normal subjects (26.9 ± 3.3 hrs, N=13), and there was a 50% increase in the plasma levels of unbound 6MNA.
- Additionally, the renal excretion of 6MNA in the moderate renal impaired patients decreased on average by 33% compared to that in the normal patients. A similar increase in the mean terminal half-life of 6MNA was seen in a small study of patients with severe renal dysfunction (creatinine clearance <30 mL/min). In patients undergoing hemodialysis, steady-state plasma concentrations of the active metabolite 6MNA were similar to those observed in healthy subjects. Due to extensive protein binding, 6MNA is not dialyzable.
- Dosage adjustment of nabumetone generally is not necessary in patients with mild renal insufficiency (≥50 mL/min). Caution should be used in prescribing nabumetone to patients with moderate or severe renal insufficiency. The maximum starting doses of nabumetone in patients with moderate or severe renal insufficiency should not exceed 750 mg or 500 mg, respectively once daily. Following careful monitoring of renal function in patients with moderate or severe renal insufficiency, daily doses may be increased to a maximum of 1,500 mg and 1,000 mg, respectively.
- Hepatic Impairment
- Data in patients with severe hepatic impairment are limited.
- Biotransformation of nabumetone to 6MNA and the further metabolism of 6MNA to inactive metabolites is dependent on hepatic function and could be reduced in patients with severe hepatic impairment (history of or biopsy-proven cirrhosis).
- Special Studies
- Gastrointestinal
- Nabumetone was compared to aspirin in inducing gastrointestinal blood loss. Food intake was not monitored. Studies utilizing 51Cr-tagged red blood cells in healthy males showed no difference in fecal blood loss after 3 or 4 weeks’ administration of nabumetone 1000 mg or 2000 mg daily when compared to either placebo-treated or nontreated subjects. In contrast, aspirin 3600 mg daily produced an increase in fecal blood loss when compared to the nabumetone-treated, placebo-treated or nontreated subjects. The clinical relevance of the data is unknown.
- The following endoscopy trials entered patients who had been previously treated with NSAIDs. These patients had varying baseline scores and different courses of treatment. The trials were not designed to correlate symptoms and endoscopy scores. The clinical relevance of these endoscopy trials, i.e., either GI symptoms or serious GI events, is not known.
- Ten endoscopy studies were conducted in 488 patients who had baseline and post-treatment endoscopy. In 5 clinical trials that compared a total of 194 patients on nabumetone 1000 mg daily or naproxen 250 mg or 500 mg twice daily for 3 to 12 weeks, nabumetone treatment resulted in fewer patients with endoscopically detected lesions (>3 mm). In 2 trials a total of 101 patients on nabumetone 1000 mg or 2000 mg daily or piroxicam 10 mg to 20 mg for 7 to 10 days, there were fewer nabumetone patients with endoscopically detected lesions. In 3 trials of a total of 47 patients on nabumetone 1000 mg daily or indomethacin 100 mg to 150 mg daily for 3 to 4 weeks, the endoscopy scores were higher with indomethacin. Another 12-week trial in a total of 171 patients compared the results of treatment with nabumetone 1000 mg/day to ibuprofen 2400 mg/day and ibuprofen 2400 mg/day plus misoprostol 800 mcg/day. The results showed that patients treated with nabumetone had a lower number of endoscopically detected lesions (>5 mm) than patients treated with ibuprofen alone but comparable to the combination of ibuprofen plus misoprostol. The results did not correlate with abdominal pain.
- Other
- In 1-week, repeat-dose studies in healthy volunteers, nabumetone 1000 mg daily had little effect on collagen-induced platelet aggregation and no effect on bleeding time. In comparison, naproxen 500 mg daily suppressed collagen-induced platelet aggregation and significantly increased bleeding time.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis: In 2 year studies conducted in mice and rats, nabumetone had no statistically significant tumorigenic effect. Nabumetone did not show mutagenic potential in the Ames test and mouse micronucleus test in vivo; however, nabumetone- and 6MNA-treated lymphocytes in culture showed chromosomal aberrations at 80 mcg/mL and higher concentrations (equal to the average human exposure to nabumetone at the maximum recommended dose).
- Impairment of Fertility: Nabumetone did not impair fertility of male or female rats treated orally at doses of 320 mg/kg/day (1,888 mg/m2) before mating.
# Clinical Studies
- The use of nabumetone in relieving the signs and symptoms of osteoarthritis (OA) was assessed in double-blind, controlled trials in which 1,047 patients were treated for 6 weeks to 6 months. In these trials, nabumetone in a dose of 1000 mg/day administered at night was comparable to naproxen 500 mg/day and to aspirin 3600 mg/day.
- The use of nabumetone in relieving the signs and symptoms of rheumatoid arthritis (RA) was assessed in double-blind, randomized, controlled trials in which 770 patients were treated for 3 weeks to 6 months. Nabumetone, in a dose of 1000 mg/day administered at night was comparable to naproxen 500 mg/day and to aspirin 3600 mg/day.
- In controlled clinical trials of rheumatoid arthritis patients, nabumetone has been used in combination with gold, d-penicillamine and corticosteroids.
- In clinical trials with osteoarthritis and rheumatoid arthritis patients, most patients responded to nabumetone in doses of 1000 mg/day administered nightly; total daily dosages up to 2000 mg were used. In open-labeled studies, 1,490 patients were permitted dosage increases and were followed for approximately 1 year (mode). Twenty percent of patients (n = 294) were withdrawn for lack of effectiveness during the first year of these open-labeled studies. The following table provides patient exposure to doses used in the U.S. clinical trials:
- As with other NSAIDs, the lowest dose should be sought for each patient. Patients weighing under 50 kg may be less likely to require dosages beyond 1000 mg. Therefore, after observing the response to initial therapy, the dose should be adjusted to meet individual patients’ requirements.
# How Supplied
- Nabumetone Tablets USP:
- 500 mg–White film-coated, oval-shaped biconvex tablets debossed with IG on one side and 257 on the other are supplied in bottles of 100 (NDC 76282-257-01) and 500 (NDC 76282-257-05).
- 750 mg–Beige colored, film-coated, oval-shaped biconvex tablets debossed with IG on one side and 258 on the other are supplied in bottles of 100 (NDC 76282-258-01), and 500 (NDC 76282-258-05).
- Store at 20° to 25°C (68° to 77°F).
- Dispense in tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
## Storage
There is limited information regarding Nabumetone 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.
- Nabumetone tablets, 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 signs or symptoms. Patients should be apprised of the importance of this follow-up.
- Nabumetone tablets, 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.
- Nabumetone tablets, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization 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 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, nabumetone tablets should be avoided because they may cause premature closure of the ductus arteriosus.
# Precautions with Alcohol
- Alcohol-Nabumetone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- NABUMETONE®
# Look-Alike Drug Names
There is limited information regarding Nabumetone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Nabumetone
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
Nabumetone is an NSAID that is FDA approved for the {{{indicationType}}} of osteoarthritis and rheumatoid arthritis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema, pruritus, rash, abdominal pain, constipation, diarrhea, flatulence, indigestion, nausea, occult blood in stools, increased liver function test, dizziness, feeling nervous, headache, insomnia, somnolence, tinnitus.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended starting dose is 1,000 mg taken as a single dose with or without food. Some patients may obtain more symptomatic relief from 1,500 mg to 2,000 mg per day. Nabumetone tablets can be given in either a single or twice-daily dose. Dosages greater than 2,000 mg per day have not been studied. The lowest effective dose should be used for chronic treatment. Patients weighing under 50 kg may be less likely to require dosages beyond 1,000 mg; therefore, after observing the response to initial therapy, the dose should be adjusted to meet individual patients' requirements.
- Dosing Information
- The recommended starting dose is 1,000 mg taken as a single dose with or without food. Some patients may obtain more symptomatic relief from 1,500 mg to 2,000 mg per day. Nabumetone tablets can be given in either a single or twice-daily dose. Dosages greater than 2,000 mg per day have not been studied. The lowest effective dose should be used for chronic treatment. Patients weighing under 50 kg may be less likely to require dosages beyond 1,000 mg; therefore, after observing the response to initial therapy, the dose should be adjusted to meet individual patients' requirements.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nabumetone in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- A single 2-gram loading dose of nabumetone was given followed by 1 gram twice daily for 7 days.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Nabumetone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nabumetone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nabumetone in pediatric patients.
# Contraindications
- Nabumetone tablets are contraindicated in patients with known hypersensitivity to nabumetone or its excipients.
- Nabumetone tablets 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-like reactions to NSAIDs have been reported in such patients.
- Nabumetone tablets are 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 3 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 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.
- Hypertension: NSAIDs, including nabumetone tablets, can lead to onset of new hypertension or worsening of preexisting 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 nabumetone tablets, 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. Nabumetone tablets should be used with caution in patients with fluid retention or heart failure.
- NSAIDs, including nabumetone tablets, 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 1 in 5 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 to 6 months, and in about 2 to 4% of patients treated for 1 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.
- In controlled clinical trials involving 1,677 patients treated with nabumetone (1,140 followed for 1 year and 927 for 2 years), the cumulative incidence of peptic ulcers was 0.3% (95% CI; 0%, 0.6%) at 3 to 6 months, 0.5% (95% CI; 0.1%, 0.9%) at 1 year and 0.8% (95% CI; 0.3%, 1.3%) at 2 years. In patients with active peptic ulcer, physicians must weigh the benefits of therapy with nabumetone against possible hazards, institute an appropriate ulcer treatment regimen and monitor the patients' progress carefully.
- NSAIDs should be prescribed with extreme caution in those with a 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.
- Renal Effects: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 an NSAID results in a dose-dependent decrease in prostaglandin synthesis and, secondarily, in a reduction of 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 the elderly. Discontinuation of NSAID therapy is typically followed by recovery to the pretreatment state.
- Advanced Renal Disease:No information is available from controlled clinical studies regarding the use of nabumetone tablets in patients with advanced renal disease. Therefore, treatment with nabumetone tablets is not recommended in these patients with advanced renal disease. If nabumetone tablets therapy must be initiated, close monitoring of the patient's renal function is advisable.
- Because nabumetone undergoes extensive hepatic metabolism, no adjustment of the dosage of nabumetone is generally necessary in patients with mild renal insufficiency; however, as with all NSAIDs, patients with impaired renal function should be monitored more closely than patients with normal renal function. In subjects with moderate renal impairment (creatinine clearance 30 to 49 mL/min) there is a 50% increase in unbound plasma 6MNA and dose adjustment may be warranted. The oxidized and conjugated metabolites of 6MNA are eliminated primarily by the kidneys.
- Anaphylactoid Reactions:As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to nabumetone tablets. Nabumetone tablets 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 anaphylactoid reaction occurs.
- Skin Reactions:NSAIDs, including nabumetone tablets, can cause serious skin 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.
- Pregnancy:In late pregnancy, as with other NSAIDs, nabumetone tablets should be avoided because it may cause premature closure of the ductus arteriosus.
### Precautions
- General
- Nabumetone tablets 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 nabumetone tablets in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
- Hepatic Effects
- Borderline elevations of 1 or more liver function tests may occur in up to 15% of patients taking NSAIDs including nabumetone tablets. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately 3 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 nabumetone tablets. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), nabumetone tablets should be discontinued.
- Hematological Effects
- Anemia is sometimes seen in patients receiving NSAIDs, including nabumetone tablets. 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 nabumetone tablets, 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 nabumetone tablets 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, nabumetone tablets should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
- Photosensitivity
- Based on ultraviolet (U.V.) light photosensitivity testing, nabumetone may be associated with more reactions to sun exposure than might be expected based on skin tanning types.
- Laboratory Tests
- Because serious G.I.tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs and symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, nabumetone tablets should be discontinued.
# Adverse Reactions
## Clinical Trials Experience
- Adverse reaction information was derived from blinded-controlled and open-labelled clinical trials and from worldwide marketing experience. In the description below, rates of the more common events (greater than 1%) and many of the less common events (less than 1%) represent results of US clinical studies.
- Of the 1,677 patients who received nabumetone during US clinical trials, 1,524 were treated for at least 1 month, 1,327 for at least 3 months, 929 for at least a year, and 750 for at least 2 years. More than 300 patients have been treated for 5 years or longer.
- The most frequently reported adverse reactions were related to the gastrointestinal tract and included diarrhea, dyspepsia, and abdominal pain.
Diarrhea (14%), dyspepsia (13%), abdominal pain (12%), constipation*, flatulence*, nausea*, positive stool guaiac*, dry mouth, gastritis, stomatitis, vomiting.
Dizziness, headache, fatigue, increased sweating, insomnia, nervousness, somnolence.
Pruritus, rash.
Tinnitus.
Edema
Anorexia, jaundice, duodenal ulcer, dysphagia, gastric ulcer, gastroenteritis, gastrointestinal bleeding, increased appetite, liver function abnormalities, melena, hepatic failure.
Asthenia, agitation, anxiety, confusion, depression, malaise, paresthesia, tremor, vertigo.
Bullous eruptions, photosensitivity, urticaria, pseudoporphyria cutanea tarda, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome.
Vasculitis.
Weight gain.
Dyspnea, eosinophilic pneumonia, hypersensitivity pneumonitis, idiopathic interstitial pneumonitis.
Albuminuria, azotemia, hyperuricemia, interstitial nephritis, nephrotic syndrome, vaginal bleeding, renal failure.
Abnormal vision.
Thrombocytopenia.
Anaphylactoid reaction, anaphylaxis, angioneurotic edema
† Adverse reactions reported only in worldwide postmarketing experience or in the literature, not seen in clinical trials, are considered rarer and are italicized.
Bilirubinuria, duodenitis, eructation, gallstones, gingivitis, glossitis, pancreatitis, rectal bleeding.
Nightmares.
Acne, alopecia.
Angina, arrhythmia, hypertension, myocardial infarction, palpitations, syncope, thrombophlebitis.
Asthma, cough.
Dysuria, hematuria, impotence, renal stones.
Taste disorder.
Fever, chills.
Anemia, leukopenia, granulocytopenia.
Hyperglycemia, hypokalemia, weight loss.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Nabumetone in the drug label.
# Drug Interactions
- ACE-inhibitors:Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.
- Aspirin:When nabumetone tablets are administered with aspirin, its protein binding is reduced, although the clearance of free nabumetone is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of nabumetone tablets and aspirin is not generally recommended because of the potential of increased adverse effects.
- Diuretics: Clinical studies, as well as post marketing observations, have shown that nabumetone 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.
- 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.
- Warfarin: 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.
- In vitro studies have shown that, because of its affinity for protein, 6MNA may displace other protein-bound drugs from their binding site. Caution should be exercised when administering nabumetone with warfarin since interactions have been seen with other NSAIDs.
- Concomitant administration of an aluminum-containing antacid had no significant effect on the bioavailability of 6MNA. When administered with food or milk, there is more rapid absorption; however, the total amount of 6MNA in the plasma is unchanged.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- 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, well-controlled studies in pregnant women. Nabumetone 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.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nabumetone 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 nabumetone tablets on labor and delivery in pregnant women are unknown.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk, however 6MNA is excreted 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 nabumetone, 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 NSAIDs, caution should be exercised in treating the elderly (65 years and older). Of the 1,677 patients in US clinical studies who were treated with nabumetone, 411 patients (24%) were 65 years or older; 22 patients (1%) were 75 years or older. No overall differences in efficacy or safety were observed between these older patients and younger ones. Similar results were observed in a 1 year, non-US postmarketing surveillance study of 10,800 patients treated with nabumetone, of whom 4,577 patients (42%) were 65 years or older.
### Gender
There is no FDA guidance on the use of Nabumetone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nabumetone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Nabumetone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Nabumetone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nabumetone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nabumetone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Nabumetone in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Nabumetone in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Symptoms following acute NSAIDs overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.
### Management
- Patients should be managed by symptomatic and supportive care following a NSAIDs overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 g/kg in children), and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
- There have been overdoses of up to 25 grams of nabumetone reported with no long-term sequelae following standard emergency treatment (i.e., activated charcoal, gastric lavage, IV H2-blockers, etc.).
## Chronic Overdose
There is limited information regarding Chronic Overdose of Nabumetone in the drug label.
# Pharmacology
## Mechanism of Action
- Nabumetone is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic properties in pharmacologic studies. As with other nonsteroidal anti-inflammatory agents, its mode of action is not known. However, the ability to inhibit prostaglandin synthesis may be involved in the anti-inflammatory effect.
## Structure
- Nabumetone is a naphthylalkanone designated chemically as 4-(6-methoxy-2-naphthalenyl)-2-butanone. It has the following structure:
- Nabumetone is a white to off-white crystalline substance with a molecular weight of 228.3. It is nonacidic and practically insoluble in water, but soluble in alcohol and most organic solvents. It has an n-octanol:phosphate buffer partition coefficient of 2400 at pH 7.4.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Nabumetone in the drug label.
## Pharmacokinetics
- After oral administration, approximately 80% of a radiolabeled dose of nabumetone is found in the urine, indicating that nabumetone is well absorbed from the gastrointestinal tract. Nabumetone itself is not detected in the plasma because, after absorption, it undergoes rapid biotransformation to the principal active metabolite, 6-methoxy-2-naphthylacetic acid (6MNA). Approximately 35% of a 1000 mg oral dose of nabumetone is converted to 6MNA and 50% is converted into unidentified metabolites which are subsequently excreted in the urine. Following oral administration of nabumetone tablets, 6MNA exhibits pharmacokinetic characteristics that generally follow a one-compartment model with first order input and first order elimination.
- 6MNA is more than 99% bound to plasma proteins. The free fraction is dependent on total concentration of 6MNA and is proportional to dose over the range of 1000 mg to 2000 mg. It is 0.2% to 0.3% at concentrations typically achieved following administration of nabumetone 1000 mg and is approximately 0.6% to 0.8% of the total concentrations at steady state following daily administration of 2000 mg.
- Steady-state plasma concentrations of 6MNA are slightly lower than predicted from single-dose data. This may result from the higher fraction of unbound 6MNA which undergoes greater hepatic clearance.
- Co-administration of food increases the rate of absorption and subsequent appearance of 6MNA in the plasma but does not affect the extent of conversion of nabumetone into 6MNA. Peak plasma concentrations of 6MNA are increased by approximately one third.
- Co-administration with an aluminum-containing antacid had no significant effect on the bioavailability of 6MNA.
- The simulated curves in the graph below illustrate the range of active metabolite plasma concentrations that would be expected from 95% of patients following 1000 mg to 2000 mg doses to steady state. The cross-hatched area represents the expected overlap in plasma concentrations due to intersubject variation following oral administration of 1000 mg to 2000 mg of nabumetone.
- Nabumetone Active Metabolite (6MNA) Plasma Concentrations at Steady State Following Once-Daily Dosing of Nabumetone
- 1000 mg (n=31) 2000 mg (n=12)
- 6MNA undergoes biotransformation in the liver, producing inactive metabolites that are eliminated as both free metabolites and conjugates. None of the known metabolites of 6MNA has been detected in plasma. Preliminary in vivo and in vitro studies suggest that unlike other NSAIDs, there is no evidence of enterohepatic recirculation of the active metabolite. Approximately 75% of a radiolabeled dose was recovered in urine in 48 hours. Approximately 80% was recovered in 168 hours. A further 9% appeared in the feces. In the first 48 hours, metabolites consisted of:
- Following oral administration of dosages of 1000 mg to 2000 mg to steady state, the mean plasma clearance of 6MNA is 20 to 30 mL/min. and the elimination half-life is approximately 24 hours.
- Elderly Patients
- Steady-state plasma concentrations in elderly patients were generally higher than in young healthy subjects. (See Table 1 for summary of pharmacokinetic parameters.)
- Renal Insufficiency
- In moderate renal insufficiency patients (creatinine clearance 30 to 49 mL/min), the terminal half-life of 6MNA was increased by approximately 50% (39.2 ± 7.8 hrs, N=12) compared to the normal subjects (26.9 ± 3.3 hrs, N=13), and there was a 50% increase in the plasma levels of unbound 6MNA.
- Additionally, the renal excretion of 6MNA in the moderate renal impaired patients decreased on average by 33% compared to that in the normal patients. A similar increase in the mean terminal half-life of 6MNA was seen in a small study of patients with severe renal dysfunction (creatinine clearance <30 mL/min). In patients undergoing hemodialysis, steady-state plasma concentrations of the active metabolite 6MNA were similar to those observed in healthy subjects. Due to extensive protein binding, 6MNA is not dialyzable.
- Dosage adjustment of nabumetone generally is not necessary in patients with mild renal insufficiency (≥50 mL/min). Caution should be used in prescribing nabumetone to patients with moderate or severe renal insufficiency. The maximum starting doses of nabumetone in patients with moderate or severe renal insufficiency should not exceed 750 mg or 500 mg, respectively once daily. Following careful monitoring of renal function in patients with moderate or severe renal insufficiency, daily doses may be increased to a maximum of 1,500 mg and 1,000 mg, respectively.
- Hepatic Impairment
- Data in patients with severe hepatic impairment are limited.
- Biotransformation of nabumetone to 6MNA and the further metabolism of 6MNA to inactive metabolites is dependent on hepatic function and could be reduced in patients with severe hepatic impairment (history of or biopsy-proven cirrhosis).
- Special Studies
- Gastrointestinal
- Nabumetone was compared to aspirin in inducing gastrointestinal blood loss. Food intake was not monitored. Studies utilizing 51Cr-tagged red blood cells in healthy males showed no difference in fecal blood loss after 3 or 4 weeks’ administration of nabumetone 1000 mg or 2000 mg daily when compared to either placebo-treated or nontreated subjects. In contrast, aspirin 3600 mg daily produced an increase in fecal blood loss when compared to the nabumetone-treated, placebo-treated or nontreated subjects. The clinical relevance of the data is unknown.
- The following endoscopy trials entered patients who had been previously treated with NSAIDs. These patients had varying baseline scores and different courses of treatment. The trials were not designed to correlate symptoms and endoscopy scores. The clinical relevance of these endoscopy trials, i.e., either GI symptoms or serious GI events, is not known.
- Ten endoscopy studies were conducted in 488 patients who had baseline and post-treatment endoscopy. In 5 clinical trials that compared a total of 194 patients on nabumetone 1000 mg daily or naproxen 250 mg or 500 mg twice daily for 3 to 12 weeks, nabumetone treatment resulted in fewer patients with endoscopically detected lesions (>3 mm). In 2 trials a total of 101 patients on nabumetone 1000 mg or 2000 mg daily or piroxicam 10 mg to 20 mg for 7 to 10 days, there were fewer nabumetone patients with endoscopically detected lesions. In 3 trials of a total of 47 patients on nabumetone 1000 mg daily or indomethacin 100 mg to 150 mg daily for 3 to 4 weeks, the endoscopy scores were higher with indomethacin. Another 12-week trial in a total of 171 patients compared the results of treatment with nabumetone 1000 mg/day to ibuprofen 2400 mg/day and ibuprofen 2400 mg/day plus misoprostol 800 mcg/day. The results showed that patients treated with nabumetone had a lower number of endoscopically detected lesions (>5 mm) than patients treated with ibuprofen alone but comparable to the combination of ibuprofen plus misoprostol. The results did not correlate with abdominal pain.
- Other
- In 1-week, repeat-dose studies in healthy volunteers, nabumetone 1000 mg daily had little effect on collagen-induced platelet aggregation and no effect on bleeding time. In comparison, naproxen 500 mg daily suppressed collagen-induced platelet aggregation and significantly increased bleeding time.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis: In 2 year studies conducted in mice and rats, nabumetone had no statistically significant tumorigenic effect. Nabumetone did not show mutagenic potential in the Ames test and mouse micronucleus test in vivo; however, nabumetone- and 6MNA-treated lymphocytes in culture showed chromosomal aberrations at 80 mcg/mL and higher concentrations (equal to the average human exposure to nabumetone at the maximum recommended dose).
- Impairment of Fertility: Nabumetone did not impair fertility of male or female rats treated orally at doses of 320 mg/kg/day (1,888 mg/m2) before mating.
# Clinical Studies
- The use of nabumetone in relieving the signs and symptoms of osteoarthritis (OA) was assessed in double-blind, controlled trials in which 1,047 patients were treated for 6 weeks to 6 months. In these trials, nabumetone in a dose of 1000 mg/day administered at night was comparable to naproxen 500 mg/day and to aspirin 3600 mg/day.
- The use of nabumetone in relieving the signs and symptoms of rheumatoid arthritis (RA) was assessed in double-blind, randomized, controlled trials in which 770 patients were treated for 3 weeks to 6 months. Nabumetone, in a dose of 1000 mg/day administered at night was comparable to naproxen 500 mg/day and to aspirin 3600 mg/day.
- In controlled clinical trials of rheumatoid arthritis patients, nabumetone has been used in combination with gold, d-penicillamine and corticosteroids.
- In clinical trials with osteoarthritis and rheumatoid arthritis patients, most patients responded to nabumetone in doses of 1000 mg/day administered nightly; total daily dosages up to 2000 mg were used. In open-labeled studies, 1,490 patients were permitted dosage increases and were followed for approximately 1 year (mode). Twenty percent of patients (n = 294) were withdrawn for lack of effectiveness during the first year of these open-labeled studies. The following table provides patient exposure to doses used in the U.S. clinical trials:
- As with other NSAIDs, the lowest dose should be sought for each patient. Patients weighing under 50 kg may be less likely to require dosages beyond 1000 mg. Therefore, after observing the response to initial therapy, the dose should be adjusted to meet individual patients’ requirements.
# How Supplied
- Nabumetone Tablets USP:
- 500 mg–White film-coated, oval-shaped biconvex tablets debossed with IG on one side and 257 on the other are supplied in bottles of 100 (NDC 76282-257-01) and 500 (NDC 76282-257-05).
- 750 mg–Beige colored, film-coated, oval-shaped biconvex tablets debossed with IG on one side and 258 on the other are supplied in bottles of 100 (NDC 76282-258-01), and 500 (NDC 76282-258-05).
- Store at 20° to 25°C (68° to 77°F).
- Dispense in tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
## Storage
There is limited information regarding Nabumetone 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.
- Nabumetone tablets, 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 signs or symptoms. Patients should be apprised of the importance of this follow-up.
- Nabumetone tablets, 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.
- Nabumetone tablets, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization 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 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, nabumetone tablets should be avoided because they may cause premature closure of the ductus arteriosus.
# Precautions with Alcohol
- Alcohol-Nabumetone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- NABUMETONE®[1]
# Look-Alike Drug Names
There is limited information regarding Nabumetone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Nabumetone | |
f927156e6a66cc0e0ded7b9a6b5f27810fdc4acf | wikidoc | Nalbuphine | Nalbuphine
# 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
Nalbuphine is an analgesic opioid that is FDA approved for the {{{indicationType}}} of general anesthesia; adjunct, pain (moderate to severe), pain (moderate to severe), including preoperative, postoperative, and obstetrical analgesia.. Common adverse reactions include dermatologic: diaphoresis (up to 9% ), gastrointestinal: nausea and vomiting (6% ), xerostomia (4% ), neurologic: dizziness (up to 5% ), headache (3% ), sedated (36% ), vertigo (up to 5% ).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- General anesthesia; adjunct: induction, 0.3-3 mg/kg IV over 10-15 min.
- General anesthesia; adjunct: maintenance, 0.25-0.5 mg/kg in single IV administrations, as needed.
- Pain (moderate to severe): 10 mg subQ, IM or IV for a 70 kg individual repeated every 3 to 6 hours as needed; max single dose is 20 mg/dose; max total daily dose is 160 mg/day.
- Pain (moderate to severe), including preoperative, postoperative, and obstetrical analgesia: 10 mg subQ, IM or IV for a 70 kg individual repeated every 3 to 6 hours as needed; max single dose is 20 mg/dose; MAX total daily dose is 160 mg/day.
- Shivering, postanesthesia: 0.08 mg/kg IV
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Nalbuphine in adult patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Nalbuphine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness not established in patients under 18 years of age
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Nalbuphine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Nalbuphine in pediatric patients.
# Contraindications
- Nalbuphine hydrochloride injection should not be administered to patients who are hypersensitive to nalbuphine hydrochloride, or to any of the other ingredients in nalbuphine hydrochloride injection.
# Warnings
- Nalbuphine hydrochloride injection should be administered as a supplement to general anesthesia only by persons specifically trained in the use of intravenous anesthetics and management of respiratory effects of potent opioids.
- Naloxone hydrochloride injection, resuscitative and intubation equipment and oxygen should be readily available.
- Caution should be observed in prescribing nalbuphine for emotionally unstable patients, or for individuals with a history of opioid abuse. Such patients should be closely supervised when long term therapy is contemplated (see Drug Abuse and Dependence).
- Nalbuphine may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery. Therefore, nalbuphine hydrochloride injection should be administered with caution to ambulatory patients who should be warned to avoid such hazards.
- Maintain patient under observation until recovered from nalbuphine effects that would affect driving or other potentially dangerous tasks.
- Severe fetal bradycardia has been reported when nalbuphine is administered during labor. Naloxone may reverse these effects. Although there are no reports of fetal bradycardia earlier in pregnancy, it is possible that this may occur. This drug should be used in pregnancy only if clearly needed, if the potential benefit outweighs the risk to the fetus, and if appropriate measures such as fetal monitoring are taken to detect and manage any potential adverse effect on the fetus.
- The possible respiratory depressant effects and the potential of potent analgesics to elevate cerebrospinal fluid pressure (resulting from vasodilation following CO2 retention) may be markedly exaggerated in the presence of head injury, intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, potent analgesics can produce effects which may obscure the clinical course of patients with head injuries. Therefore, nalbuphine hydrochloride injection should be used in these circumstances only when essential, and then should be administered with extreme caution.
- At the usual adult dose of 10 mg/70 kg, nalbuphine hydrochloride causes some respiratory depression approximately equal to that produced by equal doses of morphine. However, in contrast to morphine, respiratory depression is not appreciably increased with higher doses of nalbuphine. Respiratory depression induced by nalbuphine can be reversed by naloxone hydrochloride when indicated. Nalbuphine hydrochloride injection should be administered with caution at low doses to patients with impaired respiration (e.g., from other medication, uremia, bronchial asthma, severe infection, cyanosis or respiratory obstructions).
- As with all potent analgesics, nalbuphine hydrochloride should be used with caution in patients with myocardial infarction who have nausea or vomiting.
- As with all opioid analgesics, nalbuphine hydrochloride should be used with caution in patients about to undergo surgery of the biliary tract since it may cause spasm of the sphincter of Oddi.
- During evaluation of nalbuphine hydrochloride injection, in anesthesia, a higher incidence of bradycardia has been reported in patients who did not receive atropine pre-operatively.
# Adverse Reactions
## Clinical Trials Experience
- The most frequent adverse reaction in 1066 patients treated with nalbuphine hydrochloride injection was sedation 381 (36%). Less frequent reactions were: sweaty/clammy 99 (9%), nausea/vomiting 68 (6%), dizziness/vertigo 58 (5%), dry mouth 44 (4%), and headache 27 (3%).
- Other adverse reactions which occurred (reported incidence of 1% or less) were:
- Nervousness, depression, restlessness, crying, euphoria, floating, hostility, unusual dreams, confusion, faintness, hallucinations, dysphoria, feeling of heaviness, numbness, tingling, unreality. The incidence of psychotomimetic effects, such as unreality, depersonalization, delusions, dysphoria and hallucinations has been shown to be less than that which occurs with pentazocine.
- Hypertension, hypotension, bradycardia, tachycardia.
- Cramps, dyspepsia, bitter taste.
- Depression, dyspnea, asthma.
- Itching, burning, urticaria.
- Speech difficulty, urinary urgency, blurred vision, flushing and warmth.
- Anaphylactic/anaphylactoid and other serious hypersensitivity reactions have been reported following the use of nalbuphine and may require immediate, supportive medical treatment. These reactions may include shock, respiratory distress, respiratory arrest, bradycardia, cardiac arrest, hypotension, or laryngeal edema. Some of these allergic reactions may be life-threatening. Other allergic-type reactions reported include stridor, bronchospasm, wheezing, edema, rash, pruritus, nausea, vomiting, diaphoresis, weakness, and shakiness.
## Postmarketing Experience
- Due to the nature and limitations of spontaneous reporting, causality has not been established for the following adverse events received for nalbuphine hydrochloride injection: abdominal pain, pyrexia, depressed level or loss of consciousness, somnolence, tremor, anxiety, pulmonary edema, agitation, seizures, and injection site reactions such as pain, swelling, redness, burning, and hot sensations. Death has been reported from severe allergic reactions to nalbuphine hydrochloride treatment. Fetal death has been reported where mothers received nalbuphine hydrochloride during labor and delivery.
# Drug Interactions
- Although nalbuphine possesses opioid antagonist activity, there is evidence that in nondependent patients it will not antagonize an opioid analgesic administered just before, concurrently, or just after an injection of nalbuphine hydrochloride. Therefore, patients receiving an opioid analgesic, general anesthetics, phenothiazines, or other tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol) concomitantly with nalbuphine may exhibit an additive effect. When such combined therapy is contemplated, the dose of one or both agents should be reduced.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies have been performed in rats by subcutaneous administration of nalbuphine up to 100 mg/kg/day, or 590 mg/m2/day which is approximately 6 times the MRHD, and in rabbits by intravenous administration of nalbuphine up to 32 mg/kg/day, or 378 mg/m2/day which is approximately 4 times the MRHD. The results did not reveal evidence of developmental toxicity, including teratogenicity, or harm to the fetus. 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.
- Neonatal body weight and survival rates were reduced at birth and during lactation when
- Nalbuphine was subcutaneously administered to female and male rats prior to mating and throughout gestation and lactation or to pregnant rats during the last third of gestation and throughout lactation at doses approximately 4 times the maximum recommended human dose.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nalbuphine in women who are pregnant.
### Labor and Delivery
- The placental transfer of nalbuphine is high, rapid, and variable with a maternal to fetal ratio ranging from 1:0.37 to 1:6. Fetal and neonatal adverse effects that have been reported following the administration of nalbuphine to the mother during labor include fetal bradycardia, respiratory depression at birth, apnea, cyanosis, and hypotonia. Some of these events have been life-threatening. Maternal administration of naloxone during labor has normalized these effects in some cases. Severe and prolonged fetal bradycardia has been reported. Permanent neurological damage attributed to fetal bradycardia has occurred. A sinusoidal fetal heart rate pattern associated with the use of nalbuphine has also been reported. Nalbuphine should be used during labor and delivery only if clearly indicated and only if the potential benefit outweighs the risk to the infant. Newborns should be monitored for respiratory depression, apnea, bradycardia and arrhythmias if nalbuphine has been used.
### Nursing Mothers
- Limited data suggest that nalbuphine hydrochloride is excreted in maternal milk but only in a small amount (less than 1% of the administered dose) and with a clinically insignificant effect. Caution should be exercised when nalbuphine hydrochloride is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 18 years have not been established.
### Geriatic Use
There is no FDA guidance on the use of Nalbuphine in geriatric settings.
### Gender
There is no FDA guidance on the use of Nalbuphine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nalbuphine with respect to specific racial populations.
### Renal Impairment
- Because nalbuphine is metabolized in the liver and excreted by the kidneys, nalbuphine hydrochloride should be used with caution in patients with renal or liver dysfunction and administered in reduced amounts.
### Hepatic Impairment
- Because nalbuphine is metabolized in the liver and excreted by the kidneys, nalbuphine hydrochloride should be used with caution in patients with renal or liver dysfunction and administered in reduced amounts.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nalbuphine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nalbuphine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Nalbuphine Administration in the drug label.
### Monitoring
There is limited information regarding Nalbuphine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Nalbuphine and IV administrations.
# Overdosage
- The immediate intravenous administration of an opiate antagonist such as naloxone or nalmefene is a specific antidote. Oxygen, intravenous fluids, vasopressors and other supportive measures should be used as indicated.
- The administration of single doses of 72 mg of nalbuphine hydrochloride subcutaneously to eight normal subjects has been reported to have resulted primarily in symptoms of sleepiness and mild dysphoria.
# Pharmacology
## Mechanism of Action
- Nalbuphine hydrochloride is a potent analgesic. Its analgesic potency is essentially equivalent to that of morphine on a milligram basis. Receptor studies show that nalbuphine hydrochloride binds to mu, kappa, and delta receptors, but not to sigma receptors.
- Nalbuphine hydrochloride is primarily a kappa agonist/partial mu antagonist analgesic.
## Structure
- Nalbuphine hydrochloride is a synthetic opioid agonist-antagonist analgesic of the phenanthrene series. It is chemically related to both the widely used opioid antagonist, naloxone, and the potent opioid analgesic, oxymorphone. Chemically nalbuphine hydrochloride is 17-(cyclobutylmethyl)-4,5α-epoxymorphinan-3,6α,14-triol hydrochloride. Nalbuphine hydrochloride molecular weight is 393.91 and is soluble in H2O (35.5 mg/mL at 25ºC) and ethanol (0.8%); insoluble in CHCl3 and ether. Nalbuphine hydrochloride has pKa values of 8.71 and 9.96. The molecular formula is C21H27NO4 - HCl. The structural formula is:
- Nalbuphine Hydrochloride Injection is a sterile, nonpyrogenic solution of nalbuphine hydrochloride in water for injection. This product may be administered by subcutaneous, intramuscular or intravenous injection.
- Each milliliter (mL) contains nalbuphine hydrochloride 10 mg or 20 mg; sodium citrate, dihydrate 0.47 mg and citric acid, anhydrous 0.63 mg added as buffers and may contain sodium hydroxide and/or hydrochloric acid for pH adjustment; pH 3.7 (3.0 to 4.5). Contains sodium chloride for tonicity adjustment.
- Multiple-dose vials contain 1.8 mg/mL methylparaben and 0.2 mg/mL propylparaben added as preservatives. Single-dose products contain no bacteriostat or antimicrobial agent and unused portions must be discarded.
## Pharmacodynamics
- The onset of action of nalbuphine hydrochloride occurs within 2 to 3 minutes after intravenous administration, and in less than 15 minutes following subcutaneous or intramuscular injection. The plasma half-life of nalbuphine is 5 hours, and in clinical studies, the duration of analgesic activity has been reported to range from 3 to 6 hours.
- The opioid antagonist activity of nalbuphine is one-fourth as potent as nalorphine and 10 times that of pentazocine.
- Nalbuphine hydrochloride may produce the same degree of respiratory depression as equianalgesic doses of morphine. However, nalbuphine hydrochloride exhibits a ceiling effect such that increases in dose greater than 30 mg do not produce further respiratory depression in the absence of other CNS active medications affecting respiration.
## Pharmacokinetics
- Nalbuphine hydrochloride by itself has potent opioid antagonist activity at doses equal to or lower than its analgesic dose. When administered following or concurrent with mu agonist opioid analgesics (e.g., morphine, oxymorphone, fentanyl), nalbuphine hydrochloride may partially reverse or block opioid-induced respiratory depression from the mu agonist analgesic. Nalbuphine hydrochloride may precipitate withdrawal in patients dependent on opioid drugs. Nalbuphine hydrochloride should be used with caution in patients who have been receiving mu opioid analgesics on a regular basis.
## Nonclinical Toxicology
- Long term carcinogenicity studies were performed in rats (24 months) and mice (19 months) by oral administration at doses up to 200 mg/kg (1180 mg/m2) and 200 mg/kg (600 mg/m2) per day, respectively. There was no evidence of an increase in tumors in either species related to nalbuphine hydrochloride administration. The maximum recommend human dose (MRHD) in a day is 160 mg subcutaneously, intramuscularly or intravenously, or approximately 100 mg/m2/day for a 60 kg subject.
- Nalbuphine hydrochloride did not have mutagenic activity in the AMES test with four bacterial strains, in the Chinese Hamster Ovary HGPRT assays or in the Sister Chromatids Exchange Assay. However, nalbuphine hydrochloride induced an increased frequency of mutation in the mouse lymphoma assay. Clastogenic activity was not observed in the mouse micronucleus test of the cytogenicity bone marrow assay in rats.
- A reproduction study was performed in male and female rats at subcutaneous doses up to 56 mg/kg/day or 330 mg/m2/day. Nalbuphine hydrochloride did not affect either male or female fertility rats.
# Clinical Studies
There is limited information regarding Nalbuphine Clinical Studies in the drug label.
# How Supplied
- Nalbuphine Hydrochloride Injection is supplied as follows:
## Storage
- Store at 20 to 25°C (68 to 77°F).
- Protect from light. Store in carton until contents have been used.
- Revised: August, 2007
- Printed in USA EN-1571
- Hospira, Inc., Lake Forest, IL 60045 USA
- RL-0188
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be advised of the following information:
- Nalbuphine is associated with sedation and may impair mental and physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery.
- Nalbuphine is to be used as prescribed by a physician. Dose or frequency should not be increased without first consulting with a physician since nalbuphine may cause psychological or physical dependence.
- The use of nalbuphine with other opioids can cause signs and symptoms of withdrawal.
- Abrupt discontinuation of nalbuphine after prolonged usage may cause signs and symptoms of withdrawal.
# Precautions with Alcohol
Alcohol-Nalbuphine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Nalbuphine Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Nalbuphine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Nalbuphine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Nalbuphine is an analgesic opioid that is FDA approved for the {{{indicationType}}} of general anesthesia; adjunct, pain (moderate to severe), pain (moderate to severe), including preoperative, postoperative, and obstetrical analgesia.. Common adverse reactions include dermatologic: diaphoresis (up to 9% ), gastrointestinal: nausea and vomiting (6% ), xerostomia (4% ), neurologic: dizziness (up to 5% ), headache (3% ), sedated (36% ), vertigo (up to 5% ).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- General anesthesia; adjunct: induction, 0.3-3 mg/kg IV over 10-15 min.
- General anesthesia; adjunct: maintenance, 0.25-0.5 mg/kg in single IV administrations, as needed.
- Pain (moderate to severe): 10 mg subQ, IM or IV for a 70 kg individual repeated every 3 to 6 hours as needed; max single dose is 20 mg/dose; max total daily dose is 160 mg/day.
- Pain (moderate to severe), including preoperative, postoperative, and obstetrical analgesia: 10 mg subQ, IM or IV for a 70 kg individual repeated every 3 to 6 hours as needed; max single dose is 20 mg/dose; MAX total daily dose is 160 mg/day.
- Shivering, postanesthesia: 0.08 mg/kg IV
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Nalbuphine in adult patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Nalbuphine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness not established in patients under 18 years of age
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Nalbuphine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Nalbuphine in pediatric patients.
# Contraindications
- Nalbuphine hydrochloride injection should not be administered to patients who are hypersensitive to nalbuphine hydrochloride, or to any of the other ingredients in nalbuphine hydrochloride injection.
# Warnings
- Nalbuphine hydrochloride injection should be administered as a supplement to general anesthesia only by persons specifically trained in the use of intravenous anesthetics and management of respiratory effects of potent opioids.
- Naloxone hydrochloride injection, resuscitative and intubation equipment and oxygen should be readily available.
- Caution should be observed in prescribing nalbuphine for emotionally unstable patients, or for individuals with a history of opioid abuse. Such patients should be closely supervised when long term therapy is contemplated (see Drug Abuse and Dependence).
- Nalbuphine may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery. Therefore, nalbuphine hydrochloride injection should be administered with caution to ambulatory patients who should be warned to avoid such hazards.
- Maintain patient under observation until recovered from nalbuphine effects that would affect driving or other potentially dangerous tasks.
- Severe fetal bradycardia has been reported when nalbuphine is administered during labor. Naloxone may reverse these effects. Although there are no reports of fetal bradycardia earlier in pregnancy, it is possible that this may occur. This drug should be used in pregnancy only if clearly needed, if the potential benefit outweighs the risk to the fetus, and if appropriate measures such as fetal monitoring are taken to detect and manage any potential adverse effect on the fetus.
- The possible respiratory depressant effects and the potential of potent analgesics to elevate cerebrospinal fluid pressure (resulting from vasodilation following CO2 retention) may be markedly exaggerated in the presence of head injury, intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, potent analgesics can produce effects which may obscure the clinical course of patients with head injuries. Therefore, nalbuphine hydrochloride injection should be used in these circumstances only when essential, and then should be administered with extreme caution.
- At the usual adult dose of 10 mg/70 kg, nalbuphine hydrochloride causes some respiratory depression approximately equal to that produced by equal doses of morphine. However, in contrast to morphine, respiratory depression is not appreciably increased with higher doses of nalbuphine. Respiratory depression induced by nalbuphine can be reversed by naloxone hydrochloride when indicated. Nalbuphine hydrochloride injection should be administered with caution at low doses to patients with impaired respiration (e.g., from other medication, uremia, bronchial asthma, severe infection, cyanosis or respiratory obstructions).
- As with all potent analgesics, nalbuphine hydrochloride should be used with caution in patients with myocardial infarction who have nausea or vomiting.
- As with all opioid analgesics, nalbuphine hydrochloride should be used with caution in patients about to undergo surgery of the biliary tract since it may cause spasm of the sphincter of Oddi.
- During evaluation of nalbuphine hydrochloride injection, in anesthesia, a higher incidence of bradycardia has been reported in patients who did not receive atropine pre-operatively.
# Adverse Reactions
## Clinical Trials Experience
- The most frequent adverse reaction in 1066 patients treated with nalbuphine hydrochloride injection was sedation 381 (36%). Less frequent reactions were: sweaty/clammy 99 (9%), nausea/vomiting 68 (6%), dizziness/vertigo 58 (5%), dry mouth 44 (4%), and headache 27 (3%).
- Other adverse reactions which occurred (reported incidence of 1% or less) were:
- Nervousness, depression, restlessness, crying, euphoria, floating, hostility, unusual dreams, confusion, faintness, hallucinations, dysphoria, feeling of heaviness, numbness, tingling, unreality. The incidence of psychotomimetic effects, such as unreality, depersonalization, delusions, dysphoria and hallucinations has been shown to be less than that which occurs with pentazocine.
- Hypertension, hypotension, bradycardia, tachycardia.
- Cramps, dyspepsia, bitter taste.
- Depression, dyspnea, asthma.
- Itching, burning, urticaria.
- Speech difficulty, urinary urgency, blurred vision, flushing and warmth.
- Anaphylactic/anaphylactoid and other serious hypersensitivity reactions have been reported following the use of nalbuphine and may require immediate, supportive medical treatment. These reactions may include shock, respiratory distress, respiratory arrest, bradycardia, cardiac arrest, hypotension, or laryngeal edema. Some of these allergic reactions may be life-threatening. Other allergic-type reactions reported include stridor, bronchospasm, wheezing, edema, rash, pruritus, nausea, vomiting, diaphoresis, weakness, and shakiness.
## Postmarketing Experience
- Due to the nature and limitations of spontaneous reporting, causality has not been established for the following adverse events received for nalbuphine hydrochloride injection: abdominal pain, pyrexia, depressed level or loss of consciousness, somnolence, tremor, anxiety, pulmonary edema, agitation, seizures, and injection site reactions such as pain, swelling, redness, burning, and hot sensations. Death has been reported from severe allergic reactions to nalbuphine hydrochloride treatment. Fetal death has been reported where mothers received nalbuphine hydrochloride during labor and delivery.
# Drug Interactions
- Although nalbuphine possesses opioid antagonist activity, there is evidence that in nondependent patients it will not antagonize an opioid analgesic administered just before, concurrently, or just after an injection of nalbuphine hydrochloride. Therefore, patients receiving an opioid analgesic, general anesthetics, phenothiazines, or other tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol) concomitantly with nalbuphine may exhibit an additive effect. When such combined therapy is contemplated, the dose of one or both agents should be reduced.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies have been performed in rats by subcutaneous administration of nalbuphine up to 100 mg/kg/day, or 590 mg/m2/day which is approximately 6 times the MRHD, and in rabbits by intravenous administration of nalbuphine up to 32 mg/kg/day, or 378 mg/m2/day which is approximately 4 times the MRHD. The results did not reveal evidence of developmental toxicity, including teratogenicity, or harm to the fetus. 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.
- Neonatal body weight and survival rates were reduced at birth and during lactation when
- Nalbuphine was subcutaneously administered to female and male rats prior to mating and throughout gestation and lactation or to pregnant rats during the last third of gestation and throughout lactation at doses approximately 4 times the maximum recommended human dose.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nalbuphine in women who are pregnant.
### Labor and Delivery
- The placental transfer of nalbuphine is high, rapid, and variable with a maternal to fetal ratio ranging from 1:0.37 to 1:6. Fetal and neonatal adverse effects that have been reported following the administration of nalbuphine to the mother during labor include fetal bradycardia, respiratory depression at birth, apnea, cyanosis, and hypotonia. Some of these events have been life-threatening. Maternal administration of naloxone during labor has normalized these effects in some cases. Severe and prolonged fetal bradycardia has been reported. Permanent neurological damage attributed to fetal bradycardia has occurred. A sinusoidal fetal heart rate pattern associated with the use of nalbuphine has also been reported. Nalbuphine should be used during labor and delivery only if clearly indicated and only if the potential benefit outweighs the risk to the infant. Newborns should be monitored for respiratory depression, apnea, bradycardia and arrhythmias if nalbuphine has been used.
### Nursing Mothers
- Limited data suggest that nalbuphine hydrochloride is excreted in maternal milk but only in a small amount (less than 1% of the administered dose) and with a clinically insignificant effect. Caution should be exercised when nalbuphine hydrochloride is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 18 years have not been established.
### Geriatic Use
There is no FDA guidance on the use of Nalbuphine in geriatric settings.
### Gender
There is no FDA guidance on the use of Nalbuphine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nalbuphine with respect to specific racial populations.
### Renal Impairment
- Because nalbuphine is metabolized in the liver and excreted by the kidneys, nalbuphine hydrochloride should be used with caution in patients with renal or liver dysfunction and administered in reduced amounts.
### Hepatic Impairment
- Because nalbuphine is metabolized in the liver and excreted by the kidneys, nalbuphine hydrochloride should be used with caution in patients with renal or liver dysfunction and administered in reduced amounts.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nalbuphine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nalbuphine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Nalbuphine Administration in the drug label.
### Monitoring
There is limited information regarding Nalbuphine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Nalbuphine and IV administrations.
# Overdosage
- The immediate intravenous administration of an opiate antagonist such as naloxone or nalmefene is a specific antidote. Oxygen, intravenous fluids, vasopressors and other supportive measures should be used as indicated.
- The administration of single doses of 72 mg of nalbuphine hydrochloride subcutaneously to eight normal subjects has been reported to have resulted primarily in symptoms of sleepiness and mild dysphoria.
# Pharmacology
## Mechanism of Action
- Nalbuphine hydrochloride is a potent analgesic. Its analgesic potency is essentially equivalent to that of morphine on a milligram basis. Receptor studies show that nalbuphine hydrochloride binds to mu, kappa, and delta receptors, but not to sigma receptors.
- Nalbuphine hydrochloride is primarily a kappa agonist/partial mu antagonist analgesic.
## Structure
- Nalbuphine hydrochloride is a synthetic opioid agonist-antagonist analgesic of the phenanthrene series. It is chemically related to both the widely used opioid antagonist, naloxone, and the potent opioid analgesic, oxymorphone. Chemically nalbuphine hydrochloride is 17-(cyclobutylmethyl)-4,5α-epoxymorphinan-3,6α,14-triol hydrochloride. Nalbuphine hydrochloride molecular weight is 393.91 and is soluble in H2O (35.5 mg/mL at 25ºC) and ethanol (0.8%); insoluble in CHCl3 and ether. Nalbuphine hydrochloride has pKa values of 8.71 and 9.96. The molecular formula is C21H27NO4 • HCl. The structural formula is:
- Nalbuphine Hydrochloride Injection is a sterile, nonpyrogenic solution of nalbuphine hydrochloride in water for injection. This product may be administered by subcutaneous, intramuscular or intravenous injection.
- Each milliliter (mL) contains nalbuphine hydrochloride 10 mg or 20 mg; sodium citrate, dihydrate 0.47 mg and citric acid, anhydrous 0.63 mg added as buffers and may contain sodium hydroxide and/or hydrochloric acid for pH adjustment; pH 3.7 (3.0 to 4.5). Contains sodium chloride for tonicity adjustment.
- Multiple-dose vials contain 1.8 mg/mL methylparaben and 0.2 mg/mL propylparaben added as preservatives. Single-dose products contain no bacteriostat or antimicrobial agent and unused portions must be discarded.
## Pharmacodynamics
- The onset of action of nalbuphine hydrochloride occurs within 2 to 3 minutes after intravenous administration, and in less than 15 minutes following subcutaneous or intramuscular injection. The plasma half-life of nalbuphine is 5 hours, and in clinical studies, the duration of analgesic activity has been reported to range from 3 to 6 hours.
- The opioid antagonist activity of nalbuphine is one-fourth as potent as nalorphine and 10 times that of pentazocine.
- Nalbuphine hydrochloride may produce the same degree of respiratory depression as equianalgesic doses of morphine. However, nalbuphine hydrochloride exhibits a ceiling effect such that increases in dose greater than 30 mg do not produce further respiratory depression in the absence of other CNS active medications affecting respiration.
## Pharmacokinetics
- Nalbuphine hydrochloride by itself has potent opioid antagonist activity at doses equal to or lower than its analgesic dose. When administered following or concurrent with mu agonist opioid analgesics (e.g., morphine, oxymorphone, fentanyl), nalbuphine hydrochloride may partially reverse or block opioid-induced respiratory depression from the mu agonist analgesic. Nalbuphine hydrochloride may precipitate withdrawal in patients dependent on opioid drugs. Nalbuphine hydrochloride should be used with caution in patients who have been receiving mu opioid analgesics on a regular basis.
## Nonclinical Toxicology
- Long term carcinogenicity studies were performed in rats (24 months) and mice (19 months) by oral administration at doses up to 200 mg/kg (1180 mg/m2) and 200 mg/kg (600 mg/m2) per day, respectively. There was no evidence of an increase in tumors in either species related to nalbuphine hydrochloride administration. The maximum recommend human dose (MRHD) in a day is 160 mg subcutaneously, intramuscularly or intravenously, or approximately 100 mg/m2/day for a 60 kg subject.
- Nalbuphine hydrochloride did not have mutagenic activity in the AMES test with four bacterial strains, in the Chinese Hamster Ovary HGPRT assays or in the Sister Chromatids Exchange Assay. However, nalbuphine hydrochloride induced an increased frequency of mutation in the mouse lymphoma assay. Clastogenic activity was not observed in the mouse micronucleus test of the cytogenicity bone marrow assay in rats.
- A reproduction study was performed in male and female rats at subcutaneous doses up to 56 mg/kg/day or 330 mg/m2/day. Nalbuphine hydrochloride did not affect either male or female fertility rats.
# Clinical Studies
There is limited information regarding Nalbuphine Clinical Studies in the drug label.
# How Supplied
- Nalbuphine Hydrochloride Injection is supplied as follows:
## Storage
- Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.]
- Protect from light. Store in carton until contents have been used.
- Revised: August, 2007
- Printed in USA EN-1571
- Hospira, Inc., Lake Forest, IL 60045 USA
- RL-0188
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be advised of the following information:
- Nalbuphine is associated with sedation and may impair mental and physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery.
- Nalbuphine is to be used as prescribed by a physician. Dose or frequency should not be increased without first consulting with a physician since nalbuphine may cause psychological or physical dependence.
- The use of nalbuphine with other opioids can cause signs and symptoms of withdrawal.
- Abrupt discontinuation of nalbuphine after prolonged usage may cause signs and symptoms of withdrawal.
# Precautions with Alcohol
Alcohol-Nalbuphine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Nalbuphine Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Nalbuphine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Nalbufine | |
07de1723dcf58a523432598575eaadf2dc2b11c4 | wikidoc | Nanosensor | Nanosensor
# Overview
Nanosensors are any biological, chemical, or sugery sensory points used to convey information about nanoparticles to the macroscopic world. Though humans have not yet been able to synthesize nanosensors, predictions for their use mainly include various medicinal purposes and as gateways to building other nanoproducts, such as computer chips that work at the nanoscale and nanorobots. Presently, there are several ways proposed to make nanosensors, including top-down lithography, bottom-up assembly, and molecular self-assembly.
# Predicted applications
Medicinal uses of nanosensors mainly revolve around the potential of nanosensors to accurately identify particular cells or places in the body in need. By measuring changes in volume, concentration, displacement and velocity, gravitational, electrical, and magnetic forces, pressure, or temperature of cells in a body, nanosensors may be able to distinguish between and recognize certain cells, most notably those of cancer, at the molecular level in order to deliver medicine or monitor development to specific places in the body. In addition, they may be able to detect macroscopic variations from outside the body and communicate these changes to other nanoproducts working within the body.
One example of nanosensors involves using the fluorescence properties of cadmium selenide quantum dots as sensors to uncover tumors within the body. By injecting a body with these quantum dots, a doctor could see where a tumor or cancer cell was by finding the injected quantum dots, an easy process because of their fluorescence. Developed nanosensor quantum dots would be specifically constructed to find only the particular cell for which the body was at risk. A downside to the cadmium selenide dots, however, is that they are highly toxic to the body. As a result, researchers are working on developing alternate dots made out of a different, less toxic material while still retaining some of the fluorescence properties. In particular, they have been investigating the particular benefits of zinc sulfide quantum dots which, though they are not quite as fluorescent as cadmium selenide, can be augmented with other metals including manganese and various lanthanide elements. In addition, these newer quantum dots become more fluorescent when they bond to their target cells. (Quantum) Potential predicted functions may also include sensors used to detect specific DNA in order to recognize explicit genetic defects, especially for individuals at high-risk and implanted sensors that can automatically detect glucose levels for diabetic subjects more simply than current detectors. DNA can also serve as sacrificial layer for manufacturing CMOS IC, integrating a nanodevice with sensing capabilities. Therefore, using proteomic patterns and new hybrid materials, nanobiosensors can also be used to enable components configured into a hybrid semiconductor substrate as part of the circuit assembly. The development and miniaturization of nanobiosensors should provide interesting new opportunities.
Other projected products most commonly involve using nanosensors to build smaller integrated circuits, as well as incorporating them into various other commodities made using other forms of nanotechnology for use in a variety of situations including transportation, communication, improvements in structural integrity, and robotics . Nanosensors may also eventually be valuable as more accurate monitors of material states for use in systems where size and weight are constrained, such as in satellites and other aeronautic machines.
# Existing nanosensors
Currently, the most common mass-produced functioning nanosensors exist in the biological world as natural receptors of outside stimulation. For instance, sense of smell, especially in animals in which it is particularly strong, such as dogs, functions using receptors that sense nanosized molecules. Certain plants, too, use nanosensors to detect sunlight; various fish use nanosensors to detect minuscule vibrations in the surrounding water; and many insects detect sex pheromones using nanosensors .
Certain electromagnetic sensors have also been in use in photoelectric systems. These work because the specific sensors called, aptly, photosensors are easily influenced by light of various wavelengths. The electromagnetic source transfers energy to the photosensors and energizes them into an excited state which causes them to release an electron into a semiconductor. At that point, it is relatively easy to detect the electricity coming from the sensors, and thus easy to know if the sensors are receiving light. Though more advanced uses of photosensors incorporating other forms of nanotechnology have yet to be implemented into consumer society, most film cameras have used photosensors at the nano size for years. Traditional film uses a layer of silver ions that become excited by solar energy and clump into groups, as small as four atoms apiece in some cases, that scatter light and appear dark on the frame. Various other types of film can be made using a similar process to detect other specific wavelengths of light, including x-rays, infrared, and ultraviolet .
One of the first working examples of a synthetic nanosensor was built by researchers at the Georgia Institute of Technology in 1999. It involved attaching a single particle onto the end of a carbon nanotube and measuring the vibrational frequency of the nanotube both with and without the particle. The discrepancy between the two frequencies allowed the researchers to measure the mass of the attached particle .
Chemical sensors, too, have been built using nanotubes to detect various properties of gaseous molecules. Carbon nanotubes have been used to sense ionization of gaseous molecules while nanotubes made out of titanium have been employed to detect atmospheric concentrations of hydrogen at the molecular level. Many of these involve a system by which nanosensors are built to have a specific pocket for another molecule. When that particular molecule, and only that specific molecule, fits into the nanosensor, and light is shone upon the nanosensor, it will reflect different wavelengths of light and, thus, be a different color .
# Production methods
There are currently several hypothesized ways to produce nanosensors. Top-down lithography is the manner in which most integrated circuits are now made. It involves starting out with a larger block of some material and carving out the desired form. These carved out devices, notably put to use in specific microelectromechanical systems used as microsensors, generally only reach the micro size, but the most recent of these have begun to incorporate nanosized components .
Another way to produce nanosensors is through the bottom-up method, which involves assembling the sensors out of even more minuscule components, most likely individual atoms or molecules. This would involve moving atoms of a particular substance one by one into particular positions which, though it has been achieved in laboratory tests using tools such as atomic force microscopes, is still a significant difficulty, especially to do en masse, both for logistic reasons as well as economic ones. Most likely, this process would be used mainly for building starter molecules for self-assembling sensors.
The third way, which promises far faster results, involves self-assembly, or “growing” particular nanostructures to be used as sensors. This most often entails one of two types of assembly. The first involves using a piece of some previously created or naturally formed nanostructure and immersing it in free atoms of its own kind. After a given period, the structure, having an irregular surface that would make it prone to attracting more molecules as a continuation of its current pattern, would capture some of the free atoms and continue to form more of itself to make larger components of nanosensors.
The second type of self-assembly starts with an already complete set of components that would automatically assemble themselves into a finished product. Though this has been so far successful only in assembling computer chips at the micro size, researchers hope to eventually be able to do it at the nanometer size for multiple products, including nanosensors. Accurately being able to reproduce this effect for a desired sensor in a laboratory would imply that scientists could manufacture nanosensors much more quickly and potentially far more cheaply by letting numerous molecules assemble themselves with little or no outside influence, rather than having to manually assemble each sensor.
# Economic impact
Though nanosensor technology is a relatively new field, global projections for sales of products incorporating nanosensors range from $0.6 billion to $2.7 billion in the next three to four years. They will likely be included in most modern circuitry used in advanced computing systems, since their potential to provide the link between other forms of nanotechnology and the macroscopic world allows developers to fully exploit the potential of nanotechnology to miniaturize computer chips while vastly expanding their storage potential.
First, however, nanosensor developers must overcome the present high costs of production in order to become worthwhile for implementation in consumer products. Additionally, nanosensor reliability is not yet suitable for widespread use, and, because of their scarcity, nanosensors have yet to be marketed and implemented outside of research facilities . Consequently, nanosensors have yet to be made compatible with most consumer technologies for which they have been projected to eventually enhance. | Nanosensor
Template:Nanomedicine subfields
# Overview
Nanosensors are any biological, chemical, or sugery sensory points used to convey information about nanoparticles to the macroscopic world. Though humans have not yet been able to synthesize nanosensors, predictions for their use mainly include various medicinal purposes and as gateways to building other nanoproducts, such as computer chips that work at the nanoscale and nanorobots. Presently, there are several ways proposed to make nanosensors, including top-down lithography, bottom-up assembly, and molecular self-assembly[1].
# Predicted applications
Medicinal uses of nanosensors mainly revolve around the potential of nanosensors to accurately identify particular cells or places in the body in need. By measuring changes in volume, concentration, displacement and velocity, gravitational, electrical, and magnetic forces, pressure, or temperature of cells in a body, nanosensors may be able to distinguish between and recognize certain cells, most notably those of cancer, at the molecular level in order to deliver medicine or monitor development to specific places in the body[2]. In addition, they may be able to detect macroscopic variations from outside the body and communicate these changes to other nanoproducts working within the body.
One example of nanosensors involves using the fluorescence properties of cadmium selenide quantum dots as sensors to uncover tumors within the body. By injecting a body with these quantum dots, a doctor could see where a tumor or cancer cell was by finding the injected quantum dots, an easy process because of their fluorescence. Developed nanosensor quantum dots would be specifically constructed to find only the particular cell for which the body was at risk. A downside to the cadmium selenide dots, however, is that they are highly toxic to the body. As a result, researchers are working on developing alternate dots made out of a different, less toxic material while still retaining some of the fluorescence properties. In particular, they have been investigating the particular benefits of zinc sulfide quantum dots which, though they are not quite as fluorescent as cadmium selenide, can be augmented with other metals including manganese and various lanthanide elements. In addition, these newer quantum dots become more fluorescent when they bond to their target cells. (Quantum) Potential predicted functions may also include sensors used to detect specific DNA in order to recognize explicit genetic defects, especially for individuals at high-risk and implanted sensors that can automatically detect glucose levels for diabetic subjects more simply than current detectors[3]. DNA can also serve as sacrificial layer for manufacturing CMOS IC, integrating a nanodevice with sensing capabilities[4]. Therefore, using proteomic patterns and new hybrid materials, nanobiosensors can also be used to enable components configured into a hybrid semiconductor substrate as part of the circuit assembly. The development and miniaturization of nanobiosensors should provide interesting new opportunities[5].
Other projected products most commonly involve using nanosensors to build smaller integrated circuits, as well as incorporating them into various other commodities made using other forms of nanotechnology for use in a variety of situations including transportation, communication, improvements in structural integrity, and robotics [1]. Nanosensors may also eventually be valuable as more accurate monitors of material states for use in systems where size and weight are constrained, such as in satellites and other aeronautic machines.
# Existing nanosensors
Currently, the most common mass-produced functioning nanosensors exist in the biological world as natural receptors of outside stimulation. For instance, sense of smell, especially in animals in which it is particularly strong, such as dogs, functions using receptors that sense nanosized molecules. Certain plants, too, use nanosensors to detect sunlight; various fish use nanosensors to detect minuscule vibrations in the surrounding water; and many insects detect sex pheromones using nanosensors [3].
Certain electromagnetic sensors have also been in use in photoelectric systems. These work because the specific sensors called, aptly, photosensors are easily influenced by light of various wavelengths. The electromagnetic source transfers energy to the photosensors and energizes them into an excited state which causes them to release an electron into a semiconductor. At that point, it is relatively easy to detect the electricity coming from the sensors, and thus easy to know if the sensors are receiving light. Though more advanced uses of photosensors incorporating other forms of nanotechnology have yet to be implemented into consumer society, most film cameras have used photosensors at the nano size for years. Traditional film uses a layer of silver ions that become excited by solar energy and clump into groups, as small as four atoms apiece in some cases, that scatter light and appear dark on the frame. Various other types of film can be made using a similar process to detect other specific wavelengths of light, including x-rays, infrared, and ultraviolet [3].
One of the first working examples of a synthetic nanosensor was built by researchers at the Georgia Institute of Technology in 1999[6]. It involved attaching a single particle onto the end of a carbon nanotube and measuring the vibrational frequency of the nanotube both with and without the particle. The discrepancy between the two frequencies allowed the researchers to measure the mass of the attached particle [1].
Chemical sensors, too, have been built using nanotubes to detect various properties of gaseous molecules. Carbon nanotubes have been used to sense ionization of gaseous molecules while nanotubes made out of titanium have been employed to detect atmospheric concentrations of hydrogen at the molecular level[7][8]. Many of these involve a system by which nanosensors are built to have a specific pocket for another molecule. When that particular molecule, and only that specific molecule, fits into the nanosensor, and light is shone upon the nanosensor, it will reflect different wavelengths of light and, thus, be a different color [3].
# Production methods
There are currently several hypothesized ways to produce nanosensors. Top-down lithography is the manner in which most integrated circuits are now made. It involves starting out with a larger block of some material and carving out the desired form. These carved out devices, notably put to use in specific microelectromechanical systems used as microsensors, generally only reach the micro size, but the most recent of these have begun to incorporate nanosized components [1].
Another way to produce nanosensors is through the bottom-up method, which involves assembling the sensors out of even more minuscule components, most likely individual atoms or molecules. This would involve moving atoms of a particular substance one by one into particular positions which, though it has been achieved in laboratory tests using tools such as atomic force microscopes, is still a significant difficulty, especially to do en masse, both for logistic reasons as well as economic ones. Most likely, this process would be used mainly for building starter molecules for self-assembling sensors.
The third way, which promises far faster results, involves self-assembly, or “growing” particular nanostructures to be used as sensors. This most often entails one of two types of assembly. The first involves using a piece of some previously created or naturally formed nanostructure and immersing it in free atoms of its own kind. After a given period, the structure, having an irregular surface that would make it prone to attracting more molecules as a continuation of its current pattern, would capture some of the free atoms and continue to form more of itself to make larger components of nanosensors.
The second type of self-assembly starts with an already complete set of components that would automatically assemble themselves into a finished product. Though this has been so far successful only in assembling computer chips at the micro size, researchers hope to eventually be able to do it at the nanometer size for multiple products, including nanosensors. Accurately being able to reproduce this effect for a desired sensor in a laboratory would imply that scientists could manufacture nanosensors much more quickly and potentially far more cheaply by letting numerous molecules assemble themselves with little or no outside influence, rather than having to manually assemble each sensor.
# Economic impact
Though nanosensor technology is a relatively new field, global projections for sales of products incorporating nanosensors range from $0.6 billion to $2.7 billion in the next three to four years. They will likely be included in most modern circuitry used in advanced computing systems, since their potential to provide the link between other forms of nanotechnology and the macroscopic world allows developers to fully exploit the potential of nanotechnology to miniaturize computer chips while vastly expanding their storage potential.
First, however, nanosensor developers must overcome the present high costs of production in order to become worthwhile for implementation in consumer products. Additionally, nanosensor reliability is not yet suitable for widespread use, and, because of their scarcity, nanosensors have yet to be marketed and implemented outside of research facilities [1]. Consequently, nanosensors have yet to be made compatible with most consumer technologies for which they have been projected to eventually enhance. | https://www.wikidoc.org/index.php/Nanosensor | |
9ce2f592396dd946355dce770df49a863f794c35 | wikidoc | Phenelzine | Phenelzine
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# Black Box Warning
# Overview
Phenelzine is a MAOI that is FDA approved for the {{{indicationType}}} of depression-atypical, non-endogenous, or neurotic. There is a Black Box Warning for this drug as shown here. Common adverse reactions include orthostatic hypotension, weight gain, abdominal discomfort, constipation, xerostomia, increased liver aminotransferase level, without accompanying signs and symptoms, asthenia, dizziness, dyssomnia, headache, somnolence, disorder of ejaculation, impotence, orgasm incapacity,fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Depression-atypical, non-endogenous, or neurotic
- Initial, 15 mg PO 3 times a day; increase to 60-90 mg/day
- Maintenance: after maximal therapeutic effect decrease dose slowly to the minimum effective dosage
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Phenelzine in adult patients.
### Non–Guideline-Supported Use
- Agoraphobia
- Bulimia nervosa
- 60-90 mg/day PO
- Panic disorder
- 15 mg PO for 4 days increase gradually over 2 weeks up to 15 mg 3-4 times a day.
- Social phobia
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
safety in children have not been established
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Phenelzine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Phenelzine in pediatric patients.
# Contraindications
- Phenelzine Tablets should not be used in patients who are hypersensitive to the drug or its ingredients, with pheochromocytoma, congestive heart failure, severe renal impairment or renal disease, a history of liver disease, or abnormal liver function tests.
- The potentiation of sympathomimetic substances and related compounds by MAO inhibitors may result in hypertensive crises (see WARNINGS). Therefore, patients being treated with Phenelzine Sulfate Tablets should not take sympathomimetic drugs (including amphetamines, cocaine, methylphenidate, dopamine, epinephrine, and norepinephrine) or related compounds (including methyldopa, L-dopa, L-tryptophan, L-tyrosine, and phenylalanine).
- Hypertensive crises during Phenelzine Tablets therapy may also be caused by the ingestion of foods with a high concentration of tyramine or dopamine. Therefore, patients being treated with Phenelzine Sulfate Tablets should avoid high protein food that has undergone protein breakdown by aging, fermentation, pickling, smoking, or bacterial contamination. Patients should also avoid cheeses (especially aged varieties), pickled herring, beer, wine, liver, yeast extract (including brewer’s yeast in large quantities), dry sausage (including Genoa salami, hard salami, pepperoni, and Lebanon bologna), pods of broad beans (fava beans), and yogurt. Excessive amounts of caffeine and chocolate may also cause hypertensive reactions.
- Phenelzine Tablets should not be used in combination with dextromethorphan or with CNS depressants such as alcohol and certain narcotics.
- MAOI therapy who have been given a single dose of meperidine. Phenelzine Tablets should not be administered together with or in rapid succession to other MAO inhibitors because hypertensive crisis and convulsive seizures, fever, marked sweating, excitation, delirium, tremor, coma, and circulatory collapse may occur.
- Concomitant use with meperidine is contraindicated.
# Warnings
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18–24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications.
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Phenelzine Tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Phenelzine is not approved for use in treating bipolar depression.
It should be noted that Phenelzine is not approved for use in treating any indications in the pediatric population.
The most serious reactions to Phenelzine Sulfate Tablets involve changes in blood pressure.
Hypertensive Crises
The most important reaction associated with Phenelzine administration is the occurrence of hypertensive crises, which have sometimes been fatal.
These crises are characterized by some or all of the following symptoms: occipital headache which may radiate frontally, palpitation, neck stiffness or soreness, nausea, vomiting, sweating (sometimes with fever and sometimes with cold, clammy skin), dilated pupils, and photophobia.
Either tachycardia or bradycardia may be present and can be associated with constricting chest pain.
(NOTE: Intracranial bleeding has been reported in association with the increase in blood pressure.)
Blood pressure should be observed frequently to detect evidence of any pressor response in all patients receiving Phenelzine. Therapy should be discontinued immediately upon the occurrence of palpitation or frequent headaches during therapy.
Recommended treatment in hypertensive crisis
If a hypertensive crisis occurs, Phenelzine should be discontinued immediately and therapy to lower blood pressure should be instituted immediately. On the basis of present evidence, phentolamine is recommended. (The dosage reported for phentolamine is 5 mg intravenously.) Care should be taken to administer this drug slowly in order to avoid producing an excessive hypotensive effect. Fever should be managed by means of external cooling.
Warning to the Patient
All patients should be warned that the following foods, beverages, and medications must be avoided while taking Phenelzine Sulfate Tablets, and for two weeks after discontinuing use.
Foods and Beverages To Avoid
Meat and Fish
Pickled herring
Liver
Dry sausage (including Genoa salami, hard salami, pepperoni, and Lebanon bologna)
Vegetables
Broad bean pods (fava bean pods)
Sauerkraut
Dairy Products
Cheese (cottage cheese and cream cheese are allowed)
Yogurt
Beverages
Beer and wine
Alcohol-free and reduced-alcohol beer and wine products
Miscellaneous
Yeast extract (including brewer’s yeast in large quantities)
Meat extract
Excessive amounts of chocolate and caffeine
Also, any spoiled or improperly refrigerated, handled, or stored protein-rich foods such as meats, fish, and dairy products, including foods that may have undergone protein changes by aging, pickling, fermentation, or smoking to improve flavor should be avoided.
OTC Medications To Avoid
Cold and cough preparations (including those containing dextromethorphan)
Nasal decongestants (tablets, drops, or spray)
Hay-fever medications
Sinus medications
Asthma inhalant medications
Antiappetite medicines
Weight-reducing preparations
“Pep” pills
L-tryptophan containing preparations
Also, certain prescription drugs should be avoided. Therefore, patients under the care of another physician or dentist should inform him/her that they are taking Phenelzine.
Patients should be warned that the use of the above foods, beverages, or medications may cause a reaction characterized by headache and other serious symptoms due to a rise in blood pressure, with the exception of dextromethorphan which may cause reactions similar to those seen with
meperidine. Also, there has been a report of an interaction between Phenelzine and dextromethorphan (ingested as a lozenge) causing drowsiness and bizarre behavior.
Patients should be instructed to report promptly the occurrence of headache or other unusual symptoms.
Concomitant Use with Dibenzazepine Derivative Drugs
If the decision is made to administer Phenelzine Tablets concurrently with other antidepressant drugs, or within less than 10 days after discontinuation of antidepressant therapy, the patient should be cautioned by the physician regarding the possibility of adverse drug interaction.
A List of Dibenzazepine Derivative Drugs by Generic Name Follows:
Nortriptyline hydrochloride
Amitriptyline hydrochloride
Perphenazine and amitriptyline hydrochloride
Clomipramine hydrochloride
Desipramine hydrochloride
Imipramine hydrochloride
Doxepin
Carbamazepine
Cyclobenzaprine HCl
Amoxapine
Maprotiline HCl
Trimipramine maleate
Protriptyline HCl
Mirtazapine
Phenelzine should be used with caution in combination with antihypertensive drugs, including thiazide diuretics and β-blockers, since exaggerated hypotensive effects may result.
# Adverse Reactions
## Clinical Trials Experience
Common side effects include:
Nervous System
Dizziness, headache, drowsiness, sleep disturbances (including insomnia and hypersomnia), fatigue, weakness, tremors, twitching, myoclonic movements, hyperreflexia.
Gastrointestinal
Constipation, dry mouth, gastrointestinal disturbances, elevated serum transaminases (without accompanying signs and symptoms).
Metabolic
Weight gain.
Cardiovascular
Postural hypotension, edema.
Genitourinary
Sexual disturbances, eg, anorgasmia and ejaculatory disturbances and impotence.
Less common mild to moderate side effects (some of which have been reported in a single patient or by a single physician) include:
Nervous System
Jitteriness, palilalia, euphoria, nystagmus, paresthesias.
Genitourinary
Urinary retention.
Metabolic
Hypernatremia.
Dermatologic
Pruritus, skin rash, sweating.
Special Senses
Blurred vision, glaucoma.
Although reported less frequently, and sometimes only once, additional severe side effects include:
Nervous System
Ataxia, shock-like coma, toxic delirium, manic reaction, convulsions, acute anxiety reaction, precipitation of schizophrenia, transient respiratory and cardiovascular depression following ECT.
Gastrointestinal
To date, fatal progressive necrotizing hepatocellular damage has been reported in very few patients. Reversible jaundice.
Hematologic
Leukopenia.
Immunologic
Lupus-like syndrome
Metabolic
Hypermetabolic syndrome (which may include, but is not limited to, hyperpyrexia, tachycardia, tachypnea, muscular rigidity, elevated CK levels, metabolic acidosis, hypoxia, coma and may resemble an overdose).
Respiratory
Edema of the glottis.
General
Fever associated with increased muscle tone.
## Postmarketing Experience
There is limited information regarding Phenelzine Postmarketing Experience in the drug label.
# Drug Interactions
- Serotoninergic agent
A List of MAO Inhibitors by Generic Name Follows:
- Pargyline hydrochloride
- Pargyline hydrochloride and methylclothiazide
- Furazolidone
- Isocarboxazid
- Procarbazine
- Tranylcypromine
- Guanethidine
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Phenelzine in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Phenelzine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Phenelzine during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Phenelzine in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Phenelzine in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Phenelzine in geriatric settings.
### Gender
There is no FDA guidance on the use of Phenelzine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Phenelzine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Phenelzine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Phenelzine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Phenelzine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Phenelzine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Phenelzine Administration in the drug label.
### Monitoring
There is limited information regarding Phenelzine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Phenelzine and IV administrations.
# Overdosage
There is limited information regarding Phenelzine overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
There is limited information regarding Phenelzine Mechanism of Action in the drug label.
## Structure
There is limited information regarding Phenelzine Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Phenelzine Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Phenelzine Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Phenelzine Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Phenelzine Clinical Studies in the drug label.
# How Supplied
There is limited information regarding Phenelzine How Supplied in the drug label.
## Storage
There is limited information regarding Phenelzine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Phenelzine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Phenelzine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Phenelzine Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Phenelzine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Phenelzine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Pratik Bahekar, MBBS [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Phenelzine is a MAOI that is FDA approved for the {{{indicationType}}} of depression-atypical, non-endogenous, or neurotic. There is a Black Box Warning for this drug as shown here. Common adverse reactions include orthostatic hypotension, weight gain, abdominal discomfort, constipation, xerostomia, increased liver aminotransferase level, without accompanying signs and symptoms, asthenia, dizziness, dyssomnia, headache, somnolence, disorder of ejaculation, impotence, orgasm incapacity,fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Depression-atypical, non-endogenous, or neurotic
- Initial, 15 mg PO 3 times a day; increase to 60-90 mg/day
- Maintenance: after maximal therapeutic effect decrease dose slowly to the minimum effective dosage
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Phenelzine in adult patients.
### Non–Guideline-Supported Use
- Agoraphobia
- Bulimia nervosa
- 60-90 mg/day PO
- Panic disorder
- 15 mg PO for 4 days increase gradually over 2 weeks up to 15 mg 3-4 times a day.
- Social phobia
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
safety in children have not been established
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Phenelzine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Phenelzine in pediatric patients.
# Contraindications
- Phenelzine Tablets should not be used in patients who are hypersensitive to the drug or its ingredients, with pheochromocytoma, congestive heart failure, severe renal impairment or renal disease, a history of liver disease, or abnormal liver function tests.
- The potentiation of sympathomimetic substances and related compounds by MAO inhibitors may result in hypertensive crises (see WARNINGS). Therefore, patients being treated with Phenelzine Sulfate Tablets should not take sympathomimetic drugs (including amphetamines, cocaine, methylphenidate, dopamine, epinephrine, and norepinephrine) or related compounds (including methyldopa, L-dopa, L-tryptophan, L-tyrosine, and phenylalanine).
- Hypertensive crises during Phenelzine Tablets therapy may also be caused by the ingestion of foods with a high concentration of tyramine or dopamine. Therefore, patients being treated with Phenelzine Sulfate Tablets should avoid high protein food that has undergone protein breakdown by aging, fermentation, pickling, smoking, or bacterial contamination. Patients should also avoid cheeses (especially aged varieties), pickled herring, beer, wine, liver, yeast extract (including brewer’s yeast in large quantities), dry sausage (including Genoa salami, hard salami, pepperoni, and Lebanon bologna), pods of broad beans (fava beans), and yogurt. Excessive amounts of caffeine and chocolate may also cause hypertensive reactions.
- Phenelzine Tablets should not be used in combination with dextromethorphan or with CNS depressants such as alcohol and certain narcotics.
- MAOI therapy who have been given a single dose of meperidine. Phenelzine Tablets should not be administered together with or in rapid succession to other MAO inhibitors because hypertensive crisis and convulsive seizures, fever, marked sweating, excitation, delirium, tremor, coma, and circulatory collapse may occur.
- Concomitant use with meperidine is contraindicated.
# Warnings
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18–24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications.
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Phenelzine Tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Phenelzine is not approved for use in treating bipolar depression.
It should be noted that Phenelzine is not approved for use in treating any indications in the pediatric population.
The most serious reactions to Phenelzine Sulfate Tablets involve changes in blood pressure.
Hypertensive Crises
The most important reaction associated with Phenelzine administration is the occurrence of hypertensive crises, which have sometimes been fatal.
These crises are characterized by some or all of the following symptoms: occipital headache which may radiate frontally, palpitation, neck stiffness or soreness, nausea, vomiting, sweating (sometimes with fever and sometimes with cold, clammy skin), dilated pupils, and photophobia.
Either tachycardia or bradycardia may be present and can be associated with constricting chest pain.
(NOTE: Intracranial bleeding has been reported in association with the increase in blood pressure.)
Blood pressure should be observed frequently to detect evidence of any pressor response in all patients receiving Phenelzine. Therapy should be discontinued immediately upon the occurrence of palpitation or frequent headaches during therapy.
Recommended treatment in hypertensive crisis
If a hypertensive crisis occurs, Phenelzine should be discontinued immediately and therapy to lower blood pressure should be instituted immediately. On the basis of present evidence, phentolamine is recommended. (The dosage reported for phentolamine is 5 mg intravenously.) Care should be taken to administer this drug slowly in order to avoid producing an excessive hypotensive effect. Fever should be managed by means of external cooling.
Warning to the Patient
All patients should be warned that the following foods, beverages, and medications must be avoided while taking Phenelzine Sulfate Tablets, and for two weeks after discontinuing use.
Foods and Beverages To Avoid
Meat and Fish
Pickled herring
Liver
Dry sausage (including Genoa salami, hard salami, pepperoni, and Lebanon bologna)
Vegetables
Broad bean pods (fava bean pods)
Sauerkraut
Dairy Products
Cheese (cottage cheese and cream cheese are allowed)
Yogurt
Beverages
Beer and wine
Alcohol-free and reduced-alcohol beer and wine products
Miscellaneous
Yeast extract (including brewer’s yeast in large quantities)
Meat extract
Excessive amounts of chocolate and caffeine
Also, any spoiled or improperly refrigerated, handled, or stored protein-rich foods such as meats, fish, and dairy products, including foods that may have undergone protein changes by aging, pickling, fermentation, or smoking to improve flavor should be avoided.
OTC Medications To Avoid
Cold and cough preparations (including those containing dextromethorphan)
Nasal decongestants (tablets, drops, or spray)
Hay-fever medications
Sinus medications
Asthma inhalant medications
Antiappetite medicines
Weight-reducing preparations
“Pep” pills
L-tryptophan containing preparations
Also, certain prescription drugs should be avoided. Therefore, patients under the care of another physician or dentist should inform him/her that they are taking Phenelzine.
Patients should be warned that the use of the above foods, beverages, or medications may cause a reaction characterized by headache and other serious symptoms due to a rise in blood pressure, with the exception of dextromethorphan which may cause reactions similar to those seen with
meperidine. Also, there has been a report of an interaction between Phenelzine and dextromethorphan (ingested as a lozenge) causing drowsiness and bizarre behavior.
Patients should be instructed to report promptly the occurrence of headache or other unusual symptoms.
Concomitant Use with Dibenzazepine Derivative Drugs
If the decision is made to administer Phenelzine Tablets concurrently with other antidepressant drugs, or within less than 10 days after discontinuation of antidepressant therapy, the patient should be cautioned by the physician regarding the possibility of adverse drug interaction.
A List of Dibenzazepine Derivative Drugs by Generic Name Follows:
Nortriptyline hydrochloride
Amitriptyline hydrochloride
Perphenazine and amitriptyline hydrochloride
Clomipramine hydrochloride
Desipramine hydrochloride
Imipramine hydrochloride
Doxepin
Carbamazepine
Cyclobenzaprine HCl
Amoxapine
Maprotiline HCl
Trimipramine maleate
Protriptyline HCl
Mirtazapine
Phenelzine should be used with caution in combination with antihypertensive drugs, including thiazide diuretics and β-blockers, since exaggerated hypotensive effects may result.
# Adverse Reactions
## Clinical Trials Experience
Common side effects include:
Nervous System
Dizziness, headache, drowsiness, sleep disturbances (including insomnia and hypersomnia), fatigue, weakness, tremors, twitching, myoclonic movements, hyperreflexia.
Gastrointestinal
Constipation, dry mouth, gastrointestinal disturbances, elevated serum transaminases (without accompanying signs and symptoms).
Metabolic
Weight gain.
Cardiovascular
Postural hypotension, edema.
Genitourinary
Sexual disturbances, eg, anorgasmia and ejaculatory disturbances and impotence.
Less common mild to moderate side effects (some of which have been reported in a single patient or by a single physician) include:
Nervous System
Jitteriness, palilalia, euphoria, nystagmus, paresthesias.
Genitourinary
Urinary retention.
Metabolic
Hypernatremia.
Dermatologic
Pruritus, skin rash, sweating.
Special Senses
Blurred vision, glaucoma.
Although reported less frequently, and sometimes only once, additional severe side effects include:
Nervous System
Ataxia, shock-like coma, toxic delirium, manic reaction, convulsions, acute anxiety reaction, precipitation of schizophrenia, transient respiratory and cardiovascular depression following ECT.
Gastrointestinal
To date, fatal progressive necrotizing hepatocellular damage has been reported in very few patients. Reversible jaundice.
Hematologic
Leukopenia.
Immunologic
Lupus-like syndrome
Metabolic
Hypermetabolic syndrome (which may include, but is not limited to, hyperpyrexia, tachycardia, tachypnea, muscular rigidity, elevated CK levels, metabolic acidosis, hypoxia, coma and may resemble an overdose).
Respiratory
Edema of the glottis.
General
Fever associated with increased muscle tone.
## Postmarketing Experience
There is limited information regarding Phenelzine Postmarketing Experience in the drug label.
# Drug Interactions
- Serotoninergic agent
A List of MAO Inhibitors by Generic Name Follows:
- Pargyline hydrochloride
- Pargyline hydrochloride and methylclothiazide
- Furazolidone
- Isocarboxazid
- Procarbazine
- Tranylcypromine
- Guanethidine
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Phenelzine in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Phenelzine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Phenelzine during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Phenelzine in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Phenelzine in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Phenelzine in geriatric settings.
### Gender
There is no FDA guidance on the use of Phenelzine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Phenelzine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Phenelzine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Phenelzine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Phenelzine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Phenelzine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Phenelzine Administration in the drug label.
### Monitoring
There is limited information regarding Phenelzine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Phenelzine and IV administrations.
# Overdosage
There is limited information regarding Phenelzine overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
Template:Drugbox 2
## Mechanism of Action
There is limited information regarding Phenelzine Mechanism of Action in the drug label.
## Structure
There is limited information regarding Phenelzine Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Phenelzine Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Phenelzine Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Phenelzine Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Phenelzine Clinical Studies in the drug label.
# How Supplied
There is limited information regarding Phenelzine How Supplied in the drug label.
## Storage
There is limited information regarding Phenelzine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Phenelzine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Phenelzine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Phenelzine Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Phenelzine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Nardil | |
9b1adaa52701016e3dab2d93228f67e6f025b690 | wikidoc | Nasal helm | Nasal helm
The nasal helm is a design of helm that was popular in the late Dark Ages through to the Early Medieval period.
The nasal helm was a form of helm with a domed or raised centre, usually formed around a basic skull-cap design, with a single protruding strip that extended down over the nose to provide additional facial protection. The helm appeared throughout Europe late in the 9th century, and became the predominant form of head protection, replacing the previous pudding-bowl design, and the spectical helm. One of the earliest versions of the nasal helm is the Vasgaard Helm.
The Bayeux Tapestry features many such helms, it being the most popular form of protection at the time. The helm was slowly replaced across the 13th century by helms that provided more facial protection, and although the nasal helm lost popularity amongst the higher classes of knights and men-at-arms, they were still seen amongst archers to whom a wide field of vision was crucial.
Nasal Helms have been found of both one-piece and spangenhelm construction, with the later period helms being made of a single, smooth raised dome to allow weapons to glance off with ease. | Nasal helm
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The nasal helm is a design of helm that was popular in the late Dark Ages through to the Early Medieval period.
The nasal helm was a form of helm with a domed or raised centre, usually formed around a basic skull-cap design, with a single protruding strip that extended down over the nose to provide additional facial protection. The helm appeared throughout Europe late in the 9th century, and became the predominant form of head protection, replacing the previous pudding-bowl design, and the spectical helm. One of the earliest versions of the nasal helm is the Vasgaard Helm.
The Bayeux Tapestry features many such helms, it being the most popular form of protection at the time. The helm was slowly replaced across the 13th century by helms that provided more facial protection, and although the nasal helm lost popularity amongst the higher classes of knights and men-at-arms, they were still seen amongst archers to whom a wide field of vision was crucial.
Nasal Helms have been found of both one-piece and spangenhelm construction, with the later period helms being made of a single, smooth raised dome to allow weapons to glance off with ease.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Nasal_Helm | |
ba93fbf036d3afc02e27e9ffffe41561e1ea58f7 | wikidoc | Nasal bone | Nasal bone
# Overview
The nasal bones are two small oblong bones, varying in size and form in different individuals; they are placed side by side at the middle and upper part of the face, and form, by their junction, "the bridge" of the nose.
Each has two surfaces and four borders.
# Surfaces
The outer surface is concavoconvex from above downward, convex from side to side; it is covered by the Procerus and Compressor naris, and perforated about its center by a foramen, for the transmission of a small vein.
The inner surface is concave from side to side, and is traversed from above downward, by a groove for the passage of a branch of the nasociliary nerve.
# Articulations
The nasal articulates with four bones: two of the cranium, the frontal and ethmoid, and two of the face, the opposite nasal and the maxilla.
# Additional images
- Orbital bones
- Lateral wall of nasal cavity, showing ethmoid bone in position.
- Articulation of nasal and lacrimal bones with maxilla.
- Right nasal bone. Outer surface.
- Right nasal bone. Inner surface.
- Sphenoid bone visible center right.
- Side view of the skull.
- The skull from the front.
- Horizontal section of nasal and orbital cavities.
- Medial wall of left orbit.
- Sagittal section of skull.
- Roof, floor, and lateral wall of left nasal cavity. | Nasal bone
Template:Infobox Bone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The nasal bones are two small oblong bones, varying in size and form in different individuals; they are placed side by side at the middle and upper part of the face, and form, by their junction, "the bridge" of the nose.
Each has two surfaces and four borders.
# Surfaces
The outer surface is concavoconvex from above downward, convex from side to side; it is covered by the Procerus and Compressor naris, and perforated about its center by a foramen, for the transmission of a small vein.
The inner surface is concave from side to side, and is traversed from above downward, by a groove for the passage of a branch of the nasociliary nerve.
# Articulations
The nasal articulates with four bones: two of the cranium, the frontal and ethmoid, and two of the face, the opposite nasal and the maxilla.
# Additional images
- Orbital bones
- Lateral wall of nasal cavity, showing ethmoid bone in position.
- Articulation of nasal and lacrimal bones with maxilla.
- Right nasal bone. Outer surface.
- Right nasal bone. Inner surface.
- Sphenoid bone visible center right.
- Side view of the skull.
- The skull from the front.
- Horizontal section of nasal and orbital cavities.
- Medial wall of left orbit.
- Sagittal section of skull.
- Roof, floor, and lateral wall of left nasal cavity. | https://www.wikidoc.org/index.php/Nasal_bone | |
3de6d97b83ca231329bcff19fea0af661a4e7378 | wikidoc | Nasal hair | Nasal hair
# Overview
Nasal hair, or Nose hair is the hair in the nose. Adult humans have hairs in the anterior nasal passage. These hairs act as a fibrous filter for inhaled particles. Diffusion of ultra fine particles to the nasal hair occurs mostly for particles < 5 nm. Nasal hair has important implications for the health of the human body because a lack of nasal hair could invite the transport of potentially harmful particles into the respiratory system.
Nasal hair should not be confused with cilia of the nasal cavity, which are the microscopic cellular strands that, unlike macroscopic nasal hair, draw mucus up toward the oropharynx via their coordinated, back-and-forth beating.
# Nasal Hair and Attraction
In some cultures, nose hair protruding from the nostrils may be thought of as unattractive, as is hair protruding from one's ears. A number of devices have been sold to trim the nose hair, including miniature rotary clippers and attachments for electric shavers. However, given the function of nasal hairs, many physicians recommend trimming them lightly, if at all.
# Footnotes | Nasal hair
# Overview
Nasal hair, or Nose hair is the hair in the nose. Adult humans have hairs in the anterior nasal passage. These hairs act as a fibrous filter for inhaled particles. Diffusion of ultra fine particles to the nasal hair occurs mostly for particles < 5 nm. Nasal hair has important implications for the health of the human body because a lack of nasal hair could invite the transport of potentially harmful particles into the respiratory system.
Nasal hair should not be confused with cilia of the nasal cavity, which are the microscopic cellular strands that, unlike macroscopic nasal hair, draw mucus up toward the oropharynx via their coordinated, back-and-forth beating.
# Nasal Hair and Attraction
In some cultures, nose hair protruding from the nostrils may be thought of as unattractive, as is hair protruding from one's ears. A number of devices have been sold to trim the nose hair, including miniature rotary clippers and attachments for electric shavers. However, given the function of nasal hairs, many physicians recommend trimming them lightly, if at all.
# Footnotes | https://www.wikidoc.org/index.php/Nasal_hair | |
a212ce614a99034f9a20d6f7cacc23b77cc47125 | wikidoc | Nesiritide | Nesiritide
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# Overview
Nesiritide is a natriuretic peptide that is FDA approved for the {{{indicationType}}} of patients with acutely decompensated heart failure who have dyspnea at rest or with minimal activity. Common adverse reactions include hypotension, nausea, dizziness, headache, and elevated serum creatinine.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Natrecor® (nesiritide) is for intravenous (IV) use only. There is limited experience with administering Natrecor® for longer than 96 hours. Monitor blood pressure closely during Natrecor® administration.
- Dosing Information
- Recommended Dosage: IV bolus of 2 μg/kg followed by a continuous infusion of 0.01 μg/kg/min. Do not initiate Natrecor® at a dose that is above the recommended dose.
- The loading dose may not be appropriate for those with low systolic blood pressure (SBP) <110 mm Hg or for patients recently treated with afterload reducers.
- The administration of the recommended dose of Natrecor® is a two step process:
- After preparation of the infusion bag, withdraw the bolus volume (see Table 1) from the Natrecor® infusion bag, and administer it over approximately 60 seconds through an IV port in the tubing.
- Immediately following the administration of the bolus, infuse Natrecor® at a flow rate of 0.1 mL/kg/hr. This will deliver a Natrecor® infusion dose of 0.01 μg/kg/min.
- To calculate the infusion flow rate to deliver a 0.01 μg/kg/min dose, use the following formula (see Table 2):
- The dose-limiting side effect of Natrecor® is hypotension. If hypotension occurs during the administration of Natrecor®, reduce the dose of or discontinue Natrecor® and initiate other measures to support blood pressure (IV fluids, changes in body position). When symptomatic hypotension occurs, discontinue Natrecor®. Because hypotension caused by Natrecor® may be prolonged (up to hours), a period of observation may be necessary before restarting the drug. Natrecor® may be subsequently restarted at a dose that is reduced by 30% (with no bolus administration) once the patient has stabilized.
- Do not up-titrate Natrecor® more frequently than every 3 hours. Use central hemodynamic monitoring and do not exceed 0.03 μg/kg/min.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nesiritide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nesiritide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The safety and effectiveness of Natrecor® in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nesiritide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nesiritide in pediatric patients.
# Contraindications
- Persistent systolic blood pressure <100 mm Hg prior to therapy because of an increased risk of symptomatic hypotension
- Hypersensitivity to any of its components
- Cardiogenic shock
# Warnings
- Natrecor® may cause hypotension . In the ASCEND-HF trial, the incidence of symptomatic hypotension was 7.1% in Natrecor®-treated patients compared to 4.0% in placebo-treated patients on a background of standard care. The risk of hypotension may be increased by the concomitant use of Natrecor® with drugs affecting the renin-angiotensin system (i.e., angiotensin receptor blockers and/or angiotensin-converting enzyme inhibitors) or other afterload reducers. In the VMAC trial, in patients given the recommended dose (2 μg/kg bolus followed by a 0.01 μg/kg/min infusion) or the adjustable dose, the incidence of symptomatic hypotension in the first 24 hours was similar for Natrecor® (4%) and IV nitroglycerin (5%). When hypotension occurred, however, the duration of symptomatic hypotension was longer with Natrecor® (mean duration was 2.2 hours) than with nitroglycerin (mean duration was 0.7 hours).
- Administer Natrecor® only in settings where blood pressure can be monitored closely and hypotension aggressively treated. Reduce the dose of or discontinue Natrecor® in patients who develop hypotension.
- Avoid administration of Natrecor® in patients suspected of having, or known to have, low cardiac filling pressures.
- Natrecor® is not recommended for patients for whom vasodilating agents are not appropriate, such as patients with significant valvular stenosis, restrictive or obstructive cardiomyopathy, constrictive pericarditis, pericardial tamponade, or other conditions in which cardiac output is dependent upon venous return, or for patients suspected to have low cardiac filling pressures.
- Natrecor® may decrease renal function as judged by increases in serum creatinine. Monitor serum creatinine both during and after therapy has been completed. Monitor serum creatinine until values have stabilized. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin aldosterone system, treatment with Natrecor® may be associated with azotemia. When Natrecor® was initiated at doses higher than 0.01 μg/kg/min (0.015 and 0.03 μg/kg/min), there was an increased rate of elevated serum creatinine over baseline compared with standard therapies, although the rate of acute renal failure and need for dialysis was not increased.
- Serious hypersensitivity/allergic reactions following administration of Natrecor® have been reported.
- These reactions are more likely to occur in individuals with a history of sensitivity to recombinant peptides. Before therapy with Natrecor® is instituted, careful inquiry should be made to determine whether the patient has had a previous hypersensitivity reaction to other recombinant peptides. If an allergic reaction to Natrecor® occurs, discontinue the drug. Some serious hypersensitivity/allergic reactions may require treatment with epinephrine, oxygen, IV fluids, antihistamines, corticosteroids, pressor amines and airway management, as clinically indicated.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. A causal relationship for Natrecor® cannot be reliably established in individual cases.
- Adverse drug reactions that occurred at least ≥2% more frequently on Natrecor® than on placebo during the first 24 hours of infusion (excluding the ASCEND-HF study) are shown in Table 3.
- Laboratory adverse drug reactions that occurred in ≥2% of patients and collected during the first 14 days after the start of Natrecor® infusion included: hypoglycemia.
- In the ASCEND-HF trial, through Day 30, the incidence of renal impairment as measured by a >25% decrease in glomerular filtration rate (calculated based on serum creatinine) was observed in 31.4% and 29.5% in the Natrecor® and placebo groups, respectively. Other metrics of decompensated renal function such as an increase in creatinine of > 0.5 mg/dl, a 50% increase in creatinine or a value of ≥ 2 or 100% increase in creatinine were more frequent in the Natrecor® group. At 30 days post enrollment, more subjects in the Natrecor® group had elevated levels of creatinine of 50% greater than baseline compared to placebo 4.6% versus 3.3%. In the ASCEND-HF study there were relatively few subjects requiring either hemofiltration or dialysis.
- In the PRECEDENT trial, the incidence of elevations in serum creatinine to >0.5 mg/dL above baseline through Day 14 was higher in the Natrecor® 0.015 μg/kg/min group (17%) and the Natrecor® 0.03 μg/kg/min group (19%) than with standard therapy (11%). In the VMAC trial, through Day 30, the incidence of elevations in creatinine to >0.5 mg/dL above baseline was 28% and 21% in the Natrecor® (2 μg/kg bolus followed by 0.01 μg/kg/min) and nitroglycerin groups, respectively.
- A meta-analysis performed of seven clinical trials demonstrated Natrecor® did not increase mortality in patients with acute decompensated heart failure (ADHF) at Day 30 or Day 180 (see Figures 1 and 2). Data from seven studies in which 30-day data were collected are presented in Figure 1. The data depict hazard ratios (HR) and confidence intervals (CI) of mortality data for randomized and treated patients with Natrecor® relative to active or placebo controls through Day 30 for each of the seven individual studies along with the overall combined estimate (Studies 311, 325, 326, 329 , 339 , 341 , and A093 ).
- Figure 1 (on logarithmic scale) also contains an estimate for the seven studies combined (n=8514). The results indicate that there is no increased mortality risk for Natrecor® at Day 30 (seven studies pooled: HR=0.99; 95% CI: 0.80, 1.22). The percentages are the Kaplan-Meier estimates.
- Figure 2 presents 180-day mortality hazard ratios from all six individual studies where 180-day data were collected (Studies 325, 326, 329, 339, 341 and A093 ). The results indicate that with the addition of the ASCEND-HF data, there is no increased mortality risk for Natrecor® at Day 180 (six studies pooled: HR=0.98; 95% CI: 0.88, 1.10).
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of Natrecor®. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.
- Hypersensitivity reactions
- Infusion site extravasation
- Pruritus
- Rash
# Drug Interactions
- No trials specifically examining potential drug interactions with Natrecor® were conducted, although many concomitant drugs (including IV nitroglycerin) were used in clinical trials. No drug interactions were detected except for an increase in symptomatic hypotension in patients receiving afterload reducers or affecting the renin-angiotensin system (i.e., ARBs and/or ACE inhibitors).
- The co-administration of Natrecor® with nitroprusside, milrinone, or IV ACE inhibitors has not been evaluated.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- It is not known whether Natrecor® can cause fetal harm when administered to pregnant women or if it can affect reproductive capacity. A developmental reproductive toxicology study was conducted in pregnant rabbits using doses up to 1440 μg/kg/day given by constant infusion for 13 days. At this level of exposure (based on AUC, approximately 70 × human exposure at the recommended dose) no adverse effects on live births or fetal development were observed. Natrecor® should be used during pregnancy only if the potential benefit justifies any possible risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nesiritide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nesiritide during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk.
### Pediatric Use
- The safety and effectiveness of Natrecor® in pediatric patients have not been established.
### Geriatic Use
- Of the total number of patients in clinical trials treated with Natrecor® (n=4505), 52% were 65 years or older and 27% were 75 years or older. No overall differences in effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. Some older individuals may be more sensitive to the effect of Natrecor® than younger individuals.
### Gender
There is no FDA guidance on the use of Nesiritide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nesiritide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Nesiritide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Nesiritide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nesiritide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nesiritide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
- The Natrecor® bolus must be drawn from the prepared infusion bag. Prime the IV tubing with 5 mL of the solution for infusion prior to connecting to the patient's vascular access port and prior to administering the bolus or starting the infusion.
- Reconstitute one 1.5 mg vial of Natrecor® by adding 5 mL of diluent removed from a pre-filled 250 mL plastic IV bag containing the diluent of choice. After reconstitution of the vial, each mL contains 0.32 mg of nesiritide. The following preservative-free diluents are recommended for reconstitution: 5% Dextrose Injection (D5W), USP; 0.9% Sodium Chloride Injection, USP; 5% Dextrose and 0.45% Sodium Chloride Injection, USP, or 5% Dextrose and 0.2% Sodium Chloride Injection, USP.
- Do not shake the vial. Rock the vial gently so that all surfaces, including the stopper, are in contact with the diluent to ensure complete reconstitution. Use only a clear, essentially colorless solution.
- Withdraw the entire contents of the reconstituted Natrecor® vial and add to the 250 mL plastic IV bag. This will yield a solution with a concentration of Natrecor® of approximately 6 μg/mL. Invert the IV bag several times to ensure complete mixing of the solution.
- Use the reconstituted solution within 24 hours, as Natrecor® contains no antimicrobial preservative. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Reconstituted vials of Natrecor® may be stored at 2 to 25°C (36 to 77°F) for up to 24 hours.
### Monitoring
- Monitor blood pressure closely during Natrecor® administration.
- Natrecor® may decrease renal function as judged by increases in serum creatinine. Monitor serum creatinine both during and after therapy has been completed. Monitor serum creatinine until values have stabilized.
# IV Compatibility
There is limited information regarding IV Compatibility of Nesiritide in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Overdose with Natrecor® therapy has been reported and is primarily the result of either a miscalculated Natrecor® dose or a mechanical error such as an infusion-pump malfunction or an infusion-pump programming error. The most frequently reported adverse event reported with Natrecor® overdose is hypotension , which may be symptomatic and may persist for several hours.
- Asymptomatic hypotensive events may resolve with drug stoppage.
- In some cases hypotension may persist for several hours beyond discontinuation.
### Management
- In the event of an overdose, discontinue Natrecor® and support blood pressure.
## Chronic Overdose
- There is limited information regarding Chronic Overdose of Nesiritide in the drug label.
# Pharmacology
## Mechanism of Action
- Human BNP (hBNP) is secreted by the ventricular myocardium in response to stretch and exists in several isoforms in the human body. Elevated levels of BNP have been associated with advanced heart failure and are considered to be a compensatory mechanism in this disease. Human BNP binds to the particulate guanylate cyclase receptor of vascular smooth muscle and endothelial cells, leading to increased intracellular concentrations of guanosine 3'5'-cyclic monophosphate (cGMP) and smooth muscle cell relaxation. Cyclic GMP serves as a second messenger to dilate veins and arteries. Nesiritide has been shown to relax isolated human arterial and venous tissue preparations that were precontracted with either endothelin-1 or the alpha-adrenergic agonist, phenylephrine.
- In animals, nesiritide had no effects on cardiac contractility or on measures of cardiac electrophysiology such as atrial and ventricular effective refractory times or atrioventricular node conduction.
## Structure
- Natrecor® (nesiritide) is a sterile, purified preparation of human B-type natriuretic peptide (hBNP), and is manufactured from E. coli using recombinant DNA technology. Nesiritide has a molecular weight of 3464 g/mol and an empirical formula of C143H244N50O42S4. Nesiritide has the same 32 amino acid sequence as the endogenous peptide, which is produced by the ventricular myocardium.
- Natrecor® is formulated as the citrate salt of rhBNP, and is provided in a sterile, single-use vial. Each 1.5 mg vial contains a white- to off-white lyophilized powder for intravenous (IV) administration after reconstitution. The quantitative composition of the lyophilized drug per vial is: nesiritide 1.58 mg, citric acid monohydrate 2.1 mg, mannitol 20.0 mg, and sodium citrate dihydrate 2.94 mg.
## Pharmacodynamics
- With a dosing regimen of Natrecor® of 2 μg/kg IV bolus followed by an intravenous infusion dose of 0.01 μg/kg/min, Table 4 and Figure 3 summarize the changes in the VMAC trial in PCWP and other measures during the first 3 hours.
- With this dosing regimen, 60% of the 3-hour effect on PCWP reduction is achieved within 15 minutes after the bolus, reaching 95% of the 3-hour effect within 1 hour. Approximately 70% of the 3-hour effect on SBP reduction is reached within 15 minutes. The pharmacodynamic (PD) half-life of the onset and offset of the hemodynamic effect of Natrecor® is longer than what the PK half-life of 18 minutes would predict. Longer infusions may exaggerate the discrepancy from onset and offset effects. For example, in patients who developed symptomatic hypotension in the VMAC (Vasodilation in the Management of Acute Congestive Heart Failure) trial, half of the recovery of SBP toward the baseline value after discontinuation or reduction of the dose of Natrecor® was observed in about 60 minutes. When higher doses of Natrecor® were infused, the duration of hypotension was sometimes several hours.
- No rebound increase to levels above baseline state was observed. There was also no evidence of tachyphylaxis to the hemodynamic effects of Natrecor® in the clinical trials.
- In the VMAC trial, in which the use of diuretics was not restricted, the mean change in volume status (output minus input) during the first 24 hours in the nitroglycerin and Natrecor® groups was similar: 1279 ± 1455 mL and 1257 ± 1657 mL, respectively.
## Pharmacokinetics
- In patients with heart failure (HF), Natrecor® administered intravenously by infusion or bolus exhibits biphasic disposition from the plasma. The mean terminal elimination half-life (t1/2) of nesiritide is approximately 18 minutes and was associated with approximately 2/3 of the area-under-the-curve (AUC). The mean initial elimination phase was estimated to be approximately 2 minutes.
- In these patients, the mean volume of distribution of the central compartment (Vc) of nesiritide was estimated to be 0.073 L/kg, the mean steady-state volume of distribution (Vss) was 0.19 L/kg, and the mean clearance (CL) was approximately 9.2 mL/min/kg. At steady state, plasma BNP levels increase from baseline endogenous levels by approximately 3-fold to 6-fold with Natrecor® infusion doses ranging from 0.01 to 0.03 μg/kg/min.
- The mechanism of elimination of nesiritide has not been studied specifically in humans.
- Clinical data suggest that dose adjustment is not required in patients with renal impairment. The effects of nesiritide on PCWP, cardiac index (CI), and systolic blood pressure (SBP) were not significantly different in patients with chronic renal impairment (baseline serum creatinine ranging from 2 mg/dL to 4.3 mg/dL), and patients with normal renal function.
- The population pharmacokinetic (PK) analyses carried out to determine the effects of demographics and clinical variables on PK parameters showed that clearance of nesiritide is proportional to body weight, supporting the administration of weight-adjusted dosing of nesiritide (i.e., administration on a μg/kg/min basis).
- Nesiritide clearance was not influenced significantly by age, gender, or race/ethnicity.
- Nesiritide clearance was not influenced significantly by baseline endogenous hBNP concentration, severity of HF (as indicated by baseline PCWP, baseline CI, or New York Heart Association classification).
- The co-administration of Natrecor® with enalapril did not have significant effects on the PK of Natrecor®. The PK effect of co-administration of Natrecor® with other IV vasodilators such as nitroglycerin, nitroprusside, milrinone, or IV ACE inhibitors has not been evaluated. During clinical studies, Natrecor® was administered concomitantly with other medications, including: diuretics, digoxin, oral ACE inhibitors, anticoagulants, oral nitrates, statins, class III antiarrhythmic agents, beta-blockers, dobutamine, calcium channel blockers, angiotensin II receptor antagonists, and dopamine. Although no PK interactions were specifically assessed, there did not appear to be evidence suggesting any clinically significant PK interaction.
## Nonclinical Toxicology
- Long-term studies in animals have not been performed to evaluate the carcinogenic potential or the effect on fertility of nesiritide. Nesiritide did not increase the frequency of mutations when used in an in vitro bacterial cell assay (Ames test). No other genotoxicity studies were performed.
# Clinical Studies
- Natrecor® has been studied in 11 clinical trials including 4505 patients with HF (NYHA class II–III 56%, NYHA class IV 27%; mean age 64 years, women 32%). There were six randomized, multi-center, placebo- or active-controlled studies (comparative agents included nitroglycerin, dobutamine, milrinone, nitroprusside, or dopamine) in which 4269 patients with decompensated HF received continuous infusions of Natrecor® at doses ranging from 0.01 to 0.03 μg/kg/min. Of these patients, the majority (n=3358, 79%) received the Natrecor® infusion for at least 24 hours; 2182 (51%) received Natrecor® for 24 to 48 hours, and 1176 (28%) received Natrecor® for greater than 48 hours.
- In the initial five of these six controlled trials, Natrecor® was used alone or in conjunction with other standard therapies, including diuretics (79%), digoxin (62%), oral ACE inhibitors (55%), anticoagulants (38%), oral nitrates (32%), statins (18%), class III antiarrhythmic agents (16%), beta-blockers (15%), dobutamine (15%), calcium channel blockers (11%), angiotensin II receptor antagonists (6%), and dopamine (4%).
- In the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in patients with Decompensated Heart Failure), Natrecor® was used alone or in conjunction with other standard therapies. Most patients (99.4%) received diuretic medications in conjunction with Natrecor®, with the most commonly used diuretic being furosemide (55%). The following standard therapies were used in ≥2% of patients: beta-blockers (72%), aspirin (64%); oral ACE inhibitors (60%), statins (50%), aldosterone antagonists (48%), digoxin/digitalis glycoside (39%), oral or topical nitrates (30%), oral anticoagulants (29%), clopidogrel/thienopyridine (21%), angiotensin receptor antagonists (19%), antiarrhythmic agents (16%), IV nitroglycerin (16%); calcium channel blockers (13%), hydralazine (11%), dobutamine (8%), dopamine (5%), alpha blockers (4%), IV opiates (5%), and NSAIDs (4%). The following standard therapies were used in <2% of patients: COX2 inhibitors, milrinone, epinephrine, levosimendan, nitroprusside, norepinephrine, phenylephrine, and vasopressin.
- Natrecor® has been studied in a broad range of patients, including the elderly (53% >65 years of age), women (33%), minorities (17% black), and patients with a history of significant morbidities such as hypertension (71%), previous myocardial infarction (38%), diabetes (43%), atrial fibrillation flutter (37%), ventricular tachycardia fibrillation (10%), and preserved systolic function (20%). In trials other than the ASCEND-HF trial, Natrecor® was also studied in patients with nonsustained ventricular tachycardia (25%) and patients with acute coronary syndromes less than 7 days before the start of Natrecor® (4%).
- The VMAC (Vasodilation in the Management of Acute Congestive Heart Failure) trial was a randomized, double-blind study of 489 patients (246 patients requiring a right heart catheter, 243 patients without a right heart catheter) who required hospitalization for management of shortness of breath at rest due to acutely decompensated HF. The study compared the effects of Natrecor®, placebo, and IV nitroglycerin when added to background therapy (IV and oral diuretics, non-IV cardiac medications, dobutamine and dopamine). Patients with acute coronary syndrome preserved systolic function, arrhythmia and renal impairment were not excluded. The primary endpoints of the study were the change from baseline in PCWP and the change from baseline in patients' dyspnea, evaluated after three hours. Close attention was also paid to the occurrence and persistence of hypotension , given nesiritide's relatively long (compared to nitroglycerin) PK and PD half-life.
- Natrecor® was administered as a 2 μg/kg bolus over approximately 60 seconds, followed by a continuous fixed dose infusion of 0.01 μg/kg/min. After the 3-hour placebo-controlled period, patients receiving placebo crossed over to double-blinded active therapy with either Natrecor® or nitroglycerin The nitroglycerin dose was titrated at the physician's discretion. A subset of patients in the VMAC trial with central hemodynamic monitoring who were treated with Natrecor® (62 of 124 patients) were allowed dose increases of Natrecor® after the first 3 hours of treatment if the PCWP was ≥20 mm Hg and the SBP was ≥100 mm Hg. Dose increases of a 1 μg/kg bolus followed by an increase of the infusion dose by 0.005 μg/kg/min were allowed every 3 hours, up to a maximum dose of 0.03 μg/kg/min. Overall, 23 patients in this subset had the dose of Natrecor® increased in the VMAC trial.
- In the VMAC study, patients receiving Natrecor® reported greater improvement in their dyspnea at 3 hours than patients receiving placebo (p=0.034).
- In the dose-response study, patients receiving both doses of Natrecor® reported greater improvement in dyspnea at 6 hours than patients receiving placebo.
- Natrecor® was also studied in a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial evaluating the efficacy and safety of Natrecor® compared with placebo the ASCEND-HF Study, which was a trial where both arms were administered in addition to standard care, in patients with ADHF. The study was divided into a screening phase, a double-blind treatment phase, and a follow-up phase, including a Day 30 visit and a telephone contact at Day 180. Patients who qualified for the study were ≥18 years of age, hospitalized for the management of ADHF or diagnosed with ADHF within 48 hours after being hospitalized for another reason. They were randomized to receive either Natrecor® as a continuous IV infusion at 0.010 μg/kg/min with or without an initial 2 μg/kg bolus (at the discretion of the physician) or a matching placebo bolus and infusion.
- The primary objective of ASCEND-HF was to evaluate whether treatment with Natrecor® compared to placebo improved patient outcomes (as measured by a reduction in the composite of HF rehospitalization and all-cause mortality from randomization through Day 30) or HF symptoms (as measured by patient self-assessed Likert dyspnea scale which included Markedly Better, Moderately Better, Minimally Better, No Change, Minimally Worse, Moderately Worse and Markedly Worse at 6 hours and 24 hours after Natrecor® initiation).
- A total of 7141 patients were randomized of which 7007 patients took at least one dose of study medication (modified intent-to-treat population) and received treatment for 24 to 168 hours (7 days), if the patient's clinical condition warranted continued treatment for dyspnea or pulmonary congestion at the physician's discretion. The median treatment duration was 42.9 hours for the placebo group and 40.8 hours for the Natrecor® group. The patients' mean age was 65.5 years. The patient population was 65.8% male, 55.9% Caucasian, 24.7% Asian and 15.1% Black or African American.
- The incidence rate for the composite of HF rehospitalization and all-cause mortality from randomization through Day 30 was 9.4% in the Natrecor® group compared with 10.1% in the placebo group. The difference was not statistically significant (p=0.313). The self-assessed dyspnea results did not meet the pre-specified criteria for statistical significance (p ≤0.005 for both or p ≤0.0025 for either) at either time point.
- A total of 273 deaths were reported during the first 30 days after therapy and 876 (12.5%) deaths were reported from randomization through Day 180, 429 (12.3%) patients in the Natrecor® group and 447 (12.7%) patients in the placebo group. Approximately 65% of the deaths at 180 days were cardiovascular (mostly worsening heart failure . There was no statistically significant difference between treatment groups (p=0.5).
# How Supplied
- Natrecor® (nesiritide) is provided as a sterile lyophilized powder in 1.5 mg, single-use vials. Each carton contains one vial and is available in the following package:
- Store below 25°C. Do not freeze. Keep the vial in the outer carton in order to protect from light.
## Storage
There is limited information regarding Nesiritide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients of the potential benefits and risks of Natrecor®. Advise patients to notify their physician or healthcare professional if they have symptoms of hypotension .
# Precautions with Alcohol
- Alcohol-Nesiritide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Natrecor®
# Look-Alike Drug Names
- Natrecor® — Norcuron®
# Drug Shortage Status
# Price | Nesiritide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi
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# Overview
Nesiritide is a natriuretic peptide that is FDA approved for the {{{indicationType}}} of patients with acutely decompensated heart failure who have dyspnea at rest or with minimal activity. Common adverse reactions include hypotension, nausea, dizziness, headache, and elevated serum creatinine.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Natrecor® (nesiritide) is for intravenous (IV) use only. There is limited experience with administering Natrecor® for longer than 96 hours. Monitor blood pressure closely during Natrecor® administration.
- Dosing Information
- Recommended Dosage: IV bolus of 2 μg/kg followed by a continuous infusion of 0.01 μg/kg/min. Do not initiate Natrecor® at a dose that is above the recommended dose.
- The loading dose may not be appropriate for those with low systolic blood pressure (SBP) <110 mm Hg or for patients recently treated with afterload reducers.
- The administration of the recommended dose of Natrecor® is a two step process:
- After preparation of the infusion bag, withdraw the bolus volume (see Table 1) from the Natrecor® infusion bag, and administer it over approximately 60 seconds through an IV port in the tubing.
- Immediately following the administration of the bolus, infuse Natrecor® at a flow rate of 0.1 mL/kg/hr. This will deliver a Natrecor® infusion dose of 0.01 μg/kg/min.
- To calculate the infusion flow rate to deliver a 0.01 μg/kg/min dose, use the following formula (see Table 2):
- The dose-limiting side effect of Natrecor® is hypotension. If hypotension occurs during the administration of Natrecor®, reduce the dose of or discontinue Natrecor® and initiate other measures to support blood pressure (IV fluids, changes in body position). When symptomatic hypotension occurs, discontinue Natrecor®. Because hypotension caused by Natrecor® may be prolonged (up to hours), a period of observation may be necessary before restarting the drug. Natrecor® may be subsequently restarted at a dose that is reduced by 30% (with no bolus administration) once the patient has stabilized.
- Do not up-titrate Natrecor® more frequently than every 3 hours. Use central hemodynamic monitoring and do not exceed 0.03 μg/kg/min.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nesiritide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nesiritide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The safety and effectiveness of Natrecor® in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nesiritide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nesiritide in pediatric patients.
# Contraindications
- Persistent systolic blood pressure <100 mm Hg prior to therapy because of an increased risk of symptomatic hypotension
- Hypersensitivity to any of its components
- Cardiogenic shock
# Warnings
- Natrecor® may cause hypotension . In the ASCEND-HF trial, the incidence of symptomatic hypotension was 7.1% in Natrecor®-treated patients compared to 4.0% in placebo-treated patients on a background of standard care. The risk of hypotension may be increased by the concomitant use of Natrecor® with drugs affecting the renin-angiotensin system (i.e., angiotensin receptor blockers and/or angiotensin-converting enzyme inhibitors) or other afterload reducers. In the VMAC trial, in patients given the recommended dose (2 μg/kg bolus followed by a 0.01 μg/kg/min infusion) or the adjustable dose, the incidence of symptomatic hypotension in the first 24 hours was similar for Natrecor® (4%) and IV nitroglycerin (5%). When hypotension occurred, however, the duration of symptomatic hypotension was longer with Natrecor® (mean duration was 2.2 hours) than with nitroglycerin (mean duration was 0.7 hours).
- Administer Natrecor® only in settings where blood pressure can be monitored closely and hypotension aggressively treated. Reduce the dose of or discontinue Natrecor® in patients who develop hypotension.
- Avoid administration of Natrecor® in patients suspected of having, or known to have, low cardiac filling pressures.
- Natrecor® is not recommended for patients for whom vasodilating agents are not appropriate, such as patients with significant valvular stenosis, restrictive or obstructive cardiomyopathy, constrictive pericarditis, pericardial tamponade, or other conditions in which cardiac output is dependent upon venous return, or for patients suspected to have low cardiac filling pressures.
- Natrecor® may decrease renal function as judged by increases in serum creatinine. Monitor serum creatinine both during and after therapy has been completed. Monitor serum creatinine until values have stabilized. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin aldosterone system, treatment with Natrecor® may be associated with azotemia. When Natrecor® was initiated at doses higher than 0.01 μg/kg/min (0.015 and 0.03 μg/kg/min), there was an increased rate of elevated serum creatinine over baseline compared with standard therapies, although the rate of acute renal failure and need for dialysis was not increased.
- Serious hypersensitivity/allergic reactions following administration of Natrecor® have been reported.
- These reactions are more likely to occur in individuals with a history of sensitivity to recombinant peptides. Before therapy with Natrecor® is instituted, careful inquiry should be made to determine whether the patient has had a previous hypersensitivity reaction to other recombinant peptides. If an allergic reaction to Natrecor® occurs, discontinue the drug. Some serious hypersensitivity/allergic reactions may require treatment with epinephrine, oxygen, IV fluids, antihistamines, corticosteroids, pressor amines and airway management, as clinically indicated.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. A causal relationship for Natrecor® cannot be reliably established in individual cases.
- Adverse drug reactions that occurred at least ≥2% more frequently on Natrecor® than on placebo during the first 24 hours of infusion (excluding the ASCEND-HF study) are shown in Table 3.
- Laboratory adverse drug reactions that occurred in ≥2% of patients and collected during the first 14 days after the start of Natrecor® infusion included: hypoglycemia.
- In the ASCEND-HF trial, through Day 30, the incidence of renal impairment as measured by a >25% decrease in glomerular filtration rate (calculated based on serum creatinine) was observed in 31.4% and 29.5% in the Natrecor® and placebo groups, respectively. Other metrics of decompensated renal function such as an increase in creatinine of > 0.5 mg/dl, a 50% increase in creatinine or a value of ≥ 2 or 100% increase in creatinine were more frequent in the Natrecor® group. At 30 days post enrollment, more subjects in the Natrecor® group had elevated levels of creatinine of 50% greater than baseline compared to placebo 4.6% versus 3.3%. In the ASCEND-HF study there were relatively few subjects requiring either hemofiltration or dialysis.
- In the PRECEDENT trial, the incidence of elevations in serum creatinine to >0.5 mg/dL above baseline through Day 14 was higher in the Natrecor® 0.015 μg/kg/min group (17%) and the Natrecor® 0.03 μg/kg/min group (19%) than with standard therapy (11%). In the VMAC trial, through Day 30, the incidence of elevations in creatinine to >0.5 mg/dL above baseline was 28% and 21% in the Natrecor® (2 μg/kg bolus followed by 0.01 μg/kg/min) and nitroglycerin groups, respectively.
- A meta-analysis performed of seven clinical trials demonstrated Natrecor® did not increase mortality in patients with acute decompensated heart failure (ADHF) at Day 30 or Day 180 (see Figures 1 and 2). Data from seven studies in which 30-day data were collected are presented in Figure 1. The data depict hazard ratios (HR) and confidence intervals (CI) of mortality data for randomized and treated patients with Natrecor® relative to active or placebo controls through Day 30 for each of the seven individual studies along with the overall combined estimate (Studies 311, 325, 326, 329 [PRECEDENT], 339 [VMAC], 341 [PROACTION], and A093 [ASCEND-HF]).
- Figure 1 (on logarithmic scale) also contains an estimate for the seven studies combined (n=8514). The results indicate that there is no increased mortality risk for Natrecor® at Day 30 (seven studies pooled: HR=0.99; 95% CI: 0.80, 1.22). The percentages are the Kaplan-Meier estimates.
- Figure 2 presents 180-day mortality hazard ratios from all six individual studies where 180-day data were collected (Studies 325, 326, 329, 339, 341 and A093 [ASCEND-HF]). The results indicate that with the addition of the ASCEND-HF data, there is no increased mortality risk for Natrecor® at Day 180 (six studies pooled: HR=0.98; 95% CI: 0.88, 1.10).
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of Natrecor®. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.
- Hypersensitivity reactions
- Infusion site extravasation
- Pruritus
- Rash
# Drug Interactions
- No trials specifically examining potential drug interactions with Natrecor® were conducted, although many concomitant drugs (including IV nitroglycerin) were used in clinical trials. No drug interactions were detected except for an increase in symptomatic hypotension in patients receiving afterload reducers or affecting the renin-angiotensin system (i.e., ARBs and/or ACE inhibitors).
- The co-administration of Natrecor® with nitroprusside, milrinone, or IV ACE inhibitors has not been evaluated.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- It is not known whether Natrecor® can cause fetal harm when administered to pregnant women or if it can affect reproductive capacity. A developmental reproductive toxicology study was conducted in pregnant rabbits using doses up to 1440 μg/kg/day given by constant infusion for 13 days. At this level of exposure (based on AUC, approximately 70 × human exposure at the recommended dose) no adverse effects on live births or fetal development were observed. Natrecor® should be used during pregnancy only if the potential benefit justifies any possible risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nesiritide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nesiritide during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk.
### Pediatric Use
- The safety and effectiveness of Natrecor® in pediatric patients have not been established.
### Geriatic Use
- Of the total number of patients in clinical trials treated with Natrecor® (n=4505), 52% were 65 years or older and 27% were 75 years or older. No overall differences in effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. Some older individuals may be more sensitive to the effect of Natrecor® than younger individuals.
### Gender
There is no FDA guidance on the use of Nesiritide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nesiritide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Nesiritide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Nesiritide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nesiritide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nesiritide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
- The Natrecor® bolus must be drawn from the prepared infusion bag. Prime the IV tubing with 5 mL of the solution for infusion prior to connecting to the patient's vascular access port and prior to administering the bolus or starting the infusion.
- Reconstitute one 1.5 mg vial of Natrecor® by adding 5 mL of diluent removed from a pre-filled 250 mL plastic IV bag containing the diluent of choice. After reconstitution of the vial, each mL contains 0.32 mg of nesiritide. The following preservative-free diluents are recommended for reconstitution: 5% Dextrose Injection (D5W), USP; 0.9% Sodium Chloride Injection, USP; 5% Dextrose and 0.45% Sodium Chloride Injection, USP, or 5% Dextrose and 0.2% Sodium Chloride Injection, USP.
- Do not shake the vial. Rock the vial gently so that all surfaces, including the stopper, are in contact with the diluent to ensure complete reconstitution. Use only a clear, essentially colorless solution.
- Withdraw the entire contents of the reconstituted Natrecor® vial and add to the 250 mL plastic IV bag. This will yield a solution with a concentration of Natrecor® of approximately 6 μg/mL. Invert the IV bag several times to ensure complete mixing of the solution.
- Use the reconstituted solution within 24 hours, as Natrecor® contains no antimicrobial preservative. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Reconstituted vials of Natrecor® may be stored at 2 to 25°C (36 to 77°F) for up to 24 hours.
### Monitoring
- Monitor blood pressure closely during Natrecor® administration.
- Natrecor® may decrease renal function as judged by increases in serum creatinine. Monitor serum creatinine both during and after therapy has been completed. Monitor serum creatinine until values have stabilized.
# IV Compatibility
There is limited information regarding IV Compatibility of Nesiritide in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Overdose with Natrecor® therapy has been reported and is primarily the result of either a miscalculated Natrecor® dose or a mechanical error such as an infusion-pump malfunction or an infusion-pump programming error. The most frequently reported adverse event reported with Natrecor® overdose is hypotension , which may be symptomatic and may persist for several hours.
- Asymptomatic hypotensive events may resolve with drug stoppage.
- In some cases hypotension may persist for several hours beyond discontinuation.
### Management
- In the event of an overdose, discontinue Natrecor® and support blood pressure.
## Chronic Overdose
- There is limited information regarding Chronic Overdose of Nesiritide in the drug label.
# Pharmacology
## Mechanism of Action
- Human BNP (hBNP) is secreted by the ventricular myocardium in response to stretch and exists in several isoforms in the human body. Elevated levels of BNP have been associated with advanced heart failure and are considered to be a compensatory mechanism in this disease. Human BNP binds to the particulate guanylate cyclase receptor of vascular smooth muscle and endothelial cells, leading to increased intracellular concentrations of guanosine 3'5'-cyclic monophosphate (cGMP) and smooth muscle cell relaxation. Cyclic GMP serves as a second messenger to dilate veins and arteries. Nesiritide has been shown to relax isolated human arterial and venous tissue preparations that were precontracted with either endothelin-1 or the alpha-adrenergic agonist, phenylephrine.
- In animals, nesiritide had no effects on cardiac contractility or on measures of cardiac electrophysiology such as atrial and ventricular effective refractory times or atrioventricular node conduction.
## Structure
- Natrecor® (nesiritide) is a sterile, purified preparation of human B-type natriuretic peptide (hBNP), and is manufactured from E. coli using recombinant DNA technology. Nesiritide has a molecular weight of 3464 g/mol and an empirical formula of C143H244N50O42S4. Nesiritide has the same 32 amino acid sequence as the endogenous peptide, which is produced by the ventricular myocardium.
- Natrecor® is formulated as the citrate salt of rhBNP, and is provided in a sterile, single-use vial. Each 1.5 mg vial contains a white- to off-white lyophilized powder for intravenous (IV) administration after reconstitution. The quantitative composition of the lyophilized drug per vial is: nesiritide 1.58 mg, citric acid monohydrate 2.1 mg, mannitol 20.0 mg, and sodium citrate dihydrate 2.94 mg.
## Pharmacodynamics
- With a dosing regimen of Natrecor® of 2 μg/kg IV bolus followed by an intravenous infusion dose of 0.01 μg/kg/min, Table 4 and Figure 3 summarize the changes in the VMAC trial in PCWP and other measures during the first 3 hours.
- With this dosing regimen, 60% of the 3-hour effect on PCWP reduction is achieved within 15 minutes after the bolus, reaching 95% of the 3-hour effect within 1 hour. Approximately 70% of the 3-hour effect on SBP reduction is reached within 15 minutes. The pharmacodynamic (PD) half-life of the onset and offset of the hemodynamic effect of Natrecor® is longer than what the PK half-life of 18 minutes would predict. Longer infusions may exaggerate the discrepancy from onset and offset effects. For example, in patients who developed symptomatic hypotension in the VMAC (Vasodilation in the Management of Acute Congestive Heart Failure) trial, half of the recovery of SBP toward the baseline value after discontinuation or reduction of the dose of Natrecor® was observed in about 60 minutes. When higher doses of Natrecor® were infused, the duration of hypotension was sometimes several hours.
- No rebound increase to levels above baseline state was observed. There was also no evidence of tachyphylaxis to the hemodynamic effects of Natrecor® in the clinical trials.
- In the VMAC trial, in which the use of diuretics was not restricted, the mean change in volume status (output minus input) during the first 24 hours in the nitroglycerin and Natrecor® groups was similar: 1279 ± 1455 mL and 1257 ± 1657 mL, respectively.
## Pharmacokinetics
- In patients with heart failure (HF), Natrecor® administered intravenously by infusion or bolus exhibits biphasic disposition from the plasma. The mean terminal elimination half-life (t1/2) of nesiritide is approximately 18 minutes and was associated with approximately 2/3 of the area-under-the-curve (AUC). The mean initial elimination phase was estimated to be approximately 2 minutes.
- In these patients, the mean volume of distribution of the central compartment (Vc) of nesiritide was estimated to be 0.073 L/kg, the mean steady-state volume of distribution (Vss) was 0.19 L/kg, and the mean clearance (CL) was approximately 9.2 mL/min/kg. At steady state, plasma BNP levels increase from baseline endogenous levels by approximately 3-fold to 6-fold with Natrecor® infusion doses ranging from 0.01 to 0.03 μg/kg/min.
- The mechanism of elimination of nesiritide has not been studied specifically in humans.
- Clinical data suggest that dose adjustment is not required in patients with renal impairment. The effects of nesiritide on PCWP, cardiac index (CI), and systolic blood pressure (SBP) were not significantly different in patients with chronic renal impairment (baseline serum creatinine ranging from 2 mg/dL to 4.3 mg/dL), and patients with normal renal function.
- The population pharmacokinetic (PK) analyses carried out to determine the effects of demographics and clinical variables on PK parameters showed that clearance of nesiritide is proportional to body weight, supporting the administration of weight-adjusted dosing of nesiritide (i.e., administration on a μg/kg/min basis).
- Nesiritide clearance was not influenced significantly by age, gender, or race/ethnicity.
- Nesiritide clearance was not influenced significantly by baseline endogenous hBNP concentration, severity of HF (as indicated by baseline PCWP, baseline CI, or New York Heart Association [NYHA] classification).
- The co-administration of Natrecor® with enalapril did not have significant effects on the PK of Natrecor®. The PK effect of co-administration of Natrecor® with other IV vasodilators such as nitroglycerin, nitroprusside, milrinone, or IV ACE inhibitors has not been evaluated. During clinical studies, Natrecor® was administered concomitantly with other medications, including: diuretics, digoxin, oral ACE inhibitors, anticoagulants, oral nitrates, statins, class III antiarrhythmic agents, beta-blockers, dobutamine, calcium channel blockers, angiotensin II receptor antagonists, and dopamine. Although no PK interactions were specifically assessed, there did not appear to be evidence suggesting any clinically significant PK interaction.
## Nonclinical Toxicology
- Long-term studies in animals have not been performed to evaluate the carcinogenic potential or the effect on fertility of nesiritide. Nesiritide did not increase the frequency of mutations when used in an in vitro bacterial cell assay (Ames test). No other genotoxicity studies were performed.
# Clinical Studies
- Natrecor® has been studied in 11 clinical trials including 4505 patients with HF (NYHA class II–III 56%, NYHA class IV 27%; mean age 64 years, women 32%). There were six randomized, multi-center, placebo- or active-controlled studies (comparative agents included nitroglycerin, dobutamine, milrinone, nitroprusside, or dopamine) in which 4269 patients with decompensated HF received continuous infusions of Natrecor® at doses ranging from 0.01 to 0.03 μg/kg/min. Of these patients, the majority (n=3358, 79%) received the Natrecor® infusion for at least 24 hours; 2182 (51%) received Natrecor® for 24 to 48 hours, and 1176 (28%) received Natrecor® for greater than 48 hours.
- In the initial five of these six controlled trials, Natrecor® was used alone or in conjunction with other standard therapies, including diuretics (79%), digoxin (62%), oral ACE inhibitors (55%), anticoagulants (38%), oral nitrates (32%), statins (18%), class III antiarrhythmic agents (16%), beta-blockers (15%), dobutamine (15%), calcium channel blockers (11%), angiotensin II receptor antagonists (6%), and dopamine (4%).
- In the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in patients with Decompensated Heart Failure), Natrecor® was used alone or in conjunction with other standard therapies. Most patients (99.4%) received diuretic medications in conjunction with Natrecor®, with the most commonly used diuretic being furosemide (55%). The following standard therapies were used in ≥2% of patients: beta-blockers (72%), aspirin (64%); oral ACE inhibitors (60%), statins (50%), aldosterone antagonists (48%), digoxin/digitalis glycoside (39%), oral or topical nitrates (30%), oral anticoagulants (29%), clopidogrel/thienopyridine (21%), angiotensin receptor antagonists (19%), antiarrhythmic agents (16%), IV nitroglycerin (16%); calcium channel blockers (13%), hydralazine (11%), dobutamine (8%), dopamine (5%), alpha blockers (4%), IV opiates (5%), and NSAIDs (4%). The following standard therapies were used in <2% of patients: COX2 inhibitors, milrinone, epinephrine, levosimendan, nitroprusside, norepinephrine, phenylephrine, and vasopressin.
- Natrecor® has been studied in a broad range of patients, including the elderly (53% >65 years of age), women (33%), minorities (17% black), and patients with a history of significant morbidities such as hypertension (71%), previous myocardial infarction (38%), diabetes (43%), atrial fibrillation flutter (37%), ventricular tachycardia fibrillation (10%), and preserved systolic function (20%). In trials other than the ASCEND-HF trial, Natrecor® was also studied in patients with nonsustained ventricular tachycardia (25%) and patients with acute coronary syndromes less than 7 days before the start of Natrecor® (4%).
- The VMAC (Vasodilation in the Management of Acute Congestive Heart Failure) trial was a randomized, double-blind study of 489 patients (246 patients requiring a right heart catheter, 243 patients without a right heart catheter) who required hospitalization for management of shortness of breath at rest due to acutely decompensated HF. The study compared the effects of Natrecor®, placebo, and IV nitroglycerin when added to background therapy (IV and oral diuretics, non-IV cardiac medications, dobutamine and dopamine). Patients with acute coronary syndrome preserved systolic function, arrhythmia and renal impairment were not excluded. The primary endpoints of the study were the change from baseline in PCWP and the change from baseline in patients' dyspnea, evaluated after three hours. Close attention was also paid to the occurrence and persistence of hypotension , given nesiritide's relatively long (compared to nitroglycerin) PK and PD half-life.
- Natrecor® was administered as a 2 μg/kg bolus over approximately 60 seconds, followed by a continuous fixed dose infusion of 0.01 μg/kg/min. After the 3-hour placebo-controlled period, patients receiving placebo crossed over to double-blinded active therapy with either Natrecor® or nitroglycerin The nitroglycerin dose was titrated at the physician's discretion. A subset of patients in the VMAC trial with central hemodynamic monitoring who were treated with Natrecor® (62 of 124 patients) were allowed dose increases of Natrecor® after the first 3 hours of treatment if the PCWP was ≥20 mm Hg and the SBP was ≥100 mm Hg. Dose increases of a 1 μg/kg bolus followed by an increase of the infusion dose by 0.005 μg/kg/min were allowed every 3 hours, up to a maximum dose of 0.03 μg/kg/min. Overall, 23 patients in this subset had the dose of Natrecor® increased in the VMAC trial.
- In the VMAC study, patients receiving Natrecor® reported greater improvement in their dyspnea at 3 hours than patients receiving placebo (p=0.034).
- In the dose-response study, patients receiving both doses of Natrecor® reported greater improvement in dyspnea at 6 hours than patients receiving placebo.
- Natrecor® was also studied in a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial evaluating the efficacy and safety of Natrecor® compared with placebo the ASCEND-HF Study, which was a trial where both arms were administered in addition to standard care, in patients with ADHF. The study was divided into a screening phase, a double-blind treatment phase, and a follow-up phase, including a Day 30 visit and a telephone contact at Day 180. Patients who qualified for the study were ≥18 years of age, hospitalized for the management of ADHF or diagnosed with ADHF within 48 hours after being hospitalized for another reason. They were randomized to receive either Natrecor® as a continuous IV infusion at 0.010 μg/kg/min with or without an initial 2 μg/kg bolus (at the discretion of the physician) or a matching placebo bolus and infusion.
- The primary objective of ASCEND-HF was to evaluate whether treatment with Natrecor® compared to placebo improved patient outcomes (as measured by a reduction in the composite of HF rehospitalization and all-cause mortality from randomization through Day 30) or HF symptoms (as measured by patient self-assessed Likert dyspnea scale which included Markedly Better, Moderately Better, Minimally Better, No Change, Minimally Worse, Moderately Worse and Markedly Worse at 6 hours and 24 hours after Natrecor® initiation).
- A total of 7141 patients were randomized of which 7007 patients took at least one dose of study medication (modified intent-to-treat population) and received treatment for 24 to 168 hours (7 days), if the patient's clinical condition warranted continued treatment for dyspnea or pulmonary congestion at the physician's discretion. The median treatment duration was 42.9 hours for the placebo group and 40.8 hours for the Natrecor® group. The patients' mean age was 65.5 years. The patient population was 65.8% male, 55.9% Caucasian, 24.7% Asian and 15.1% Black or African American.
- The incidence rate for the composite of HF rehospitalization and all-cause mortality from randomization through Day 30 was 9.4% in the Natrecor® group compared with 10.1% in the placebo group. The difference was not statistically significant (p=0.313). The self-assessed dyspnea results did not meet the pre-specified criteria for statistical significance (p ≤0.005 for both or p ≤0.0025 for either) at either time point.
- A total of 273 deaths were reported during the first 30 days after therapy and 876 (12.5%) deaths were reported from randomization through Day 180, 429 (12.3%) patients in the Natrecor® group and 447 (12.7%) patients in the placebo group. Approximately 65% of the deaths at 180 days were cardiovascular (mostly worsening heart failure . There was no statistically significant difference between treatment groups (p=0.5).
# How Supplied
- Natrecor® (nesiritide) is provided as a sterile lyophilized powder in 1.5 mg, single-use vials. Each carton contains one vial and is available in the following package:
- Store below 25°C. Do not freeze. Keep the vial in the outer carton in order to protect from light.
## Storage
There is limited information regarding Nesiritide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients of the potential benefits and risks of Natrecor®. Advise patients to notify their physician or healthcare professional if they have symptoms of hypotension .
# Precautions with Alcohol
- Alcohol-Nesiritide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Natrecor®
# Look-Alike Drug Names
- Natrecor® — Norcuron®[1]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Natrecor | |
9d9e4960af30012d7bc4d0df6f6e0437ec4963af | wikidoc | Navel lint | Navel lint
Navel lint, or more commonly belly button lint or navel fluff, is an accumulation of fluffy fibres in one's navel.
Many people find that, at the beginning and end of the day, a small lump of fluff has appeared in the navel cavity. The reasons for this have been the subject of idle speculation for many years but in 2001, Dr. Karl Kruszelnicki of the University of Sydney, Australia, undertook a systematic survey to determine the ins and outs of navel lint. His primary findings were as follows:
- Navel lint consists primarily of stray fibers from one's clothing, mixed with some dead skin cells and strands of body hair.
- Contrary to expectations, navel lint appears to migrate upwards from underwear rather than downwards from shirts or tops. The migration process is the result of the frictional drag of body hair on underwear, which drags stray fibers up into the navel.
- Women experience less navel lint because of their finer and shorter body hairs. Conversely, older men experience it more because of their coarser and more numerous hairs.
- Navel lint's characteristic blue-gray tint is likely the averaging of the colors of fibers present in clothing; the same color as clothes dryer lint.
- The existence of navel lint is entirely harmless, and requires no corrective action.
Dr. Kruszelnicki was awarded the Ig Nobel Prize for Interdisciplinary Research in 2002.
David Hamilton, a Toronto native, has been an avid belly button lint enthusiast for years. Travelling to many different conferences and conventions worldwide, David has become the world's foremost expert and now holds the largest private collection of Human Navel Lint. He is currently working on developing his thesis on the nutritional benefits of ingesting navel lint.
Graham Barker of Perth, Western Australia, is in the Guinness Book of Records as the record holder for collecting navel lint. He has been collecting navel lint almost every day for over 20 years since 17th January 1984. He collects about 3.03 mg per day. Contrary to the research of Dr. Kruszelnicki, his lint is in a particular shade of red, even though he rarely wears red clothes. | Navel lint
Navel lint, or more commonly belly button lint or navel fluff, is an accumulation of fluffy fibres in one's navel.
Many people find that, at the beginning and end of the day, a small lump of fluff has appeared in the navel cavity. The reasons for this have been the subject of idle speculation for many years but in 2001, Dr. Karl Kruszelnicki of the University of Sydney, Australia, undertook a systematic survey to determine the ins and outs of navel lint. His primary findings were as follows:[1]
- Navel lint consists primarily of stray fibers from one's clothing, mixed with some dead skin cells and strands of body hair.
- Contrary to expectations, navel lint appears to migrate upwards from underwear rather than downwards from shirts or tops. The migration process is the result of the frictional drag of body hair on underwear, which drags stray fibers up into the navel.
- Women experience less navel lint because of their finer and shorter body hairs. Conversely, older men experience it more because of their coarser and more numerous hairs.
- Navel lint's characteristic blue-gray tint is likely the averaging of the colors of fibers present in clothing; the same color as clothes dryer lint.[2]
- The existence of navel lint is entirely harmless, and requires no corrective action.
Dr. Kruszelnicki was awarded the Ig Nobel Prize for Interdisciplinary Research in 2002.[3]
David Hamilton, a Toronto native, has been an avid belly button lint enthusiast for years. Travelling to many different conferences and conventions worldwide, David has become the world's foremost expert and now holds the largest private collection of Human Navel Lint. He is currently working on developing his thesis on the nutritional benefits of ingesting navel lint.[citation needed]
Graham Barker of Perth, Western Australia, is in the Guinness Book of Records as the record holder for collecting navel lint. He has been collecting navel lint almost every day for over 20 years since 17th January 1984. He collects about 3.03 mg per day. Contrary to the research of Dr. Kruszelnicki, his lint is in a particular shade of red, even though he rarely wears red clothes.[4] | https://www.wikidoc.org/index.php/Navel_lint | |
ce0cbb6f096df823aae2ecfef59cf0a0c1361247 | wikidoc | Necrophagy | Necrophagy
# Overview
Necrophagy is the act of feeding on corpses or carrion that were not killed to be eaten by the predator or others of its species. The word is derived from Ancient Greek "nekros" meaning corpse or dead and "phagos" meaning to eat.
Animals who partially or completely feed on dead animals that they have not predated are usually called scavengers, most familiar examples being hyenas and vultures. Also many insects use decayed matter as a protein source, e.g. some bee species or dung beetles.
With regard to carrion from the same species, the behavior is also referred to as anthropophagy, in the case of humans, or cannibalism, in the case of other non-human animals.
In humans, necrophagy is a taboo in most societies. In the Qur'an slanderers are stigmatized as those who eat the flesh of the dead body of the person they slander. The Aghori, a Hindu sect known to live in graveyards, according to a Persian source and nineteenth century British accounts, were necrophagous. There have been many instances in history, especially in war times, where necrophagy was a survival behavior.
de:Nekrophagie | Necrophagy
# Overview
Necrophagy is the act of feeding on corpses or carrion that were not killed to be eaten by the predator or others of its species. The word is derived from Ancient Greek "nekros" meaning corpse or dead and "phagos" meaning to eat.
Animals who partially or completely feed on dead animals that they have not predated are usually called scavengers, most familiar examples being hyenas and vultures. Also many insects use decayed matter as a protein source, e.g. some bee species or dung beetles.
With regard to carrion from the same species, the behavior is also referred to as anthropophagy, in the case of humans, or cannibalism, in the case of other non-human animals.
In humans, necrophagy is a taboo in most societies. In the Qur'an slanderers are stigmatized as those who eat the flesh of the dead body of the person they slander. The Aghori, a Hindu sect known to live in graveyards, according to a Persian source and nineteenth century British accounts, were necrophagous. There have been many instances in history, especially in war times, where necrophagy was a survival behavior.
de:Nekrophagie
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Necrophagous | |
de9354525b8d6f0a3345bf73edeb41fd82412849 | wikidoc | Nedocromil | Nedocromil
# 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
Nedocromil is a mast cell stabilizer, ophthalmologic agent that is FDA approved for the treatment of allergic conjunctivitis. Common adverse reactions include headache, ocular burning, irritation and stinging, unpleasant taste, nasal congestion, conjunctivitis, eye redness, photophobia, and rhinitis..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- ALOCRIL® ophthalmic solution is indicated for the treatment of itching associated with allergic conjunctivitis.
### Dosing Information
- The recommended dosage is one or two drops in each eye twice a day. ALOCRIL® ophthalmic solution should be used at regular intervals.
- Treatment should be continued throughout the period of exposure (i.e., until the pollen season is over or until exposure to the offending allergen is terminated), even when symptoms are absent.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nedocromil in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nedocromil in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- ALOCRIL® ophthalmic solution is indicated for Allergic conjunctivitis age 3 yr and older.
### Dosing Information
- 1 to 2 drops in each eye twice daily
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nedocromil in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nedocromil in pediatric patients.
# Contraindications
- ALOCRIL® ophthalmic solution is contraindicated in those patients who have shown hypersensitivity to nedocromil sodium or to any of the other ingredients.
# Warnings
There is limited information regarding Warnings of Nedocromil in the drug label.
# Adverse Reactions
## Clinical Trials Experience
- The most frequently reported adverse experience was headache (~40%).
- Ocular burning, irritation and stinging, unpleasant taste, and nasal congestion have been reported to occur in 10 – 30% of patients. Other events occurring between 1 – 10% included asthma, conjunctivitis, eye redness, photophobia, and rhinitis.
- Some of these events were similar to the underlying ocular disease being studied.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Nedocromil in the drug label.
# Drug Interactions
There is limited information regarding Drug Interactions of Nedocromil in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies performed in mice, rats and rabbits using a subcutaneous dose of 100 mg/kg/day (more than 1600 times the maximum human daily ocular dose on a mg/kg basis) revealed no evidence of teratogenicity or harm to the fetus due to nedocromil sodium. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, ALOCRIL® ophthalmic solution 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 Nedocromil in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nedocromil during labor and delivery.
### Nursing Mothers
- After intravenous administration to lactating rats, nedocromil was excreted in milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ALOCRIL® ophthalmic solution is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in children below the age of 3 years have not been established.
### Geriatic Use
- No overall differences in safety or effectiveness have been observed between elderly and younger patients.
### Gender
There is no FDA guidance on the use of Nedocromil with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nedocromil with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Nedocromil in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Nedocromil in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nedocromil in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nedocromil in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Ophthalmic solution
### Monitoring
There is limited information regarding Monitoring of Nedocromil in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Nedocromil in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Nedocromil in the drug label.
# Pharmacology
## Mechanism of Action
- Nedocromil sodium is a mast cell stabilizer. Nedocromil sodium inhibits the release of mediators from cells involved in hypersensitivity reactions. Decreased chemotaxis and decreased activation of eosinophils have also been demonstrated.
- In vitro studies with adult human bronchoalveolar cells showed that nedocromil sodium inhibits histamine release from a population of mast cells having been defined as belonging to the mucosal sub type and inhibits beta-glucuronidase release from macrophages.
## Structure
- ALOCRIL® (nedocromil sodium ophthalmic solution) 2% is a clear, yellow, sterile solution for topical ophthalmic use.
- Nedocromil sodium is represented by the following structural formula:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Nedocromil in the drug label.
## Pharmacokinetics
- Nedocromil sodium exhibits low systemic absorption. When administered as a 2% ophthalmic solution in adult human volunteers, less than 4% of the total dose was systemically absorbed following multiple dosing. Absorption is mainly through the nasolacrimal duct rather than through the conjunctiva. It is not metabolized and is eliminated primarily unchanged in urine (70%) and feces (30%).
## Nonclinical Toxicology
- A two-year inhalation carcinogenicity study of nedocromil sodium at a dose of 24 mg/kg/day (approximately 400 times the maximum recommended human daily ocular dose on a mg/kg basis) in Wistar rats showed no carcinogenic potential.
- Nedocromil sodium showed no mutagenic potential in the Ames Salmonella/microsome plate assay, mitotic gene conversion in Saccharomyces cerevisiae, mouse lymphoma forward mutation and mouse micronucleus assays.
- Reproduction and fertility studies in mice and rats showed no effects on male and female fertility at a subcutaneous dose of 100 mg/kg/day (more than 1600 times the maximum recommended human daily ocular dose).
# Clinical Studies
There is limited information regarding Clinical Studies of Nedocromil in the drug label.
# How Supplied
ALOCRIL® (nedocromil sodium ophthalmic solution) 2% is supplied sterile in opaque white LDPE plastic bottles with dropper tips and white high impact polystyrene (HIPS) caps as follows:
5 mL in 10 mL bottle NDC 0023-8842-05
Revised: 12/2012
© 2013 Allergan, Inc.
Irvine, CA 92612, U.S.A.
® marks owned by Allergan, Inc.
Made in the U.S.A.
71761US12
## Storage
- Storage: Store at 2º–25º C (36º–77º F).
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
NDC 0023-8842-05
Alocril®
(nedocromil sodium
-phthalmic solution) 2%
STERILE
For topical application in the eye
5 mL
ALLERGAN
# Patient Counseling Information
- Patients should be advised to follow the patient instructions listed on the Information for Patients sheet.
- Users of contact lenses should refrain from wearing lenses while exhibiting the signs and symptoms of allergic conjunctivitis.
- Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye, surrounding structures, fingers, or any other surface in order to avoid contamination of the solution by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.
# Precautions with Alcohol
- Alcohol-Nedocromil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Alocril®
# Look-Alike Drug Names
There is limited information regarding Nedocromil Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Nedocromil
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Nedocromil is a mast cell stabilizer, ophthalmologic agent that is FDA approved for the treatment of allergic conjunctivitis. Common adverse reactions include headache, ocular burning, irritation and stinging, unpleasant taste, nasal congestion, conjunctivitis, eye redness, photophobia, and rhinitis..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- ALOCRIL® ophthalmic solution is indicated for the treatment of itching associated with allergic conjunctivitis.
### Dosing Information
- The recommended dosage is one or two drops in each eye twice a day. ALOCRIL® ophthalmic solution should be used at regular intervals.
- Treatment should be continued throughout the period of exposure (i.e., until the pollen season is over or until exposure to the offending allergen is terminated), even when symptoms are absent.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nedocromil in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nedocromil in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- ALOCRIL® ophthalmic solution is indicated for Allergic conjunctivitis age 3 yr and older.
### Dosing Information
- 1 to 2 drops in each eye twice daily
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nedocromil in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nedocromil in pediatric patients.
# Contraindications
- ALOCRIL® ophthalmic solution is contraindicated in those patients who have shown hypersensitivity to nedocromil sodium or to any of the other ingredients.
# Warnings
There is limited information regarding Warnings of Nedocromil in the drug label.
# Adverse Reactions
## Clinical Trials Experience
- The most frequently reported adverse experience was headache (~40%).
- Ocular burning, irritation and stinging, unpleasant taste, and nasal congestion have been reported to occur in 10 – 30% of patients. Other events occurring between 1 – 10% included asthma, conjunctivitis, eye redness, photophobia, and rhinitis.
- Some of these events were similar to the underlying ocular disease being studied.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Nedocromil in the drug label.
# Drug Interactions
There is limited information regarding Drug Interactions of Nedocromil in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies performed in mice, rats and rabbits using a subcutaneous dose of 100 mg/kg/day (more than 1600 times the maximum human daily ocular dose on a mg/kg basis) revealed no evidence of teratogenicity or harm to the fetus due to nedocromil sodium. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, ALOCRIL® ophthalmic solution 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 Nedocromil in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nedocromil during labor and delivery.
### Nursing Mothers
- After intravenous administration to lactating rats, nedocromil was excreted in milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ALOCRIL® ophthalmic solution is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in children below the age of 3 years have not been established.
### Geriatic Use
- No overall differences in safety or effectiveness have been observed between elderly and younger patients.
### Gender
There is no FDA guidance on the use of Nedocromil with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nedocromil with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Nedocromil in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Nedocromil in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nedocromil in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nedocromil in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Ophthalmic solution
### Monitoring
There is limited information regarding Monitoring of Nedocromil in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Nedocromil in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Nedocromil in the drug label.
# Pharmacology
## Mechanism of Action
- Nedocromil sodium is a mast cell stabilizer. Nedocromil sodium inhibits the release of mediators from cells involved in hypersensitivity reactions. Decreased chemotaxis and decreased activation of eosinophils have also been demonstrated.
- In vitro studies with adult human bronchoalveolar cells showed that nedocromil sodium inhibits histamine release from a population of mast cells having been defined as belonging to the mucosal sub type and inhibits beta-glucuronidase release from macrophages.
## Structure
- ALOCRIL® (nedocromil sodium ophthalmic solution) 2% is a clear, yellow, sterile solution for topical ophthalmic use.
- Nedocromil sodium is represented by the following structural formula:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Nedocromil in the drug label.
## Pharmacokinetics
- Nedocromil sodium exhibits low systemic absorption. When administered as a 2% ophthalmic solution in adult human volunteers, less than 4% of the total dose was systemically absorbed following multiple dosing. Absorption is mainly through the nasolacrimal duct rather than through the conjunctiva. It is not metabolized and is eliminated primarily unchanged in urine (70%) and feces (30%).
## Nonclinical Toxicology
- A two-year inhalation carcinogenicity study of nedocromil sodium at a dose of 24 mg/kg/day (approximately 400 times the maximum recommended human daily ocular dose on a mg/kg basis) in Wistar rats showed no carcinogenic potential.
- Nedocromil sodium showed no mutagenic potential in the Ames Salmonella/microsome plate assay, mitotic gene conversion in Saccharomyces cerevisiae, mouse lymphoma forward mutation and mouse micronucleus assays.
- Reproduction and fertility studies in mice and rats showed no effects on male and female fertility at a subcutaneous dose of 100 mg/kg/day (more than 1600 times the maximum recommended human daily ocular dose).
# Clinical Studies
There is limited information regarding Clinical Studies of Nedocromil in the drug label.
# How Supplied
ALOCRIL® (nedocromil sodium ophthalmic solution) 2% is supplied sterile in opaque white LDPE plastic bottles with dropper tips and white high impact polystyrene (HIPS) caps as follows:
5 mL in 10 mL bottle NDC 0023-8842-05
Revised: 12/2012
© 2013 Allergan, Inc.
Irvine, CA 92612, U.S.A.
® marks owned by Allergan, Inc.
Made in the U.S.A.
71761US12
## Storage
- Storage: Store at 2º–25º C (36º–77º F).
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
NDC 0023-8842-05
Alocril®
(nedocromil sodium
ophthalmic solution) 2%
STERILE
For topical application in the eye
5 mL
ALLERGAN
# Patient Counseling Information
- Patients should be advised to follow the patient instructions listed on the Information for Patients sheet.
- Users of contact lenses should refrain from wearing lenses while exhibiting the signs and symptoms of allergic conjunctivitis.
- Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye, surrounding structures, fingers, or any other surface in order to avoid contamination of the solution by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.
# Precautions with Alcohol
- Alcohol-Nedocromil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Alocril®
# Look-Alike Drug Names
There is limited information regarding Nedocromil Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Nedocromil |
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