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d3c1e249282daaa4fb48ebaffb65f505f7b6aab0
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wikidoc
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Transportin-3
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Transportin-3
Transportin-3 is a protein that in humans is encoded by the TNPO3 gene.
# Function
TNPO3 is a nuclear import receptor for serine/arginine-rich (SR) proteins, including Serine/arginine-rich splicing factor 1, which are essential precursor-mRNA splicing factors.
# Clinical significance
The TNPO3-IRF5 locus is implicated in primary biliary cirrhosis and systemic sclerosis.
|
Transportin-3
Transportin-3 is a protein that in humans is encoded by the TNPO3 gene.[1][2][3]
# Function
TNPO3 is a nuclear import receptor for serine/arginine-rich (SR) proteins, including Serine/arginine-rich splicing factor 1, which are essential precursor-mRNA splicing factors.[1][3]
# Clinical significance
The TNPO3-IRF5 locus is implicated in primary biliary cirrhosis and systemic sclerosis.[4]
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https://www.wikidoc.org/index.php/Transportin-3
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2da8988796ea767bc2ac26af4bb6e4a2ead0a3d1
|
wikidoc
|
Transportin 1
|
Transportin 1
Transportin-1 (or Importin-β 2) is a protein that in humans is encoded by the TNPO1 gene.
# Function
This protein is a karyopherin which interacts with nuclear localization sequence to target nuclear proteins to the nucleus. The classical karyopherin receptor complex, such as the complex that uses Importin-β1 (encoded by gene KPNB1), is a heterodimer of an alpha subunit which recognizes the nuclear localization signal and a beta subunit which docks the complex at nucleoporins. However, Transportin-1 can directly bind to the cargo proteins and may not need importin alpha subunit to do it.
Transportin-1 is thought to use the same principal mechanism to carry out nuclear transport as other Importins. It mediates docking to the nuclear pore complex through binding to nucleoporin and is subsequently translocated through the pore by an energy requiring mechanism. Then, in the nucleus Ran binds to Transportin-1, it dissociates from cargo, and Transportin-1 is re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran. Then Transportin-1 is free to bind new cargo.
In addition, Transportin-1 is implicated in helping protein transport into primary cilium. The function of Transportin-1 in this case is thought to be similar to carrying proteins into the nucleus through a nuclear pore. Transportin-1 binds cargo and then is helping this cargo to pass through a pore at the base of the cilium. Ran and nucleoporins are also implicated in this mechanism.
Alternate splicing of this gene results in two transcript variants encoding different proteins.
# Targets
Transportin 1 (TRN1) is part of the non-classical nuclear import pathway. In conjunction with the RanGTP hydroysis cascade TRN1 acts to import a selection of proteins into the nucleus of cells. These targets typically contain a PY-motif otherwise known as a M9 nuclear localisation signal. Well described examples include hnRNP A1.
The type of cargo proteins that Transportin 1 can carry into the nucleus include RNA-binding proteins (such as hnRNP A1 and hnRNP F) and also ribosomal proteins.
# Clinical Significance
TRN1 has been implicated in the pathogenesis of two neurodegenerative diseases namely Amyotrophic lateral sclerosis and frontotemporal dementia.
# Interactions
Transportin 1 has been shown to interact with:
- RGPD5 and
- Ran (biology).
|
Transportin 1
Transportin-1 (or Importin-β 2) is a protein that in humans is encoded by the TNPO1 gene.[1][2][3]
# Function
This protein is a karyopherin which interacts with nuclear localization sequence to target nuclear proteins to the nucleus. The classical karyopherin receptor complex, such as the complex that uses Importin-β1 (encoded by gene KPNB1), is a heterodimer of an alpha subunit which recognizes the nuclear localization signal and a beta subunit which docks the complex at nucleoporins. However, Transportin-1 can directly bind to the cargo proteins and may not need importin alpha subunit to do it.[4]
Transportin-1 is thought to use the same principal mechanism to carry out nuclear transport as other Importins. It mediates docking to the nuclear pore complex through binding to nucleoporin and is subsequently translocated through the pore by an energy requiring mechanism. Then, in the nucleus Ran binds to Transportin-1, it dissociates from cargo, and Transportin-1 is re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran. Then Transportin-1 is free to bind new cargo.
In addition, Transportin-1 is implicated in helping protein transport into primary cilium.[5] The function of Transportin-1 in this case is thought to be similar to carrying proteins into the nucleus through a nuclear pore. Transportin-1 binds cargo and then is helping this cargo to pass through a pore at the base of the cilium. Ran and nucleoporins are also implicated in this mechanism.[6]
Alternate splicing of this gene results in two transcript variants encoding different proteins.[3]
# Targets
Transportin 1 (TRN1) is part of the non-classical nuclear import pathway. In conjunction with the RanGTP hydroysis cascade TRN1 acts to import a selection of proteins into the nucleus of cells. These targets typically contain a PY-motif otherwise known as a M9 nuclear localisation signal. Well described examples include hnRNP A1.[7]
The type of cargo proteins that Transportin 1 can carry into the nucleus include RNA-binding proteins (such as hnRNP A1 and hnRNP F) and also ribosomal proteins.[8]
# Clinical Significance
TRN1 has been implicated in the pathogenesis of two neurodegenerative diseases namely Amyotrophic lateral sclerosis and frontotemporal dementia.[9]
# Interactions
Transportin 1 has been shown to interact with:
- RGPD5[10] and
- Ran (biology).[11][12]
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https://www.wikidoc.org/index.php/Transportin_1
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00aba266bb80876224a371403e75ea1d0c603351
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wikidoc
|
Trauma center
|
Trauma center
# Overview
A trauma center is a hospital equipped to perform as a casualty receiving station for the emergency medical services by providing the best possible medical care for traumatic injuries 24 hours a day, 365 days per year. Trauma centers were established as the medical establishment realized that such injuries often require immediate and complex surgery to save the patient.
In order to qualify as a trauma center, a hospital must have a number of facilities, including a high-quality intensive-care ward and an operating room staffed around the clock. A trauma service is led by a team of trauma surgeons, including such specialists as neurosurgeons and orthopedic surgeons. A trauma center will often have a helipad for receiving patients by MEDEVAC.
The operation of a trauma center is extremely expensive. Some areas are under-served by trauma centers because of this expense (for example, Harborview Medical Center in Seattle, Washington serves the states of Washington, Idaho, Montana, and Alaska). In Florida, Orlando Regional Medical Center, built to serve five counties, serves more than twenty. Still, in many cases, persons injured in remote areas and brought to a trauma center by helicopter can receive faster and better care than a person injured in a city and taken to a normal hospital by ground ambulance.
In the United States, trauma centers are ranked, from limited-care facilities up to comprehensive service in Level I centers. Some centers specialize in adult or pediatric care.
# History
The concept of a trauma center was developed at the University of Maryland, Baltimore in the 1960s and 1970s by heart surgeon and shock researcher R Adams Cowley, who founded what became the Shock Trauma Center in Baltimore, Maryland in 1961 . Cook County Hospital in Chicago, Illinois claims to be the first trauma center (opened in 1966) in the United States. Dr. David R Boyd interned at Cook County Hospital from 1963-1964 before being drafted into the United States Army. Upon his release from the Army, Dr. Boyd became the first shock-trauma fellow at the Shock Trauma Center from 1967-1968. Dr. Boyd returned to Cook County Hospital, where he went on to serve as resident director of the Cook County Trauma Unit.
# Definitions
The four levels refer to the kinds of resources available in a trauma center and the number of patients admitted yearly. These are categories that define national standards for trauma care in hospitals. Developed and recommended by the American College of Surgeons.
|
Trauma center
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A trauma center is a hospital equipped to perform as a casualty receiving station for the emergency medical services by providing the best possible medical care for traumatic injuries 24 hours a day, 365 days per year. Trauma centers were established as the medical establishment realized that such injuries often require immediate and complex surgery to save the patient.
In order to qualify as a trauma center, a hospital must have a number of facilities, including a high-quality intensive-care ward and an operating room staffed around the clock. A trauma service is led by a team of trauma surgeons, including such specialists as neurosurgeons and orthopedic surgeons. A trauma center will often have a helipad for receiving patients by MEDEVAC.
The operation of a trauma center is extremely expensive. Some areas are under-served by trauma centers because of this expense (for example, Harborview Medical Center in Seattle, Washington serves the states of Washington, Idaho, Montana, and Alaska). In Florida, Orlando Regional Medical Center, built to serve five counties, serves more than twenty. Still, in many cases, persons injured in remote areas and brought to a trauma center by helicopter can receive faster and better care than a person injured in a city and taken to a normal hospital by ground ambulance.
In the United States, trauma centers are ranked, from limited-care facilities up to comprehensive service in Level I centers. Some centers specialize in adult or pediatric care.
# History
The concept of a trauma center was developed at the University of Maryland, Baltimore in the 1960s and 1970s by heart surgeon and shock researcher R Adams Cowley, who founded what became the Shock Trauma Center in Baltimore, Maryland in 1961 [2][3]. Cook County Hospital in Chicago, Illinois claims to be the first trauma center (opened in 1966) in the United States.[4] Dr. David R Boyd interned at Cook County Hospital from 1963-1964 before being drafted into the United States Army. Upon his release from the Army, Dr. Boyd became the first shock-trauma fellow at the Shock Trauma Center from 1967-1968. Dr. Boyd returned to Cook County Hospital, where he went on to serve as resident director of the Cook County Trauma Unit.[5]
# Definitions
The four levels refer to the kinds of resources available in a trauma center and the number of patients admitted yearly. These are categories that define national standards for trauma care in hospitals. Developed and recommended by the American College of Surgeons.
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https://www.wikidoc.org/index.php/Trauma_center
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2e6250724ef8fb1220370c2861fae4e28e695f78
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wikidoc
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Tree marigold
|
Tree marigold
The tree marigold, Mexican tournesol, Mexican sunflower or Nitobe chrysanthemum (Tithonia diversifolia) is a species of plant in the Asteraceae family now distributed in tropical and subtropical areas such as Central America, Southeast Asia and Africa. Depending on the area they may be either annual or perennial, two to three metres in height with upright and sometimes ligneous stalks in the form of woody shrubs. The flowers are orange. It is widely accepted that they were at one stage native to Central America or Mexico, hence the name.
# Symbolism and Uses
- In Japan, towards the end of the Meiji Period, they were imported as ornamental plants although seldom cultivated there. Having a characteristic bitter taste, they were used to induce a fever to help fight poisoning, although not used for direct medicinal purposes. There is also the story of the species being introduced to Japan by Nitobe Inazo, hence its Japanese name, the Nitobe chrysanthemum (ニトベギク; Nitobegiku).
- In Mexico, they are used to treat sprains, bone fractures, bruises and contusions.
- In Southern China they are used to treat skin diseases (such as athlete's foot), night sweats, as a diuretic, hepatitis, jaundice and cystitis.
- They are sold in herbal medicine markets in Taiwan to be infused to improve liver function.
- It is the provincial flower of Mae Hong Son Province, Thailand.
de:Mexikanische Sonnenblume
th:บัวตอง
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Tree marigold
The tree marigold, Mexican tournesol, Mexican sunflower or Nitobe chrysanthemum (Tithonia diversifolia) is a species of plant in the Asteraceae family now distributed in tropical and subtropical areas such as Central America, Southeast Asia and Africa. Depending on the area they may be either annual or perennial, two to three metres in height with upright and sometimes ligneous stalks in the form of woody shrubs. The flowers are orange. It is widely accepted that they were at one stage native to Central America or Mexico, hence the name.
# Symbolism and Uses
- In Japan, towards the end of the Meiji Period, they were imported as ornamental plants although seldom cultivated there. Having a characteristic bitter taste, they were used to induce a fever to help fight poisoning, although not used for direct medicinal purposes. There is also the story of the species being introduced to Japan by Nitobe Inazo, hence its Japanese name, the Nitobe chrysanthemum (ニトベギク; Nitobegiku).
- In Mexico, they are used to treat sprains, bone fractures, bruises and contusions.
- In Southern China they are used to treat skin diseases (such as athlete's foot), night sweats, as a diuretic, hepatitis, jaundice and cystitis.
- They are sold in herbal medicine markets in Taiwan to be infused to improve liver function.
- It is the provincial flower of Mae Hong Son Province, Thailand.
de:Mexikanische Sonnenblume
th:บัวตอง
Template:Asteraceae-stub
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https://www.wikidoc.org/index.php/Tree_marigold
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aee93b1b8bbe9fcb5dd5cbcd531cfdf20136136f
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wikidoc
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Tricep reflex
|
Tricep reflex
The tricep reflex is tested as part of the neurological examination to asses the sensory and motor pathways within the C7 and C8 spinal nerves. The triceps reflex originates from the triceps brachii muscle, and is initiated by the C7 nerve root.
# Testing
The test is performed by tapping the tendon while the forearm is hanging loose at a right angle to the arm. A sudden contraction of the triceps muscle causes extension of the forearm, and indicates a normal reflex.
# Test indicators
- Normal: There are no problems detected.
- Absence of a reflex (areflexia): If no reflex is elicited then it is essential to try again with reinforcement, with the patient clenching his or her teeth just as the reflex hammer strikes.
- Hyper-reflexia (a response far larger than considered normal): Indicates a potential upper motor neurone lesion.
# Absence of reflex
An absence of reflex can be an indicator of several medical conditions: Myopathy, neuropathy, spondylosis, sensory nerve disease, euritis, potential lower motor neurone lesion, or poliomyelitis.
Other medical problems that may cause irregular reflexes include Hyperthyroidism and Hypothyroidism.
|
Tricep reflex
The tricep reflex is tested as part of the neurological examination to asses the sensory and motor pathways within the C7 and C8 spinal nerves. The triceps reflex originates from the triceps brachii muscle, and is initiated by the C7 nerve root.[1]
# Testing
The test is performed by tapping the tendon while the forearm is hanging loose at a right angle to the arm. A sudden contraction of the triceps muscle causes extension of the forearm, and indicates a normal reflex.[2][3]
# Test indicators
- Normal: There are no problems detected.
- Absence of a reflex (areflexia): If no reflex is elicited then it is essential to try again with reinforcement, with the patient clenching his or her teeth just as the reflex hammer strikes.
- Hyper-reflexia (a response far larger than considered normal): Indicates a potential upper motor neurone lesion.
# Absence of reflex
An absence of reflex can be an indicator of several medical conditions: Myopathy, neuropathy, spondylosis, sensory nerve disease, euritis, potential lower motor neurone lesion, or poliomyelitis.[4]
Other medical problems that may cause irregular reflexes include Hyperthyroidism and Hypothyroidism.
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https://www.wikidoc.org/index.php/Tricep_reflex
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611ec19362b3a09e0f9ab44aa44b203e1f64746f
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wikidoc
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Trimeperidine
|
Trimeperidine
Trimeperidine (Promedol) is an opioid analgesic that is an analogue of prodine. It was developed in the 1950s during research into the related drug pethidine.
Trimeperidine has four structural isomers, of which two are active, the γ isomer trimeperidine, and the β isomer isopromedol. It is around half the potency of morphine as an analgesic, and has been widely used for the treatment of pain.
Trimeperidine produces similar effects to other opioids, such as analgesia and sedation, along with side effects such as nausea, itching, vomiting and respiratory depression which may be harmful or fatal.
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Trimeperidine
Trimeperidine (Promedol) is an opioid analgesic that is an analogue of prodine. It was developed in the 1950s during research into the related drug pethidine.
Trimeperidine has four structural isomers, of which two are active, the γ isomer trimeperidine, and the β isomer isopromedol.[1] It is around half the potency of morphine as an analgesic,[2][3] and has been widely used for the treatment of pain.[4][5]
Trimeperidine produces similar effects to other opioids, such as analgesia and sedation, along with side effects such as nausea, itching, vomiting and respiratory depression which may be harmful or fatal.
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https://www.wikidoc.org/index.php/Trimeperidine
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f2e6cd3af1bf50b78f637f13eb06386bebcf1519
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wikidoc
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Trimetazidine
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Trimetazidine
# Overview
Trimetazidine is a drug for angina pectoris sometimes referred to by the brand name Vastarel MR. Each tablet contains 35 mg of trimetazidine.
Trimetazidine is an anti-ischemic (anti-anginal) metabolic agent, that improves myocardial glucose utilization through inhibition of Fatty acid metabolism.
By preserving the energy metabolism in cells exposed to hypoxia or ischemia, trimetazidine prevents a decrease in intracellular adenosine triphosphate levels, thereby ensuring the proper functioning of ionic pumps and transmembranous sodium-potassium flow whilst maintaining cellular homeostasis.
The drug also inhibit b oxidation of fatty acid in blood vessles
Controlled studies in angina patients have shown that trimetazidine increases coronary flow reserve, thereby delaying the onset of ischemia associated with exercise, limits rapid swings in blood pressure without any significant variations in heart rate, significantly decreases the frequency of angina attacks, and leads to a significant decrease in the use of nitrates.
It improves left ventricular function in diabetic patients with coronary artery disease. Recently, it has been shown to be effective in patients with heart failure of different etiologies.
It is described as the first cytoprotective anti-ischemic agent, acts by directly counteracting all the major metabolic disorders occurring within the ischemic cell. The actions of trimetazidine include limitation of intracellular acidosis, correction of disturbances of transmembrane ion exchanges, and prevention of excessive production of free radicals.
It is usually prescribed as a long-term treatment of angina pectoris, and in some countries (including France) for tinnitus and dizziness.
# Interactions
Vastarel MR has high safety and tolerability profile.
Q. Can i use sildenafil(viagra) while taking Vastarel MR?
A. Go on, unlike nitrates, Vastarel MR with sildenafil is fully safe (allowed).
Vastarel MR is very safe (no drug-drug interactions)
# Dosage and Administration
Vastarel MR tablets is taken twice daily, providing 24-hr cardioprotection.
# World Wide
Vastarel MR is also distributed as: Vastarel 35 mg, Vastarel 20 mg, Vastarel LM, Vastarel LP, Preductal MR, Flavedon MR and Trizedon MR.
|
Trimetazidine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Trimetazidine is a drug for angina pectoris sometimes referred to by the brand name Vastarel MR. Each tablet contains 35 mg of trimetazidine.
Trimetazidine is an anti-ischemic (anti-anginal) metabolic agent, that improves myocardial glucose utilization through inhibition of Fatty acid metabolism.
By preserving the energy metabolism in cells exposed to hypoxia or ischemia, trimetazidine prevents a decrease in intracellular adenosine triphosphate levels, thereby ensuring the proper functioning of ionic pumps and transmembranous sodium-potassium flow whilst maintaining cellular homeostasis.
The drug also inhibit b oxidation of fatty acid in blood vessles
Controlled studies in angina patients have shown that trimetazidine increases coronary flow reserve, thereby delaying the onset of ischemia associated with exercise, limits rapid swings in blood pressure without any significant variations in heart rate, significantly decreases the frequency of angina attacks, and leads to a significant decrease in the use of nitrates.
It improves left ventricular function in diabetic patients with coronary artery disease. Recently, it has been shown to be effective in patients with heart failure of different etiologies.
It is described as the first cytoprotective anti-ischemic agent, acts by directly counteracting all the major metabolic disorders occurring within the ischemic cell. The actions of trimetazidine include limitation of intracellular acidosis, correction of disturbances of transmembrane ion exchanges, and prevention of excessive production of free radicals.
It is usually prescribed as a long-term treatment of angina pectoris, and in some countries (including France) for tinnitus and dizziness.
# Interactions
Vastarel MR has high safety and tolerability profile.
Q. Can i use sildenafil(viagra) while taking Vastarel MR?
A. Go on, unlike nitrates, Vastarel MR with sildenafil is fully safe (allowed).
Vastarel MR is very safe (no drug-drug interactions)
# Dosage and Administration
Vastarel MR tablets is taken twice daily, providing 24-hr cardioprotection.
# World Wide
Vastarel MR is also distributed as: Vastarel 35 mg, Vastarel 20 mg, Vastarel LM, Vastarel LP, Preductal MR, Flavedon MR and Trizedon MR.
|
https://www.wikidoc.org/index.php/Trimetazidine
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e9a32296302cf5959cab481744eb8329b7271963
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wikidoc
|
Trimethadione
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Trimethadione
# 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
Trimethadione is a anticonvulsant that is FDA approved for the treatment of petit mal seizures that are refractory to treatment with other drugs. Common adverse reactions include nausea, sleepiness, tiredness,increase in seizures, feelings of anger and frustration, changes in behavior.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- TRIDIONE (trimethadione) is indicated for the control of petit mal seizures that are refractory to treatment with other drugs.
### Dosage
- 0.9-2.4 grams daily in 3 or 4 equally divided doses (i.e., 300−600 mg 3 or 4 times daily).
- Initially, give 0.9 gram daily; increase this dose by 300 mg at weekly intervals until therapeutic results are seen or until toxic symptoms appear.
- Maintenance dosage should be the least amount of drug required to maintain control.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Trimethadione in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Trimethadione in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indications
- TRIDIONE (trimethadione) is indicated for the control of petit mal seizures that are refractory to treatment with other drugs.
### Dosage
- Usually 0.3-0.9 gram daily in 3 or 4 equally divided doses.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Trimethadione in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Trimethadione in pediatric patients.
# Contraindications
- TRIDIONE is contraindicated in patients with a known hypersensitivity to the drug.
# Warnings
- TRIDIONE may cause serious side effects. Strict medical supervision of the patient is mandatory, especially during the initial year of therapy.
- TRIDIONE (trimethadione) should be withdrawn promptly if skin rash appears, because of the grave possibility of the occurrence of exfoliative dermatitis or severe forms of erythema multiforme. Even a minor acneiform or morbilliform rash should be allowed to clear completely before treatment with TRIDIONE is resumed; reinstitute therapy cautiously.
- A complete blood count should be done prior to initiating therapy with TRIDIONE, and at monthly intervals thereafter. A marked depression of the blood count is an indication for withdrawal of the drug. If no abnormality appears within 12 months, the interval between blood counts may be extended. A moderate degree of neutropenia with or without a corresponding drop in the leukocyte count is not uncommon. Therapy need not be withdrawn unless the neutrophil count is 2500 or less; more frequent blood examinations should be done when the count is less than 3,000. Other blood dyscrasias, including leukopenia, eosinophilia, thrombocytopenia, pancytopenia, agranulocytosis, hypoplastic anemia, and fatal aplastic anemia, have occurred. Patients should be advised to report immediately such signs and symptoms as sore throat, fever, malaise, easy bruising, petechiae, or epistaxis, or others that may be indicative of an infection or bleeding tendency. TRIDIONE should ordinarily not be used in patients with severe blood dyscrasias.
- Liver function tests should be done prior to initiating therapy with TRIDIONE, and at monthly intervals thereafter. Hepatitis has been reported rarely. Jaundice or other signs of liver dysfunction are an indication for withdrawal of the drug. TRIDIONE should ordinarily not be used in patients with severe hepatic impairment.
- A urinalysis should be done prior to initiating therapy with TRIDIONE and at monthly intervals thereafter. Fatal nephrosis has been reported. Persistent or increasing albuminuria, or the development of any other significant renal abnormality, is an indication for withdrawal of the drug. TRIDIONE should ordinarily not be used in patients with severe renal dysfunction.
- Hemeralopia has occurred; this appears to be an effect of TRIDIONE on the neural layers of the retina, and usually can be reversed by a reduction in dosage. Scotomata are an indication for withdrawal of the drug. Caution should be observed when treating patients who have diseases of the retina or optic nerve.
- Manifestations of systemic lupus erythematosus have been associated with the use of TRIDIONE, as they have with the use of certain other anticonvulsants. Lymphadenopathies simulating malignant lymphoma have occurred. Lupus-like manifestations or lymph node enlargement are indications for withdrawal of the drug. Signs and symptoms may disappear after discontinuation of therapy, and specific treatment may be unnecessary.
- A myasthenia gravis-like syndrome has been associated with the chronic use of trimethadione. Symptoms suggestive of this condition are indications for withdrawal of the drug.
- Drugs known to cause toxic effects similar to those of TRIDIONE should be avoided or used only with extreme caution during therapy with TRIDIONE.
- THERE ARE MULTIPLE REPORTS IN THE CLINICAL LITERATURE WHICH INDICATE THAT THE USE OF ANTICONVULSANT DRUGS DURING PREGNANCY RESULTS IN AN INCREASED INCIDENCE OF BIRTH DEFECTS IN THE OFFSPRING. DATA ARE MORE EXTENSIVE WITH RESPECT TO TRIMETHADIONE, PARAMETHADIONE, PHENYTOIN AND PHENOBARBITAL THAN WITH OTHER ANTICONVULSANT DRUGS.
- THEREFORE, ANTICONVULSANT DRUGS SUCH AS TRIDIONE (TRIMETHADIONE) SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING POTENTIAL ONLY IF THEY ARE CLEARLY SHOWN TO BE ESSENTIAL IN THE MANAGEMENT OF THEIR SEIZURES. EFFECTIVE MEANS OF CONTRACEPTION SHOULD ACCOMPANY THE USE OF TRIDIONE IN SUCH PATIENTS. IF A PATIENT BECOMES PREGNANT WHILE TAKING TRIDIONE, TERMINATION OF THE PREGNANCY SHOULD BE CONSIDERED. A PATIENT WHO REQUIRES THERAPY WITH TRIDIONE AND WHO WISHES TO BECOME PREGNANT SHOULD BE ADVISED OF THE RISKS.
- REPORTS HAVE SUGGESTED THAT THE MATERNAL INGESTION OF ANTICONVULSANT DRUGS, PARTICULARLY BARBITURATES, IS ASSOCIATED WITH A NEONATAL COAGULATION DEFECT THAT MAY CAUSE BLEEDING DURING THE EARLY (USUALLY WITHIN 24 HOURS OF BIRTH) NEONATAL PERIOD. THE POSSIBILITY OF THE OCCURRENCE OF THIS DEFECT WITH THE USE OF TRIDIONE SHOULD BE KEPT IN MIND. THE DEFECT IS CHARACTERIZED BY DECREASED LEVELS OF VITAMIN K-DEPENDENT CLOTTING FACTORS, AND PROLONGATION OF EITHER THE PROTHROMBIN TIME OR THE PARTIAL THROMBOPLASTIN TIME, OR BOTH. IT HAS BEEN SUGGESTED THAT PROPHYLACTIC VITAMIN K BE GIVEN TO THE MOTHER ONE MONTH PRIOR TO, AND DURING DELIVERY, AND TO THE INFANT, INTRAVENOUSLY, IMMEDIATELY AFTER BIRTH.
- THE SAFETY OF TRIDIONE FOR USE DURING LACTATION HAS NOT BEEN ESTABLISHED.
- To provide information regarding the effects of in utero exposure to Tridione, physicians are advised to recommend that pregnant patients taking Tridione enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website /.
- Antiepileptic drugs (AEDs), including Tridione, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.
- TABLE 1 shows absolute and relative risk by indication for all evaluated AEDs.
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
- Anyone considering prescribing Tridione or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
### Precautions
- Abrupt discontinuation of TRIDIONE may precipitate petit mal status. TRIDIONE should always be withdrawn gradually unless serious adverse effects dictate otherwise. In the latter case, another anticonvulsant may be substituted to protect the patient.
- Physicians should inform patients and their caregivers of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to taking Tridione. Patients should be instructed to take Tridione only as prescribed.
- Patients, their caregivers, and families should be counseled that AEDs, including Tridione, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to the healthcare providers.
- Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334
# Adverse Reactions
## Clinical Trials Experience
- The following side effects, some of them serious, have been associated with the use of TRIDIONE (trimethadione).
- Nausea, vomiting, abdominal pain, gastric distress.
- Drowsiness, fatigue, malaise, insomnia, vertigo, headache, paresthesias, precipitation of grand mal seizures, increased irritability, personality changes.
- Drowsiness usually subsides with continued therapy. If it persists, a reduction in dosage is indicated.
- Bleeding gums, epistaxis, retinal and petechial hemorrhages, vaginal bleeding, neutropenia, leukopenia, eosinophilia, thrombocytopenia, pancytopenia, agranulocytosis, hypoplastic anemia, and fatal aplastic anemia.
- Acneiform or morbilliform skin rash that may progress to exfoliative dermatitis or to severe forms of erythema multiforme.
- Hiccups, anorexia, weight loss, hair loss, changes in blood pressure, albuminuria, hemeralopia, photophobia, diplopia.
- Fatal nephrosis has occurred.
- Hepatitis has been reported rarely.
- Lupus erythematosus, and lymphadenopathies simulating malignant lymphoma, have been reported.
- Pruritus associated with lymphadenopathy and hepatosplenomegaly has occurred in hypersensitive individuals.
- A myasthenia gravis-like syndrome has been reported.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Trimethadione in the drug label.
# Drug Interactions
There is limited information regarding Trimethadione Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- THERE ARE MULTIPLE REPORTS IN THE CLINICAL LITERATURE WHICH INDICATE THAT THE USE OF ANTICONVULSANT DRUGS DURING PREGNANCY RESULTS IN AN INCREASED INCIDENCE OF BIRTH DEFECTS IN THE OFFSPRING. DATA ARE MORE EXTENSIVE WITH RESPECT TO TRIMETHADIONE, PARAMETHADIONE, PHENYTOIN AND PHENOBARBITAL THAN WITH OTHER ANTICONVULSANT DRUGS.
- THEREFORE, ANTICONVULSANT DRUGS SUCH AS TRIDIONE (TRIMETHADIONE) SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING POTENTIAL ONLY IF THEY ARE CLEARLY SHOWN TO BE ESSENTIAL IN THE MANAGEMENT OF THEIR SEIZURES. EFFECTIVE MEANS OF CONTRACEPTION SHOULD ACCOMPANY THE USE OF TRIDIONE IN SUCH PATIENTS. IF A PATIENT BECOMES PREGNANT WHILE TAKING TRIDIONE, TERMINATION OF THE PREGNANCY SHOULD BE CONSIDERED. A PATIENT WHO REQUIRES THERAPY WITH TRIDIONE AND WHO WISHES TO BECOME PREGNANT SHOULD BE ADVISED OF THE RISKS.
- REPORTS HAVE SUGGESTED THAT THE MATERNAL INGESTION OF ANTICONVULSANT DRUGS, PARTICULARLY BARBITURATES, IS ASSOCIATED WITH A NEONATAL COAGULATION DEFECT THAT MAY CAUSE BLEEDING DURING THE EARLY (USUALLY WITHIN 24 HOURS OF BIRTH) NEONATAL PERIOD. THE POSSIBILITY OF THE OCCURRENCE OF THIS DEFECT WITH THE USE OF TRIDIONE SHOULD BE KEPT IN MIND. THE DEFECT IS CHARACTERIZED BY DECREASED LEVELS OF VITAMIN K-DEPENDENT CLOTTING FACTORS, AND PROLONGATION OF EITHER THE PROTHROMBIN TIME OR THE PARTIAL THROMBOPLASTIN TIME, OR BOTH. IT HAS BEEN SUGGESTED THAT PROPHYLACTIC VITAMIN K BE GIVEN TO THE MOTHER ONE MONTH PRIOR TO, AND DURING DELIVERY, AND TO THE INFANT, INTRAVENOUSLY, IMMEDIATELY AFTER BIRTH.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Trimethadione in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Trimethadione during labor and delivery.
### Nursing Mothers
- THE SAFETY OF TRIDIONE FOR USE DURING LACTATION HAS NOT BEEN ESTABLISHED.
### Pediatric Use
There is no FDA guidance on the use of Trimethadione with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Trimethadione with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Trimethadione with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Trimethadione with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Trimethadione in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Trimethadione in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Trimethadione in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Trimethadione in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Liver function tests should be done prior to initiating therapy with TRIDIONE, and at monthly intervals thereafter.
- A urinalysis should be done prior to initiating therapy with TRIDIONE and at monthly intervals thereafter.
- A complete blood count should be done prior to initiating therapy with TRIDIONE, and at monthly intervals thereafter.
# IV Compatibility
There is limited information regarding IV Compatibility of Trimethadione in the drug label.
# Overdosage
- Symptoms of acute TRIDIONE overdosage include drowsiness, nausea, dizziness, ataxia, visual disturbances. Coma may follow massive overdosage.
- Gastric evacuation, either by induced emesis, or by lavage, or both, should be done immediately. General supportive care, including frequent monitoring of the vital signs and close observations of the patient, are required.
- Alkalinization of the urine has been reported to enhance the renal excretion of dimethadione, the active metabolite of TRIDIONE.
- A blood count and a careful evaluation of hepatic and renal function should be done following recovery.
# Pharmacology
## Mechanism of Action
- TRIDIONE has been shown to prevent pentylenetetrazol-induced and thujone-induced seizures in experimental animals; the drug has a less marked effect on seizures induced by picrotoxin, procaine, cocaine, or strychnine. Unlike the hydantoins and antiepileptic barbiturates, TRIDIONE does not modify the maximal seizure pattern in patients undergoing electroconvulsive therapy.
## Structure
- TRIDIONE (trimethadione) is an antiepileptic agent. An oxazolidinedione compound, it is chemically identified as 3,5,5-trimethyloxozolidine-2,4-dione, and has the following structural formula:
- TRIDIONE is a synthetic, water-soluble, white, crystalline powder. It is supplied in tablets for oral use only.
- 150 mg Dulcet Tablet: Corn starch, lactose, magnesium stearate, magnesium trisilicate, sucrose and natural/synthetic flavor.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Trimethadione in the drug label.
## Pharmacokinetics
- TRIDIONE has a sedative effect that may increase to the point of ataxia when excessive doses are used. A toxic dose of the drug in animals (approximately 2 g/kg) produced sleep, unconsciousness, and respiratory depression.
- Trimethadione is rapidly absorbed from the gastrointestinal tract. It is demethylated by liver microsomes to the active metabolite, dimethadione.
- Approximately 3% of a daily dose of TRIDIONE is recovered in the urine as unchanged drug. The majority of trimethadione is excreted slowly by the kidney in the form of dimethadione.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Trimethadione in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Trimethadione in the drug label.
# How Supplied
- TRIDIONE Dulcet® Tablets (trimethadione tablets) are supplied as white, chewable tablets bearing the “a” logo and a two-letter code designation LE for the 150 mg tablet, in bottles of 100 (NDC 0074-3753-01).
## Storage
- Store Dulcet tablets in refrigerator 36° to 46°F (2° - 8°C) to minimize crystallization. However some crystallization not harmful to product may occur. Keep tightly closed.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
NDC 0074–3753–01
100 Tablets Dulcet®
TRIDIONE®
TRIMETHADIONE TABLETS 150 mg (2 1/2 grs)
Rx only abbvie
### Ingredients and Appearance
# Patient Counseling Information
- Physicians should inform patients and their caregivers of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to taking Tridione. Patients should be instructed to take Tridione only as prescribed.
- Patients, their caregivers, and families should be counseled that AEDs, including Tridione, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to the healthcare providers.
- Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334
### MEDICATION GUIDE
(trimethadione)
Tablets
- Read this Medication Guide before you start taking TRIDIONE and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.
- Do not stop taking TRIDIONE without first talking to your healthcare provider.
- Stopping TRIDIONE suddenly can cause serious problems.
- TRIDIONE can cause serious side effects, including:
- Rash. This may need to be treated in a hospital and may be life-threatening.
- Call your healthcare provider right away if you have any of these symptoms:
- skin rash
- hives
- sores in your mouth
- Blood problems that can be life-threatening. Call your healthcare provider right away if you have any of these symptoms:
- Fever, swollen glands, or sore throat that come and go or do not go away
- Frequent infections or an infection that does not go away
- Easy bruising
- Red or purple spots on your body
- Bleeding gums or nose bleeds
- Severe fatigue or weakness
- Liver problems. Call your healthcare provider right away if you have any of these symptoms:
- yellowing of your skin or the whites of your eyes (jaundice)
- dark urine
- nausea or vomiting
- loss of appetite
- pain on the right side of your stomach (abdomen)
- Kidney problems that may be life-threatening.
- Eye problems. Call your healthcare provider right away if you have any new changes in your vision such as:
- problems seeing in bright light
- blurred vision
- Birth defects in your unborn baby.
- Women who can become pregnant should talk to their healthcare provider about using other possible treatments instead of TRIDIONE. If the decision is made to use TRIDIONE, women should use effective birth control (contraception). Talk with your healthcare provider if you are pregnant or plan to become pregnant. Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors.
- Tell your healthcare provider right away if you become pregnant while taking TRIDIONE. You and your healthcare provider should decide if you will continue to take TRIDIONE while you are pregnant.
- If you become pregnant while taking TRIDIONE, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.
- Tell your healthcare provider right away if you are breastfeeding or plan to breastfeed. It is unknown if TRIDIONE passes into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take TRIDIONE.
- Like other antiepileptic drugs, TRIDIONE may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.
- Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:
- thoughts about suicide or dying
- attempts to commit suicide
- new or worse depression
- new or worse anxiety
- feeling agitated or restless
- panic attacks
- trouble sleeping (insomnia)
- new or worse irritability
- acting aggressive, being angry, or violent
- acting on dangerous impulses
- an extreme increase in activity and talking (mania)
- other unusual changes in behavior or mood
- How can I watch for early symptoms of suicidal thoughts and actions?
- Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings.
- Keep all follow-up visits with your healthcare provider as scheduled.
- Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
- Do not stop TRIDIONE without first talking to a healthcare provider. Stopping TRIDIONE suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).
- Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.
- TRIDIONE is a prescription medicine used to treat absence (petit mal) seizures that are not controlled with other drugs.
- Do not take TRIDIONE if you are allergic to trimethadione or any of the ingredients in TRIDIONE. See the end of this leaflet for a complete list of ingredients in TRIDIONE.
- Before you take TRIDIONE, tell your healthcare provider if you have or have had:
- blood problems
- kidney problems
- liver problems
- eye problems
- depression, mood problems or suicidal thoughts or behavior
- any other medical conditions
- Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist each time you get a new medicine.
- Take TRIDIONE exactly as your healthcare provider tells you.
- TRIDIONE can be chewed or swallowed whole.
- Your healthcare provider may change your dose of TRIDIONE. Do not change your dose of TRIDIONE without talking to your healthcare provider.
- If you take too much TRIDIONE, call your healthcare provider or local Poison Control Center right away.
- Do not stop taking TRIDIONE without talking to your healthcare provider. Stopping TRIDIONE suddenly can cause serious problems, including seizures that will not stop (status epilepticus).
- Do not drink alcohol or take other drugs that make you sleepy or dizzy while taking TRIDIONE until you talk to your healthcare provider. TRIDIONE taken with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse.
- Do not drive, operate heavy machinery, or do other dangerous activities until you know how TRIDIONE affects you. TRIDIONE can slow your thinking and motor skills.
- See “What is the most important information I should know about TRIDIONE?”
- TRIDIONE may cause other serious side effects, including:
- Symptoms that are like the symptoms of lupus or myasthenia gravis. Call your healthcare provider right away if you have any of these symptoms:
droopy eyelids
- a rash on your cheeks or other parts of your body
- sensitivity to the sun
- new joint or muscle pains
- chest pain or shortness of breath
- swelling of your feet, ankles, and legs
- weakness of your arms or legs
- problems swallowing
- speech problems
- swollen glands (enlarged lymph nodes)
- The most common side effects of TRIDIONE include:
- nausea
- sleepiness
- tiredness
- increase in seizures
- feelings of anger and frustration
- changes in behavior
- These are not all the possible side effects of TRIDIONE. For more information, ask your healthcare provider or pharmacist.
- Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- Store TRIDIONE in the refrigerator at 36 to 460F (2 to 80C).
- Keep TRIDIONE in a tightly closed container.
- Keep TRIDIONE 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 TRIDIONE for a condition for which it was not prescribed. Do not give TRIDIONE 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 TRIDIONE. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about TRIDIONE that is written for health professionals. For more information, go to www.rxabbvie.com or call 1-800-633-9110.
- Active ingredient: trimethadione
- Inactive ingredient: corn starch, lactose, magnesium stearate, magnesium trisilicate, sucrose and natural/synthetic flavor
Dulcet sweetened tablets, AbbVie Inc.
AbbVie Inc.
North Chicago, IL 60064, U.S.A.
- This Medication Guide has been approved by the U.S. Food and Drug Administration.
# Precautions with Alcohol
- Alcohol-Trimethadione interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- TRIDIONE®
# Look-Alike Drug Names
There is limited information regarding Trimethadione Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price
|
Trimethadione
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
Trimethadione is a anticonvulsant that is FDA approved for the treatment of petit mal seizures that are refractory to treatment with other drugs. Common adverse reactions include nausea, sleepiness, tiredness,increase in seizures, feelings of anger and frustration, changes in behavior.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- TRIDIONE (trimethadione) is indicated for the control of petit mal seizures that are refractory to treatment with other drugs.
### Dosage
- 0.9-2.4 grams daily in 3 or 4 equally divided doses (i.e., 300−600 mg 3 or 4 times daily).
- Initially, give 0.9 gram daily; increase this dose by 300 mg at weekly intervals until therapeutic results are seen or until toxic symptoms appear.
- Maintenance dosage should be the least amount of drug required to maintain control.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Trimethadione in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Trimethadione in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indications
- TRIDIONE (trimethadione) is indicated for the control of petit mal seizures that are refractory to treatment with other drugs.
### Dosage
- Usually 0.3-0.9 gram daily in 3 or 4 equally divided doses.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Trimethadione in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Trimethadione in pediatric patients.
# Contraindications
- TRIDIONE is contraindicated in patients with a known hypersensitivity to the drug.
# Warnings
- TRIDIONE may cause serious side effects. Strict medical supervision of the patient is mandatory, especially during the initial year of therapy.
- TRIDIONE (trimethadione) should be withdrawn promptly if skin rash appears, because of the grave possibility of the occurrence of exfoliative dermatitis or severe forms of erythema multiforme. Even a minor acneiform or morbilliform rash should be allowed to clear completely before treatment with TRIDIONE is resumed; reinstitute therapy cautiously.
- A complete blood count should be done prior to initiating therapy with TRIDIONE, and at monthly intervals thereafter. A marked depression of the blood count is an indication for withdrawal of the drug. If no abnormality appears within 12 months, the interval between blood counts may be extended. A moderate degree of neutropenia with or without a corresponding drop in the leukocyte count is not uncommon. Therapy need not be withdrawn unless the neutrophil count is 2500 or less; more frequent blood examinations should be done when the count is less than 3,000. Other blood dyscrasias, including leukopenia, eosinophilia, thrombocytopenia, pancytopenia, agranulocytosis, hypoplastic anemia, and fatal aplastic anemia, have occurred. Patients should be advised to report immediately such signs and symptoms as sore throat, fever, malaise, easy bruising, petechiae, or epistaxis, or others that may be indicative of an infection or bleeding tendency. TRIDIONE should ordinarily not be used in patients with severe blood dyscrasias.
- Liver function tests should be done prior to initiating therapy with TRIDIONE, and at monthly intervals thereafter. Hepatitis has been reported rarely. Jaundice or other signs of liver dysfunction are an indication for withdrawal of the drug. TRIDIONE should ordinarily not be used in patients with severe hepatic impairment.
- A urinalysis should be done prior to initiating therapy with TRIDIONE and at monthly intervals thereafter. Fatal nephrosis has been reported. Persistent or increasing albuminuria, or the development of any other significant renal abnormality, is an indication for withdrawal of the drug. TRIDIONE should ordinarily not be used in patients with severe renal dysfunction.
- Hemeralopia has occurred; this appears to be an effect of TRIDIONE on the neural layers of the retina, and usually can be reversed by a reduction in dosage. Scotomata are an indication for withdrawal of the drug. Caution should be observed when treating patients who have diseases of the retina or optic nerve.
- Manifestations of systemic lupus erythematosus have been associated with the use of TRIDIONE, as they have with the use of certain other anticonvulsants. Lymphadenopathies simulating malignant lymphoma have occurred. Lupus-like manifestations or lymph node enlargement are indications for withdrawal of the drug. Signs and symptoms may disappear after discontinuation of therapy, and specific treatment may be unnecessary.
- A myasthenia gravis-like syndrome has been associated with the chronic use of trimethadione. Symptoms suggestive of this condition are indications for withdrawal of the drug.
- Drugs known to cause toxic effects similar to those of TRIDIONE should be avoided or used only with extreme caution during therapy with TRIDIONE.
- THERE ARE MULTIPLE REPORTS IN THE CLINICAL LITERATURE WHICH INDICATE THAT THE USE OF ANTICONVULSANT DRUGS DURING PREGNANCY RESULTS IN AN INCREASED INCIDENCE OF BIRTH DEFECTS IN THE OFFSPRING. DATA ARE MORE EXTENSIVE WITH RESPECT TO TRIMETHADIONE, PARAMETHADIONE, PHENYTOIN AND PHENOBARBITAL THAN WITH OTHER ANTICONVULSANT DRUGS.
- THEREFORE, ANTICONVULSANT DRUGS SUCH AS TRIDIONE (TRIMETHADIONE) SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING POTENTIAL ONLY IF THEY ARE CLEARLY SHOWN TO BE ESSENTIAL IN THE MANAGEMENT OF THEIR SEIZURES. EFFECTIVE MEANS OF CONTRACEPTION SHOULD ACCOMPANY THE USE OF TRIDIONE IN SUCH PATIENTS. IF A PATIENT BECOMES PREGNANT WHILE TAKING TRIDIONE, TERMINATION OF THE PREGNANCY SHOULD BE CONSIDERED. A PATIENT WHO REQUIRES THERAPY WITH TRIDIONE AND WHO WISHES TO BECOME PREGNANT SHOULD BE ADVISED OF THE RISKS.
- REPORTS HAVE SUGGESTED THAT THE MATERNAL INGESTION OF ANTICONVULSANT DRUGS, PARTICULARLY BARBITURATES, IS ASSOCIATED WITH A NEONATAL COAGULATION DEFECT THAT MAY CAUSE BLEEDING DURING THE EARLY (USUALLY WITHIN 24 HOURS OF BIRTH) NEONATAL PERIOD. THE POSSIBILITY OF THE OCCURRENCE OF THIS DEFECT WITH THE USE OF TRIDIONE SHOULD BE KEPT IN MIND. THE DEFECT IS CHARACTERIZED BY DECREASED LEVELS OF VITAMIN K-DEPENDENT CLOTTING FACTORS, AND PROLONGATION OF EITHER THE PROTHROMBIN TIME OR THE PARTIAL THROMBOPLASTIN TIME, OR BOTH. IT HAS BEEN SUGGESTED THAT PROPHYLACTIC VITAMIN K BE GIVEN TO THE MOTHER ONE MONTH PRIOR TO, AND DURING DELIVERY, AND TO THE INFANT, INTRAVENOUSLY, IMMEDIATELY AFTER BIRTH.
- THE SAFETY OF TRIDIONE FOR USE DURING LACTATION HAS NOT BEEN ESTABLISHED.
- To provide information regarding the effects of in utero exposure to Tridione, physicians are advised to recommend that pregnant patients taking Tridione enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.
- Antiepileptic drugs (AEDs), including Tridione, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.
- TABLE 1 shows absolute and relative risk by indication for all evaluated AEDs.
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
- Anyone considering prescribing Tridione or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
### Precautions
- Abrupt discontinuation of TRIDIONE may precipitate petit mal status. TRIDIONE should always be withdrawn gradually unless serious adverse effects dictate otherwise. In the latter case, another anticonvulsant may be substituted to protect the patient.
- Physicians should inform patients and their caregivers of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to taking Tridione. Patients should be instructed to take Tridione only as prescribed.
- Patients, their caregivers, and families should be counseled that AEDs, including Tridione, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to the healthcare providers.
- Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334
# Adverse Reactions
## Clinical Trials Experience
- The following side effects, some of them serious, have been associated with the use of TRIDIONE (trimethadione).
- Nausea, vomiting, abdominal pain, gastric distress.
- Drowsiness, fatigue, malaise, insomnia, vertigo, headache, paresthesias, precipitation of grand mal seizures, increased irritability, personality changes.
- Drowsiness usually subsides with continued therapy. If it persists, a reduction in dosage is indicated.
- Bleeding gums, epistaxis, retinal and petechial hemorrhages, vaginal bleeding, neutropenia, leukopenia, eosinophilia, thrombocytopenia, pancytopenia, agranulocytosis, hypoplastic anemia, and fatal aplastic anemia.
- Acneiform or morbilliform skin rash that may progress to exfoliative dermatitis or to severe forms of erythema multiforme.
- Hiccups, anorexia, weight loss, hair loss, changes in blood pressure, albuminuria, hemeralopia, photophobia, diplopia.
- Fatal nephrosis has occurred.
- Hepatitis has been reported rarely.
- Lupus erythematosus, and lymphadenopathies simulating malignant lymphoma, have been reported.
- Pruritus associated with lymphadenopathy and hepatosplenomegaly has occurred in hypersensitive individuals.
- A myasthenia gravis-like syndrome has been reported.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Trimethadione in the drug label.
# Drug Interactions
There is limited information regarding Trimethadione Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- THERE ARE MULTIPLE REPORTS IN THE CLINICAL LITERATURE WHICH INDICATE THAT THE USE OF ANTICONVULSANT DRUGS DURING PREGNANCY RESULTS IN AN INCREASED INCIDENCE OF BIRTH DEFECTS IN THE OFFSPRING. DATA ARE MORE EXTENSIVE WITH RESPECT TO TRIMETHADIONE, PARAMETHADIONE, PHENYTOIN AND PHENOBARBITAL THAN WITH OTHER ANTICONVULSANT DRUGS.
- THEREFORE, ANTICONVULSANT DRUGS SUCH AS TRIDIONE (TRIMETHADIONE) SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING POTENTIAL ONLY IF THEY ARE CLEARLY SHOWN TO BE ESSENTIAL IN THE MANAGEMENT OF THEIR SEIZURES. EFFECTIVE MEANS OF CONTRACEPTION SHOULD ACCOMPANY THE USE OF TRIDIONE IN SUCH PATIENTS. IF A PATIENT BECOMES PREGNANT WHILE TAKING TRIDIONE, TERMINATION OF THE PREGNANCY SHOULD BE CONSIDERED. A PATIENT WHO REQUIRES THERAPY WITH TRIDIONE AND WHO WISHES TO BECOME PREGNANT SHOULD BE ADVISED OF THE RISKS.
- REPORTS HAVE SUGGESTED THAT THE MATERNAL INGESTION OF ANTICONVULSANT DRUGS, PARTICULARLY BARBITURATES, IS ASSOCIATED WITH A NEONATAL COAGULATION DEFECT THAT MAY CAUSE BLEEDING DURING THE EARLY (USUALLY WITHIN 24 HOURS OF BIRTH) NEONATAL PERIOD. THE POSSIBILITY OF THE OCCURRENCE OF THIS DEFECT WITH THE USE OF TRIDIONE SHOULD BE KEPT IN MIND. THE DEFECT IS CHARACTERIZED BY DECREASED LEVELS OF VITAMIN K-DEPENDENT CLOTTING FACTORS, AND PROLONGATION OF EITHER THE PROTHROMBIN TIME OR THE PARTIAL THROMBOPLASTIN TIME, OR BOTH. IT HAS BEEN SUGGESTED THAT PROPHYLACTIC VITAMIN K BE GIVEN TO THE MOTHER ONE MONTH PRIOR TO, AND DURING DELIVERY, AND TO THE INFANT, INTRAVENOUSLY, IMMEDIATELY AFTER BIRTH.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Trimethadione in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Trimethadione during labor and delivery.
### Nursing Mothers
- THE SAFETY OF TRIDIONE FOR USE DURING LACTATION HAS NOT BEEN ESTABLISHED.
### Pediatric Use
There is no FDA guidance on the use of Trimethadione with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Trimethadione with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Trimethadione with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Trimethadione with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Trimethadione in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Trimethadione in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Trimethadione in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Trimethadione in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Liver function tests should be done prior to initiating therapy with TRIDIONE, and at monthly intervals thereafter.
- A urinalysis should be done prior to initiating therapy with TRIDIONE and at monthly intervals thereafter.
- A complete blood count should be done prior to initiating therapy with TRIDIONE, and at monthly intervals thereafter.
# IV Compatibility
There is limited information regarding IV Compatibility of Trimethadione in the drug label.
# Overdosage
- Symptoms of acute TRIDIONE overdosage include drowsiness, nausea, dizziness, ataxia, visual disturbances. Coma may follow massive overdosage.
- Gastric evacuation, either by induced emesis, or by lavage, or both, should be done immediately. General supportive care, including frequent monitoring of the vital signs and close observations of the patient, are required.
- Alkalinization of the urine has been reported to enhance the renal excretion of dimethadione, the active metabolite of TRIDIONE.
- A blood count and a careful evaluation of hepatic and renal function should be done following recovery.
# Pharmacology
## Mechanism of Action
- TRIDIONE has been shown to prevent pentylenetetrazol-induced and thujone-induced seizures in experimental animals; the drug has a less marked effect on seizures induced by picrotoxin, procaine, cocaine, or strychnine. Unlike the hydantoins and antiepileptic barbiturates, TRIDIONE does not modify the maximal seizure pattern in patients undergoing electroconvulsive therapy.
## Structure
- TRIDIONE (trimethadione) is an antiepileptic agent. An oxazolidinedione compound, it is chemically identified as 3,5,5-trimethyloxozolidine-2,4-dione, and has the following structural formula:
- TRIDIONE is a synthetic, water-soluble, white, crystalline powder. It is supplied in tablets for oral use only.
- 150 mg Dulcet Tablet: Corn starch, lactose, magnesium stearate, magnesium trisilicate, sucrose and natural/synthetic flavor.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Trimethadione in the drug label.
## Pharmacokinetics
- TRIDIONE has a sedative effect that may increase to the point of ataxia when excessive doses are used. A toxic dose of the drug in animals (approximately 2 g/kg) produced sleep, unconsciousness, and respiratory depression.
- Trimethadione is rapidly absorbed from the gastrointestinal tract. It is demethylated by liver microsomes to the active metabolite, dimethadione.
- Approximately 3% of a daily dose of TRIDIONE is recovered in the urine as unchanged drug. The majority of trimethadione is excreted slowly by the kidney in the form of dimethadione.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Trimethadione in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Trimethadione in the drug label.
# How Supplied
- TRIDIONE Dulcet® Tablets (trimethadione tablets) are supplied as white, chewable tablets bearing the “a” logo and a two-letter code designation LE for the 150 mg tablet, in bottles of 100 (NDC 0074-3753-01).
## Storage
- Store Dulcet tablets in refrigerator 36° to 46°F (2° - 8°C) to minimize crystallization. However some crystallization not harmful to product may occur. Keep tightly closed.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
NDC 0074–3753–01
100 Tablets Dulcet®
TRIDIONE®
TRIMETHADIONE TABLETS 150 mg (2 1/2 grs)
Rx only abbvie
### Ingredients and Appearance
# Patient Counseling Information
- Physicians should inform patients and their caregivers of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to taking Tridione. Patients should be instructed to take Tridione only as prescribed.
- Patients, their caregivers, and families should be counseled that AEDs, including Tridione, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to the healthcare providers.
- Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334
### MEDICATION GUIDE
(trimethadione)
Tablets
- Read this Medication Guide before you start taking TRIDIONE and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.
- Do not stop taking TRIDIONE without first talking to your healthcare provider.
- Stopping TRIDIONE suddenly can cause serious problems.
- TRIDIONE can cause serious side effects, including:
- Rash. This may need to be treated in a hospital and may be life-threatening.
- Call your healthcare provider right away if you have any of these symptoms:
- skin rash
- hives
- sores in your mouth
- Blood problems that can be life-threatening. Call your healthcare provider right away if you have any of these symptoms:
- Fever, swollen glands, or sore throat that come and go or do not go away
- Frequent infections or an infection that does not go away
- Easy bruising
- Red or purple spots on your body
- Bleeding gums or nose bleeds
- Severe fatigue or weakness
- Liver problems. Call your healthcare provider right away if you have any of these symptoms:
- yellowing of your skin or the whites of your eyes (jaundice)
- dark urine
- nausea or vomiting
- loss of appetite
- pain on the right side of your stomach (abdomen)
- Kidney problems that may be life-threatening.
- Eye problems. Call your healthcare provider right away if you have any new changes in your vision such as:
- problems seeing in bright light
- blurred vision
- Birth defects in your unborn baby.
- Women who can become pregnant should talk to their healthcare provider about using other possible treatments instead of TRIDIONE. If the decision is made to use TRIDIONE, women should use effective birth control (contraception). Talk with your healthcare provider if you are pregnant or plan to become pregnant. Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors.
- Tell your healthcare provider right away if you become pregnant while taking TRIDIONE. You and your healthcare provider should decide if you will continue to take TRIDIONE while you are pregnant.
- If you become pregnant while taking TRIDIONE, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.
- Tell your healthcare provider right away if you are breastfeeding or plan to breastfeed. It is unknown if TRIDIONE passes into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take TRIDIONE.
- Like other antiepileptic drugs, TRIDIONE may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.
- Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:
- thoughts about suicide or dying
- attempts to commit suicide
- new or worse depression
- new or worse anxiety
- feeling agitated or restless
- panic attacks
- trouble sleeping (insomnia)
- new or worse irritability
- acting aggressive, being angry, or violent
- acting on dangerous impulses
- an extreme increase in activity and talking (mania)
- other unusual changes in behavior or mood
- How can I watch for early symptoms of suicidal thoughts and actions?
- Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings.
- Keep all follow-up visits with your healthcare provider as scheduled.
- Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
- Do not stop TRIDIONE without first talking to a healthcare provider. Stopping TRIDIONE suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).
- Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.
- TRIDIONE is a prescription medicine used to treat absence (petit mal) seizures that are not controlled with other drugs.
- Do not take TRIDIONE if you are allergic to trimethadione or any of the ingredients in TRIDIONE. See the end of this leaflet for a complete list of ingredients in TRIDIONE.
- Before you take TRIDIONE, tell your healthcare provider if you have or have had:
- blood problems
- kidney problems
- liver problems
- eye problems
- depression, mood problems or suicidal thoughts or behavior
- any other medical conditions
- Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist each time you get a new medicine.
- Take TRIDIONE exactly as your healthcare provider tells you.
- TRIDIONE can be chewed or swallowed whole.
- Your healthcare provider may change your dose of TRIDIONE. Do not change your dose of TRIDIONE without talking to your healthcare provider.
- If you take too much TRIDIONE, call your healthcare provider or local Poison Control Center right away.
- Do not stop taking TRIDIONE without talking to your healthcare provider. Stopping TRIDIONE suddenly can cause serious problems, including seizures that will not stop (status epilepticus).
- Do not drink alcohol or take other drugs that make you sleepy or dizzy while taking TRIDIONE until you talk to your healthcare provider. TRIDIONE taken with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse.
- Do not drive, operate heavy machinery, or do other dangerous activities until you know how TRIDIONE affects you. TRIDIONE can slow your thinking and motor skills.
- See “What is the most important information I should know about TRIDIONE?”
- TRIDIONE may cause other serious side effects, including:
- Symptoms that are like the symptoms of lupus or myasthenia gravis. Call your healthcare provider right away if you have any of these symptoms:
droopy eyelids
- a rash on your cheeks or other parts of your body
- sensitivity to the sun
- new joint or muscle pains
- chest pain or shortness of breath
- swelling of your feet, ankles, and legs
- weakness of your arms or legs
- problems swallowing
- speech problems
- swollen glands (enlarged lymph nodes)
- The most common side effects of TRIDIONE include:
- nausea
- sleepiness
- tiredness
- increase in seizures
- feelings of anger and frustration
- changes in behavior
- These are not all the possible side effects of TRIDIONE. For more information, ask your healthcare provider or pharmacist.
- Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- Store TRIDIONE in the refrigerator at 36 to 460F (2 to 80C).
- Keep TRIDIONE in a tightly closed container.
- Keep TRIDIONE 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 TRIDIONE for a condition for which it was not prescribed. Do not give TRIDIONE 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 TRIDIONE. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about TRIDIONE that is written for health professionals. For more information, go to www.rxabbvie.com or call 1-800-633-9110.
- Active ingredient: trimethadione
- Inactive ingredient: corn starch, lactose, magnesium stearate, magnesium trisilicate, sucrose and natural/synthetic flavor
Dulcet sweetened tablets, AbbVie Inc.
AbbVie Inc.
North Chicago, IL 60064, U.S.A.
- This Medication Guide has been approved by the U.S. Food and Drug Administration.
# Precautions with Alcohol
- Alcohol-Trimethadione interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- TRIDIONE®[1]
# Look-Alike Drug Names
There is limited information regarding Trimethadione Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price
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487d9715716e4679797eb5a05ed4b050496c727b
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Triplet state
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Triplet state
In physics, spin is the angular momentum intrinsic to a body, as opposed to orbital angular momentum, which is the motion of its center of mass about an external point. In quantum mechanics, spin is particularly important for systems at atomic length scales, such as individual atoms, protons, or electrons. Such particles and the spin of quantum mechanical systems ("particle spin") possesses several unusual or non-classical features, and for such systems, spin angular momentum cannot be associated with rotation but instead refers only to the presence of angular momentum. A spin triplet is a set of three quantum states of a system, each with total spin S = 1. The system could consist of a single elementary massive spin 1 particle such as a W or Z boson, or be some multiparticle state with total spin angular momentum of one (in units of \hbar).
# Two Spin 1/2 Particles
In a system with two spin 1/2 particles - for example the proton and electron in the ground state of hydrogen, measured on a given axis, each particle can be either spin up or spin down so the system has four basis states in all
using the single particle spins to label the basis states, where the first and second arrow in each combination indicate the spin direction of the first and second particle respectively.
More rigorously
and since for spin-1/2 particles, the |1/2,m\rangle basis states span a 2-dimensional space. Therefore the |1/2,m_1\rangle|1/2,m_2\rangle basis states span a 4-dimensional space.
Now the total spin and its projection onto the previously defined axis can be computed using the rules for adding angular momentum in quantum mechanics using the Clebsch–Gordan coefficients. In general
substituting in the four basis states
returns the possible values for total spin given along with their representation in the |1/2\ m_1\rangle|1/2\ m_2\rangle basis. There are three states with total angular momentum 1
\left(
\begin{array}{ll}
\end{array}
\right)\ s=1\ (\mathrm{triplet})
and a fourth with total angular momentum 0.
The result is that a combination of two spin 1/2 particles can carry a total spin of 1 or 0, depending on whether they occupy a triplet or singlet state.
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Triplet state
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
In physics, spin is the angular momentum intrinsic to a body, as opposed to orbital angular momentum, which is the motion of its center of mass about an external point. In quantum mechanics, spin is particularly important for systems at atomic length scales, such as individual atoms, protons, or electrons. Such particles and the spin of quantum mechanical systems ("particle spin") possesses several unusual or non-classical features, and for such systems, spin angular momentum cannot be associated with rotation but instead refers only to the presence of angular momentum. A spin triplet is a set of three quantum states of a system, each with total spin S = 1. The system could consist of a single elementary massive spin 1 particle such as a W or Z boson, or be some multiparticle state with total spin angular momentum of one (in units of <math>\hbar</math>).
# Two Spin 1/2 Particles
In a system with two spin 1/2 particles - for example the proton and electron in the ground state of hydrogen, measured on a given axis, each particle can be either spin up or spin down so the system has four basis states in all
using the single particle spins to label the basis states, where the first and second arrow in each combination indicate the spin direction of the first and second particle respectively.
More rigorously
</math>
and since for spin-1/2 particles, the <math>|1/2,m\rangle</math> basis states span a 2-dimensional space. Therefore the <math>|1/2,m_1\rangle|1/2,m_2\rangle</math> basis states span a 4-dimensional space.
Now the total spin and its projection onto the previously defined axis can be computed using the rules for adding angular momentum in quantum mechanics using the Clebsch–Gordan coefficients. In general
substituting in the four basis states
returns the possible values for total spin given along with their representation in the <math>|1/2\ m_1\rangle|1/2\ m_2\rangle</math> basis. There are three states with total angular momentum 1
\left(
\begin{array}{ll}
\end{array}
\right)\ s=1\ (\mathrm{triplet})
</math>
and a fourth with total angular momentum 0.
The result is that a combination of two spin 1/2 particles can carry a total spin of 1 or 0, depending on whether they occupy a triplet or singlet state.
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Trofile assay
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Trofile assay
The Trofile (TM) assay is a blood test that identifies the tropism of a patient's HIV.
A molecular assay, Trofile was developed by Monogram Biosciences for use in HIV treatment. The assay's purpose is to identify the tropism of an individual patient's HIV strain – R5, X4, or a combination of these known as dual/mixed (D/M). The results show whether the patient is infected with virus that enters cells using the R5 co-receptor, the X4 co-receptor, or both (dual/mixed).
Patients with strains of HIV that prefer the R5 receptor tend to remain healthy longer than those with the strains that prefer X4. However, over the course of the disease, a patient's viral population may undergo a "tropism switch" from R5 to X4.
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Trofile assay
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The Trofile (TM) assay is a blood test that identifies the tropism of a patient's HIV.
A molecular assay, Trofile was developed by Monogram Biosciences for use in HIV treatment. The assay's purpose is to identify the tropism of an individual patient's HIV strain – R5, X4, or a combination of these known as dual/mixed (D/M). The results show whether the patient is infected with virus that enters cells using the R5 co-receptor, the X4 co-receptor, or both (dual/mixed).
Patients with strains of HIV that prefer the R5 receptor tend to remain healthy longer than those with the strains that prefer X4. However, over the course of the disease, a patient's viral population may undergo a "tropism switch" from R5 to X4.
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https://www.wikidoc.org/index.php/Trofile_assay
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Tumor antigen
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Tumor antigen
# Overview
Tumor antigen is a substance produced in tumor cells that triggers an immune response in the host. Tumor antigens are useful in identifying tumor cells and are potential candidates for use in cancer therapy.
# Mechanism of tumor antigenesis
Normal proteins in the body are not antigenic because of self-tolerance, a process in which self-reacting cytotoxic T lymphocytes (CTLs) and autoantibody-producing B lymphocytes are culled in the thymus. Thus any protein that is not exposed to the immune system triggers an immune response. This may include normal proteins that are well sequestered from the immune system, proteins that are normally produced in extremely small quantities, proteins that are normally produced only in certain stages of development, or proteins whose structure is modified due to mutation.
# Types
Any protein produced in a a tumor cell that has an abnormal structure due to mutation can act as a tumor antigen. Such abnormal proteins are produced due to mutation of the concerned gene. Mutation of protooncogenes and tumor suppressors which lead to abnormal protein production are the cause of the tumor and thus such abnormal proteins are called tumor-specific antigens. Examples of tumor-specific antigens include the abnormal products of ras and p53 genes. In contrast, mutation of other genes unrelated to the tumor formation may lead to synthesis of abnormal proteins which are called tumor-associated antigens.
Proteins that are normally produced in very low quantities but whose production is dramatically increased in tumor cells, trigger an immune response. An example of such a protein is the enzyme tyrosinase, which is required for melanin production. Normally tyrosinase is produced in minute quantities but its levels are very much elevated in melanoma cells.
Oncofetal antigens are another important class of tumor antigens. Examples are alphafetoprotein (AFP) and carcinoembryonic antigen (CEA). These proteins are normally produced in the early stages of embryonic development and disappear by the time the immune system is fully developed. Thus self-tolerance does not develop against these antigens.
Abnormal proteins are also produced by cells infected with oncoviruses, eg. EBV and HPV. Cells infected by these viruses contain latent viral DNA which is transcribed and the resulting protein produces an immune response.
In addition to proteins, other substances like cell surface glycolipids and glycoproteins may also have an abnormal structure in tumor cells and could thus be targets of the immune system.
# Importance of tumor antigens
Tumor antigens, because of their relative abundance in tumor cells are useful in identifying specific tumor cells. Certain tumors have certain tumor antigens in abundance.
Certain tumor antigens are thus used as tumor markers. More importantly, tumor antigens can be used in cancer therapy as tumor antigen vaccines.
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Tumor antigen
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Tumor antigen is a substance produced in tumor cells that triggers an immune response in the host. Tumor antigens are useful in identifying tumor cells and are potential candidates for use in cancer therapy.
# Mechanism of tumor antigenesis
Normal proteins in the body are not antigenic because of self-tolerance, a process in which self-reacting cytotoxic T lymphocytes (CTLs) and autoantibody-producing B lymphocytes are culled in the thymus. Thus any protein that is not exposed to the immune system triggers an immune response. This may include normal proteins that are well sequestered from the immune system, proteins that are normally produced in extremely small quantities, proteins that are normally produced only in certain stages of development, or proteins whose structure is modified due to mutation.
# Types
Any protein produced in a a tumor cell that has an abnormal structure due to mutation can act as a tumor antigen. Such abnormal proteins are produced due to mutation of the concerned gene. Mutation of protooncogenes and tumor suppressors which lead to abnormal protein production are the cause of the tumor and thus such abnormal proteins are called tumor-specific antigens. Examples of tumor-specific antigens include the abnormal products of ras and p53 genes. In contrast, mutation of other genes unrelated to the tumor formation may lead to synthesis of abnormal proteins which are called tumor-associated antigens.
Proteins that are normally produced in very low quantities but whose production is dramatically increased in tumor cells, trigger an immune response. An example of such a protein is the enzyme tyrosinase, which is required for melanin production. Normally tyrosinase is produced in minute quantities but its levels are very much elevated in melanoma cells.
Oncofetal antigens are another important class of tumor antigens. Examples are alphafetoprotein (AFP) and carcinoembryonic antigen (CEA). These proteins are normally produced in the early stages of embryonic development and disappear by the time the immune system is fully developed. Thus self-tolerance does not develop against these antigens.
Abnormal proteins are also produced by cells infected with oncoviruses, eg. EBV and HPV. Cells infected by these viruses contain latent viral DNA which is transcribed and the resulting protein produces an immune response.
In addition to proteins, other substances like cell surface glycolipids and glycoproteins may also have an abnormal structure in tumor cells and could thus be targets of the immune system.
# Importance of tumor antigens
Tumor antigens, because of their relative abundance in tumor cells are useful in identifying specific tumor cells. Certain tumors have certain tumor antigens in abundance.
Certain tumor antigens are thus used as tumor markers. More importantly, tumor antigens can be used in cancer therapy as tumor antigen vaccines. [1]
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Tunable laser
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Tunable laser
A tunable laser is a laser whose wavelength of operation can be altered in a controlled manner. While all laser gain media allow small shifts in output wavelength, only a few types of lasers allow continuous tuning over a significant wavelength range.
There are many types and categories of tunable lasers. They exist in the gas, liquid, and solid state. Among the types of tunable lasers are excimer lasers, CO2 lasers, dye lasers (liquid and solid state), transition metal solid-state lasers, semiconductor diode lasers, and free electron lasers.
Tunable lasers find applications in spectroscopy, photochemistry and optical communications.
# Types of tunability
## Single line tuning
Since no real laser is truly monochromatic, all lasers can emit light over some range of frequencies, known as the linewidth of the laser transition. In most lasers, this linewidth is quite narrow (for example, the 1064 nm wavelength transition of a Nd:YAG laser has a linewidth of approximately 120 GHz, corresponding to a 0.45 nm wavelength range). Tuning of the laser output across this range can be achieved by placing wavelength-selective optical elements (such as an etalon) into the laser's optical cavity, to provide selection of a particular longitudinal mode of the cavity.
## Multi-line tuning
Most laser gain media have a number of transition wavelengths on which laser operation can be achieved. For example, as well as the principal 1064 nm output line, Nd:YAG has weaker transitions at wavelengths of 1052 nm, 1074 nm, 1112 nm, 1319 nm, and a number of other lines. Usually, these lines do not operate unless the gain of the strongest transition is suppressed, e.g., by use of wavelength-selective dielectric mirrors. If a dispersive element, such as a prism, is introduced into the optical cavity, tilting of the cavity's mirrors can cause tuning of the laser as it "hops" between different laser lines. Such schemes are common in argon-ion lasers, allowing tuning of the laser to a number of lines from the ultraviolet and blue through to green wavelengths.
## Broadband tuning
Some types of laser have an inherently large linewidth, and thus can be continuously tuned over a significant wavelength range by modification of the laser's cavity.
Distributed feedback (DFB) semiconductor lasers and vertical cavity surface emitting lasers (VCSELs) use periodic distributed Bragg reflector (DBR) structures to form the mirrors of the optical cavity. If the temperature of the laser is changed, thermal expansion of the DBR structure causes a shift in its peak reflective wavelength and thus the wavelength of the laser. The tuning range of such lasers is typically a few nanometres, up to a maximum of approximately 8 nm, as the laser temperature is changed over ~50 K. Such lasers are commonly used in optical communications applications such as DWDM-systems to allow adjustment of the signal wavelength. Additionally, Sample Grating Distributed Bragg Reflector lasers (SGDBR) have a much larger tunable range, by the use of vernier tunable Bragg mirrors and a phase section, a single mode output range of >50 nm can be selected.
The first true broadly tunable laser was the dye laser .
Dye lasers and some vibronic solid-state lasers have extremely large linewidths, allowing tuning over a range of tens to hundreds of nanometres. Titanium-doped sapphire is the most common tunable solid-state laser, capable of laser operation from 670 nm to 1100 nm wavelength. Typically these laser systems incorporate a Lyot filter into the laser cavity, which is rotated to tune the laser. Other tuning techniques involve diffraction gratings, prisms, etalons, and combinations of these.
|
Tunable laser
A tunable laser is a laser whose wavelength of operation can be altered in a controlled manner. While all laser gain media allow small shifts in output wavelength, only a few types of lasers allow continuous tuning over a significant wavelength range.
There are many types and categories of tunable lasers. They exist in the gas, liquid, and solid state. Among the types of tunable lasers are excimer lasers, CO2 lasers, dye lasers (liquid and solid state), transition metal solid-state lasers, semiconductor diode lasers, and free electron lasers[1].
Tunable lasers find applications in spectroscopy, photochemistry and optical communications.
# Types of tunability
## Single line tuning
Since no real laser is truly monochromatic, all lasers can emit light over some range of frequencies, known as the linewidth of the laser transition. In most lasers, this linewidth is quite narrow (for example, the 1064 nm wavelength transition of a Nd:YAG laser has a linewidth of approximately 120 GHz, corresponding to a 0.45 nm wavelength range[2]). Tuning of the laser output across this range can be achieved by placing wavelength-selective optical elements (such as an etalon) into the laser's optical cavity, to provide selection of a particular longitudinal mode of the cavity.
## Multi-line tuning
Most laser gain media have a number of transition wavelengths on which laser operation can be achieved. For example, as well as the principal 1064 nm output line, Nd:YAG has weaker transitions at wavelengths of 1052 nm, 1074 nm, 1112 nm, 1319 nm, and a number of other lines[3]. Usually, these lines do not operate unless the gain of the strongest transition is suppressed, e.g., by use of wavelength-selective dielectric mirrors. If a dispersive element, such as a prism, is introduced into the optical cavity, tilting of the cavity's mirrors can cause tuning of the laser as it "hops" between different laser lines. Such schemes are common in argon-ion lasers, allowing tuning of the laser to a number of lines from the ultraviolet and blue through to green wavelengths.
## Broadband tuning
Some types of laser have an inherently large linewidth, and thus can be continuously tuned over a significant wavelength range by modification of the laser's cavity.
Distributed feedback (DFB) semiconductor lasers and vertical cavity surface emitting lasers (VCSELs) use periodic distributed Bragg reflector (DBR) structures to form the mirrors of the optical cavity. If the temperature of the laser is changed, thermal expansion of the DBR structure causes a shift in its peak reflective wavelength and thus the wavelength of the laser. The tuning range of such lasers is typically a few nanometres, up to a maximum of approximately 8 nm, as the laser temperature is changed over ~50 K. Such lasers are commonly used in optical communications applications such as DWDM-systems to allow adjustment of the signal wavelength. Additionally, Sample Grating Distributed Bragg Reflector lasers (SGDBR) have a much larger tunable range, by the use of vernier tunable Bragg mirrors and a phase section, a single mode output range of >50 nm can be selected.
The first true broadly tunable laser was the dye laser [4] [5].
Dye lasers and some vibronic solid-state lasers have extremely large linewidths, allowing tuning over a range of tens to hundreds of nanometres[6]. Titanium-doped sapphire is the most common tunable solid-state laser, capable of laser operation from 670 nm to 1100 nm wavelength. Typically these laser systems incorporate a Lyot filter into the laser cavity, which is rotated to tune the laser. Other tuning techniques involve diffraction gratings, prisms, etalons, and combinations of these[7].
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https://www.wikidoc.org/index.php/Tunable_laser
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0ffafbe66ae87d794f69ca0c5320b7319ba2abd9
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wikidoc
|
Ugie Hospital
|
Ugie Hospital
Ugie Hospital is a small hospital in Peterhead, Scotland, providing psychogeriatric services.
# MRSA outbreak
In 2004 the Ravenscraig geriatric ward at the hospital was closed to new admissions because of an outbreak of MRSA among the elderly patients. Eight of the 13 patients were found to be carriers of the bacteria, although none of the patients was actually infected.
# Possible closure
In August 2005 Aberdeenshire Community Health Partnership issued a consultation document on Older People’s Services, Maternity Services and Diagnostic and Treatment Services which includes several proposals for reorganisation of services in these areas. One of the options would "create one centralised Aberdeenshire psycho-geriatric assessment unit. This would allow for the relocation of all psychogeriatric services out of Ugie Hospital and enable it to be closed".
|
Ugie Hospital
Ugie Hospital is a small hospital in Peterhead, Scotland, providing psychogeriatric services.
# MRSA outbreak
In 2004 the Ravenscraig geriatric ward at the hospital was closed to new admissions because of an outbreak of MRSA among the elderly patients. Eight of the 13 patients were found to be carriers of the bacteria, although none of the patients was actually infected.[1]
# Possible closure
In August 2005 Aberdeenshire Community Health Partnership issued a consultation document on Older People’s Services, Maternity Services and Diagnostic and Treatment Services which includes several proposals for reorganisation of services in these areas. One of the options would "create one centralised Aberdeenshire psycho-geriatric assessment unit. This would allow for the relocation of all psychogeriatric services out of Ugie Hospital and enable it to be closed".[2]
|
https://www.wikidoc.org/index.php/Ugie_Hospital
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92212853b1eca5396b807fb97b127850ddc97ece
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wikidoc
|
Umbelliferone
|
Umbelliferone
Umbelliferone or 7-hydroxycoumarin is a widespread natural product of the coumarin family. It occurs in many familiar plants from the Apiaceae (Umbelliferae) family such as carrot, coriander and garden angelica, as well plants from other families such as the mouse-ear hawkweed. It is a yellowish-white crystalline solid which has a slight solubility in hot water, but high solubility in ethanol. It absorbs ultraviolet light strongly at several wavelengths, leading to its use in sunscreen creams and lotions.
# Chemical synthesis
Umbelliferone is traditionally synthesized using the Pechmann condensation, from resorcinol and formylacetic acid (generated from malic acid in situ).
A newer synthesis uses methyl propiolate and a palladium catalyst.
# Ultraviolet fluorescence
Umbelliferone absorbs strongly at 300, 305 and 325 nm, with log ε values of 3.9, 3.95 and 4.15 respectively, and it fluoresces blue in both ultraviolet and visible light. The powerful absorption at three different wavelengths, coupled with the fact that the energy is dissipated safely as visible light, make umbelliferone a useful sunscreen agent. The absorption changes in alkaline solution, since the phenolic hydroxyl group is deprotonated (pKa = 7.7).
# Uses
The ultraviolet activity of umbelliferone lead to its use as a sunscreen agent, and an optical brightener for textiles. It has also been used as a gain medium for dye lasers. Umbelliferone can be used as a fluorescence indicator for metal ions such as copper and calcium. It acts as a pH indicator in the range 6.5-8.9.
# Derivatives of umbelliferone
Umbelliferone is the parent compound for a large number of natural products. Herniarin or 7-O-methylumbelliferone (7-methoxycoumarin) occurs in the leaves of water hemp (Eupatorium ayapana) and rupturewort. O-glycosylated derivatives such as skimmin (7-O-β-D-glucopyranosylumbelliferone) occur naturally and are used for the fluorimetric determination of glycoside hydrolase enzymes. Isoprenylated derivatives are also widespread, such as marmin (found in grapefruit skin and in the bark of the Bael tree) and furocoumarins such as marmesin, angelicin and psoralen.
|
Umbelliferone
Umbelliferone or 7-hydroxycoumarin is a widespread natural product of the coumarin family. It occurs in many familiar plants from the Apiaceae (Umbelliferae) family such as carrot, coriander and garden angelica, as well plants from other families such as the mouse-ear hawkweed. It is a yellowish-white crystalline solid which has a slight solubility in hot water, but high solubility in ethanol. It absorbs ultraviolet light strongly at several wavelengths, leading to its use in sunscreen creams and lotions.
# Chemical synthesis
Umbelliferone is traditionally synthesized using the Pechmann condensation, from resorcinol and formylacetic acid (generated from malic acid in situ).
A newer synthesis uses methyl propiolate and a palladium catalyst.
# Ultraviolet fluorescence
Umbelliferone absorbs strongly at 300, 305 and 325 nm, with log ε values of 3.9, 3.95 and 4.15 respectively, and it fluoresces blue in both ultraviolet and visible light. The powerful absorption at three different wavelengths, coupled with the fact that the energy is dissipated safely as visible light, make umbelliferone a useful sunscreen agent. The absorption changes in alkaline solution, since the phenolic hydroxyl group is deprotonated (pKa = 7.7).
# Uses
The ultraviolet activity of umbelliferone lead to its use as a sunscreen agent, and an optical brightener for textiles. It has also been used as a gain medium for dye lasers. Umbelliferone can be used as a fluorescence indicator for metal ions such as copper and calcium. It acts as a pH indicator in the range 6.5-8.9.
# Derivatives of umbelliferone
Umbelliferone is the parent compound for a large number of natural products. Herniarin or 7-O-methylumbelliferone (7-methoxycoumarin) occurs in the leaves of water hemp (Eupatorium ayapana) and rupturewort. O-glycosylated derivatives such as skimmin (7-O-β-D-glucopyranosylumbelliferone) occur naturally and are used for the fluorimetric determination of glycoside hydrolase enzymes. Isoprenylated derivatives are also widespread, such as marmin (found in grapefruit skin and in the bark of the Bael tree) and furocoumarins such as marmesin, angelicin and psoralen.
# External links
- USDA ARS info on uses
|
https://www.wikidoc.org/index.php/Umbelliferone
| |
3be5c5c7b59337e999366f90e7115ae2e68ff3bd
|
wikidoc
|
Unhappy triad
|
Unhappy triad
# Overview
An unhappy triad (or terrible triad, or O'Donoghue's triad) is an injury to the knee. It commonly occurs in contact sports (such as American football). The mechanism for this injury occurs when a lateral (outside) force to the knee is received while the foot is fixed on the ground.
# Structures in triad
This scenario causes an injury to three knee structures:
- the anterior cruciate ligament
- the medial collateral ligament (or "tibial collateral ligament")
- the lateral meniscus
The inclusion of the lateral meniscus in the triad has been recently ascertained as it previously had been incorrectly postulated that the medial meniscus was the third component.
# Terminology
The term "unhappy triad" was coined by O'Donoghue in 1950. However, since then, this term and the term "terrible triad" have also been used to describe several other combinations of joint injuries, including those of the elbow and shoulder.
The term "terrible triad" is also sometimes used in the popular press to describe conditions relating to pain, or even to refer to the MacDonald triad.
MR images demonstrate O'Donoghue's unhappy triad
- ACL tear
- Medial meniscal tear
- Medial meniscal tear Image:
- Medial collateral ligament tear
|
Unhappy triad
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
An unhappy triad (or terrible triad, or O'Donoghue's triad[1]) is an injury to the knee. It commonly occurs in contact sports (such as American football). The mechanism for this injury occurs when a lateral (outside) force to the knee is received while the foot is fixed on the ground.
# Structures in triad
This scenario causes an injury to three knee structures:
- the anterior cruciate ligament
- the medial collateral ligament (or "tibial collateral ligament")
- the lateral meniscus
The inclusion of the lateral meniscus in the triad has been recently ascertained as it previously had been incorrectly postulated that the medial meniscus was the third component.[2]
# Terminology
The term "unhappy triad" was coined by O'Donoghue in 1950.[2][3][4] However, since then, this term and the term "terrible triad" have also been used to describe several other combinations of joint injuries, including those of the elbow[5] and shoulder.[6]
The term "terrible triad" is also sometimes used in the popular press to describe conditions relating to pain, or even to refer to the MacDonald triad.
MR images demonstrate O'Donoghue's unhappy triad
- ACL tear
- Medial meniscal tear
- Medial meniscal tear Image:
- Medial collateral ligament tear
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https://www.wikidoc.org/index.php/Unhappy_Triad
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e6f4850c99cfa20785fb03925d8ed3d5ad080b75
|
wikidoc
|
Urate oxidase
|
Urate oxidase
The enzyme urate oxidase (UO), or uricase or factor-independent urate hydroxylase, absent in humans, catalyzes the oxidation of uric acid to 5-hydroxyisourate:
# Structure
Urate oxidase is mainly localised in the liver, where it forms a large electron-dense paracrystalline core in many peroxisomes. The enzyme exists as a tetramer of identical subunits, each containing a possible type 2 copper-binding site.
Urate oxidase is a homotetrameric enzyme containing four identical active sites situated at the interfaces between its four subunits. UO from A. flavus is made up of 301 residues and has a molecular weight of 33438 daltons. It is unique among the oxidases in that it does not require a metal atom or an organic co-factor for catalysis. Sequence analysis of several organisms has determined that there are 24 amino acids which are conserved, and of these, 15 are involved with the active site.
# Reaction mechanism
Urate oxidase is the first in a pathway of three enzymes to convert uric acid to S-(+)-allantoin. After uric acid is converted to 5-hydroxyisourate by urate oxidase, 5-hydroxyisourate (HIU) is converted to 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline (OHCU) by HIU hydrolase, and then to S-(+)-allantoin by 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline decarboxylase (OHCU decarboxylase). Without HIU hydrolase and OHCU decarboxylase, HIU will spontaneously decompose into racemic allantoin.
Within the active site of urate oxidase, there is a catalytic site that holds uric acid and its analogues in the same orientation and a common catalytic site where oxygen, water, and hydrogen peroxide are sequentially driven. This mechanism is similar to that of catalase, which reverses hydrogen peroxide back to oxygen and also sequentially drives hydrogen peroxide and water through the common catalytic site. X-ray crystallography has shown that uric acid first binds to the active site as a monoanion, and is then deprotonated to a dianion. The dianion is stabilized by Arg 176 and Gln 228 of the enzyme. Oxygen will subsequently accept an electron pair from the uric acid dianion and be converted to hydrogen peroxide, which is replaced by water that performs a nucleophilic attack on the intermediate to produce 5-hydroxyisourate.
Urate oxidase is known to be inhibited by both cyanide and chloride ions. This occurs because of anion-π interactions between the inhibitor and the uric acid substrate.
# Significance of absence in humans
Urate oxidase is found in nearly all organisms, from bacteria to mammals, but is inactive in humans and several other great apes, having been lost in early primate evolution. This means that instead of producing allantoin as the end product of purine oxidation, the pathway ends with uric acid. This leads to humans having much higher and more highly variable levels of urate in the blood than most other mammals.
Genetically, the loss of urate oxidase function in humans was caused by two nonsense mutations at codons 33 and 187 and an aberrant splice site.
It has been proposed that the loss of urate oxidase gene expression has been advantageous to hominids, since uric acid is a powerful antioxidant and scavenger of singlet oxygen and radicals. Its presence provides the body with protection from oxidative damage, thus prolonging life and decreasing age-specific cancer rates.
However, uric acid plays a complex physiological role in several processes, including inflammation and danger signalling, and modern purine-rich diets can lead to hyperuricaemia, which is linked to many diseases including an increased risk of developing gout.
# Disease relevance
Urate oxidase is formulated as a protein drug (rasburicase) for the treatment of acute hyperuricemia in patients receiving chemotherapy. A PEGylated form of urate oxidase, pegloticase, was FDA approved in 2010 for the treatment of chronic gout in adult patients refractory to "conventional therapy".
Children with non-Hodgkin's lymphoma (NHL), specifically with Burkitt's lymphoma and B-cell acute lymphoblastic leukemia (B-ALL), often experience tumor lysis syndrome (TLS), which occurs when breakdown of tumor cells by chemotherapy releases uric acid and cause the formation of uric acid crystals in the renal tubules and collecting ducts. This can lead to kidney failure and even death. Studies suggest that patients at a high risk of developing TLS may benefit from the administration of urate oxidase. However, humans lack the subsequent enzyme HIU hydroxylase in the pathway to degrade uric acid to allantoin, so long-term urate oxidase therapy could potentially have harmful effects because of toxic effects of HIU.
Higher uric acid levels have also been associated with epilepsy. However, it was found in mouse models that disrupting urate oxidase actually decreases brain excitability and susceptibility to seizures.
Graft-versus-host disease (GVHD) is often a side effect of allogeneic hematopoietic stem cell transplantation (HSCT), driven by donor T cells destroying host tissue. Uric acid has been shown to increase T cell response, so clinical trials have shown that urate oxidase can be administered to decrease uric acid levels in the patient and subsequently decrease the likelihood of GVHD.
# In legumes
UO is also an essential enzyme in the ureide pathway, where nitrogen fixation occurs in the root nodules of legumes. The fixed nitrogen is converted to metabolites that are transported from the roots throughout the plant to provide the needed nitrogen for amino acid biosynthesis.
In legumes, 2 forms of uricase are found: in the roots, the tetrameric form; and, in the uninfected cells of root nodules, a monomeric form, which plays an important role in nitrogen-fixation.
|
Urate oxidase
The enzyme urate oxidase (UO), or uricase or factor-independent urate hydroxylase, absent in humans, catalyzes the oxidation of uric acid to 5-hydroxyisourate:[1]
# Structure
Urate oxidase is mainly localised in the liver, where it forms a large electron-dense paracrystalline core in many peroxisomes.[2] The enzyme exists as a tetramer of identical subunits, each containing a possible type 2 copper-binding site.[3]
Urate oxidase is a homotetrameric enzyme containing four identical active sites situated at the interfaces between its four subunits. UO from A. flavus is made up of 301 residues and has a molecular weight of 33438 daltons. It is unique among the oxidases in that it does not require a metal atom or an organic co-factor for catalysis. Sequence analysis of several organisms has determined that there are 24 amino acids which are conserved, and of these, 15 are involved with the active site.
# Reaction mechanism
Urate oxidase is the first in a pathway of three enzymes to convert uric acid to S-(+)-allantoin. After uric acid is converted to 5-hydroxyisourate by urate oxidase, 5-hydroxyisourate (HIU) is converted to 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline (OHCU) by HIU hydrolase, and then to S-(+)-allantoin by 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline decarboxylase (OHCU decarboxylase). Without HIU hydrolase and OHCU decarboxylase, HIU will spontaneously decompose into racemic allantoin.[4]
Within the active site of urate oxidase, there is a catalytic site that holds uric acid and its analogues in the same orientation and a common catalytic site where oxygen, water, and hydrogen peroxide are sequentially driven. This mechanism is similar to that of catalase, which reverses hydrogen peroxide back to oxygen and also sequentially drives hydrogen peroxide and water through the common catalytic site.[5] X-ray crystallography has shown that uric acid first binds to the active site as a monoanion, and is then deprotonated to a dianion. The dianion is stabilized by Arg 176 and Gln 228 of the enzyme.[6] Oxygen will subsequently accept an electron pair from the uric acid dianion and be converted to hydrogen peroxide, which is replaced by water that performs a nucleophilic attack on the intermediate to produce 5-hydroxyisourate.[7]
Urate oxidase is known to be inhibited by both cyanide and chloride ions. This occurs because of anion-π interactions between the inhibitor and the uric acid substrate.[8]
# Significance of absence in humans
Urate oxidase is found in nearly all organisms, from bacteria to mammals, but is inactive in humans and several other great apes, having been lost in early primate evolution[3]. This means that instead of producing allantoin as the end product of purine oxidation, the pathway ends with uric acid. This leads to humans having much higher and more highly variable levels of urate in the blood than most other mammals.[9]
Genetically, the loss of urate oxidase function in humans was caused by two nonsense mutations at codons 33 and 187 and an aberrant splice site.[10]
It has been proposed that the loss of urate oxidase gene expression has been advantageous to hominids, since uric acid is a powerful antioxidant and scavenger of singlet oxygen and radicals.[11] Its presence provides the body with protection from oxidative damage, thus prolonging life and decreasing age-specific cancer rates.
However, uric acid plays a complex physiological role in several processes, including inflammation and danger signalling[12], and modern purine-rich diets can lead to hyperuricaemia, which is linked to many diseases including an increased risk of developing gout.[13]
# Disease relevance
Urate oxidase is formulated as a protein drug (rasburicase) for the treatment of acute hyperuricemia in patients receiving chemotherapy. A PEGylated form of urate oxidase, pegloticase, was FDA approved in 2010 for the treatment of chronic gout in adult patients refractory to "conventional therapy".[14]
Children with non-Hodgkin's lymphoma (NHL), specifically with Burkitt's lymphoma and B-cell acute lymphoblastic leukemia (B-ALL), often experience tumor lysis syndrome (TLS), which occurs when breakdown of tumor cells by chemotherapy releases uric acid and cause the formation of uric acid crystals in the renal tubules and collecting ducts. This can lead to kidney failure and even death. Studies suggest that patients at a high risk of developing TLS may benefit from the administration of urate oxidase.[15] However, humans lack the subsequent enzyme HIU hydroxylase in the pathway to degrade uric acid to allantoin, so long-term urate oxidase therapy could potentially have harmful effects because of toxic effects of HIU.[16]
Higher uric acid levels have also been associated with epilepsy. However, it was found in mouse models that disrupting urate oxidase actually decreases brain excitability and susceptibility to seizures.[17]
Graft-versus-host disease (GVHD) is often a side effect of allogeneic hematopoietic stem cell transplantation (HSCT), driven by donor T cells destroying host tissue. Uric acid has been shown to increase T cell response, so clinical trials have shown that urate oxidase can be administered to decrease uric acid levels in the patient and subsequently decrease the likelihood of GVHD.[18]
# In legumes
UO is also an essential enzyme in the ureide pathway, where nitrogen fixation occurs in the root nodules of legumes. The fixed nitrogen is converted to metabolites that are transported from the roots throughout the plant to provide the needed nitrogen for amino acid biosynthesis.
In legumes, 2 forms of uricase are found: in the roots, the tetrameric form; and, in the uninfected cells of root nodules, a monomeric form, which plays an important role in nitrogen-fixation.[19]
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https://www.wikidoc.org/index.php/Urate_oxidase
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bdedbe670dd73500a15b97639547da5ab187213e
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wikidoc
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UserExamQuery
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UserExamQuery
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63f3915b873699da391252703ffc9519ab4dfe98
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wikidoc
|
Ustilaginales
|
Ustilaginales
Ustilaginales is an order of fungi within the class Ustilaginomycetes.
The order Ustinaginales is also known and classified as the "smut fungi"
# Morphology
Has a thick-walled resting spore (teliospore), known as the "brand" (burn) spore or chlamydospore.
# Economic Importance
Ustilaginales are serious plant pathogens, with only the dikaryotic stage being obligately parasitic.
|
Ustilaginales
Ustilaginales is an order of fungi within the class Ustilaginomycetes.
The order Ustinaginales is also known and classified as the "smut fungi"
# Morphology
Has a thick-walled resting spore (teliospore), known as the "brand" (burn) spore or chlamydospore.
# Economic Importance
Ustilaginales are serious plant pathogens, with only the dikaryotic stage being obligately parasitic.
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https://www.wikidoc.org/index.php/Ustilaginales
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5d52473d55ae108a2766bfffa375f294e597b0f4
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wikidoc
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Uterine atony
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Uterine atony
Synonyms and keywords:
# Overview
Physiologically, contraction of the myometrium occurs in response to oxytocin, therefore, mediates the uterine hemostasis by mechanically compressing the blood vessels supplying the placenta. The uterine atony is caused by inadequate contraction of the myometrium following the delivery. Uterine atony must be differentiated from other diseases that cause postpartum hemorrhage, such as retained placental tissue, obstetric lacerations, placenta accreta spectrum (placenta accreta, increta, and percreta), uterine inversion, maternal coagulation defects, and disseminated intravascular coagulation (DIC). Uterine atony is responsible for up to 80% of cases of postpartum hemorrhage, and approximately 25% of maternal deaths are due to postpartum hemorrhage, which is the leading cause of maternal deaths. The presence of a large, soft and boggy uterus on physical examination is highly suggestive of uterine atony. The mainstay of treatment for uterine atony is bimanual uterine massage with the administration of oxytocin (IV or IM) simultaneously. If oxytocin fails, second-line pharmacologic agents (methylergonovine or carboprost) should be considered. If medical therapy fails, surgical procedures such as uterine compression sutures (brace sutures) should be considered.
# Historical Perspective
In 1953, Du Vigneaud et al. were the first to discover the aminoacid sequence of oxytocin and its biochemical synthesis. Following his discoveries about polypeptide hormones, The Nobel Prize for chemistry was awarded to Vincent du Vigneaud in 1955.
# Classification
There is no established system for the classification of uterine atony.
# Pathophysiology
It is thought that the uterine atony is caused by inadequate contraction of the myometrium following the delivery. Physiologically, contraction of the myometrium occurs in response to oxytocin, therefore, mediates the uterine hemostasis by mechanically compressing the blood vessels supplying the placenta.
# Causes and Risk Factors
Common risk factors in the development of uterine atony include:
- Uterine overdistention
Polyhydramnios
Multiple pregnancy
Macrosomia
- Polyhydramnios
- Multiple pregnancy
- Macrosomia
- Intrinsic factors
Advanced maternal age
Obesity
Maternal race/ethnicity (Hispanic and non-Hispanic white)
Previous postpartum hemorrhage
Anemia
Preeclampsia
Fibroids
- Advanced maternal age
- Obesity
- Maternal race/ethnicity (Hispanic and non-Hispanic white)
- Previous postpartum hemorrhage
- Anemia
- Preeclampsia
- Fibroids
- Delivery-related factors
Prolonged labor
Precipitate labor
Prolonged use of oxytocin
Induction of labor
Manual removal of placenta
- Prolonged labor
- Precipitate labor
- Prolonged use of oxytocin
- Induction of labor
- Manual removal of placenta
- Chorioamnionitis
- Administration of magnesium sulfate
- Administration of inhaled anesthetic agents
# Differentiating Uterine Atony from other Diseases
Uterine atony must be differentiated from other diseases that cause postpartum hemorrhage, such as retained placental tissue, obstetric lacerations, placenta accreta spectrum (placenta accreta, increta, and percreta), uterine inversion, maternal coagulation defects, and disseminated intravascular coagulation (DIC)
- Detection of the uterine atony might be challenging in the presence of uterine inversion which causes the absence of typical findings of uterine atony such as soft and boggy uterus. The specific finding of uterine inversion is a visible protruding mass through the vagina.
# Epidemiology and Demographics
Uterine atony is responsible for up to 80% of cases of postpartum hemorrhage, and approximately 25% of maternal deaths are due to postpartum hemorrhage, which is the leading cause of maternal deaths.
# Screening
There is insufficient evidence to recommend routine screening for uterine atony. However, identifying the risk factors might provide a better prediction of women at risk for uterine atony, therefore, planning and preparation might be provided more sufficiently.
# Natural History, Complications, and Prognosis
- Previous history of postpartum hemorrhage increases the risk of recurrence by up to 15% in the next pregnancy.
- Common complications of uterine atony include:
Postpartum anemia
Hypovolemic shock
Disseminated intravascular coagulation (DIC)
Transfusion-associated morbidities (transfusion-related acute lung injury (TRALI), transfusion-associated volume overload)
Acute respiratory distress syndrome (ARDS)
Uterine necrosis
Sheehan syndrome
- Postpartum anemia
- Hypovolemic shock
- Disseminated intravascular coagulation (DIC)
- Transfusion-associated morbidities (transfusion-related acute lung injury (TRALI), transfusion-associated volume overload)
- Acute respiratory distress syndrome (ARDS)
- Uterine necrosis
- Sheehan syndrome
# Diagnosis
## Diagnostic Study of Choice
For the diagnostic definition of postpartum hemorrhage, click here.
## History and Symptoms
- A detailed prenatal history is important for the detection of risk factors in the development of uterine atony.
- The hallmark of postpartum hemorrhage is hypovolemia. For more symptoms of postpartum hemorrhage, click here.
## Physical Examination
Abdominal examination by palpation is one of the main methods of physical examination in the diagnosis of uterine atony. Palpation of the uterus might be either direct (following the cesarean delivery) or indirect (bimanual examination after the vaginal delivery).
- The presence of a large, soft and boggy uterus on physical examination is highly suggestive of uterine atony.
- In case of focal localized atony of the uterine lower segments with normal contraction of uterine fundus, it might be challenging to detect the uterine atony with abdominal examination. Thus, manual exploration of the uterine cavity or ultrasound imaging might be useful in suspected cases.
## Laboratory Findings
Laboratory findings consistent with the diagnosis of uterine atony include a decreased concentration of hemoglobin and hematocrit.
- Severe anemia (Hb ⩽ 7 g/dl) might decrease the ability of contraction of the myometrium. Therefore, low maternal hemoglobin levels at the beginning of the delivery might predict the possibility and the severity of the uterine atony.
## Electrocardiogram
There are no ECG findings associated with uterine atony.
## X-ray
There are no x-ray findings associated with uterine atony.
## Ultrasound
Ultrasound may be helpful in the diagnosis of uterine atony. Findings on ultrasound suggestive of uterine atony include echogenic endometrial stripe and intrauterine blood clots with no intrinsic vascularity.
- On the other hand, findings on ultrasound suggestive of retained products of conception, which is another cause of postpartum hemorrhage, include intrauterine mass with intrinsic vascularity.
## CT scan
Dynamic CT (dCT) scan may be helpful in the detection of intractable uterine atony. Findings on dCT scan suggestive of intractable uterine atony include arterial contrast extravasation and significant difference of size and shape between the upper and lower uterine cavity.
- The eventual requirement of embolization might be predicted by the presence of arterial contrast extravasation on dynamic CT scan.
## MRI
There are no MRI findings associated with uterine atony.
## Other Imaging Findings
There are no other imaging findings associated with uterine atony.
## Other Diagnostic Studies
There are no other diagnostic studies associated with uterine atony.
# Treatment
## Medical Therapy
The mainstay of treatment for uterine atony is bimanual uterine massage with the administration of oxytocin (IV or IM) simultaneously.
- It is thought that the stimulation of uterine contractions can be mediated by bimanual uterine massage by the secretion of endogenous prostaglandins.
If oxytocin fails, second-line pharmacologic agents (methylergonovine or carboprost) should be considered.
- Methylergonovine is generally preferred as a second-line pharmacologic treatment. However, it should be avoided in patients with hypertension and cardiovascular diseases.
- Carboprost should be avoided in patients with asthma, cardiovascular diseases, hepatic diseases, and renal diseases.
If pharmacotherapy fails, uterine compression sutures or placement of a uterine balloon tamponade (success rate >85%) such as Bakri balloon tamponade may be considered.
## Surgery
Surgery is not the first-line treatment option for patients with uterine atony. Surgery is usually reserved for patients with bleeding resistant to the medical therapy.
- Uterine compression sutures (brace sutures) such as the B-Lynch method is recommended in patients with uterine atony resistant to the medical therapy (bimanual uterine massage, administration of uterotonic agents, etc.).
Possible complications of uterine compression sutures include intrauterine synechiae and uterine necrosis.
- Possible complications of uterine compression sutures include intrauterine synechiae and uterine necrosis.
- If uterine compression sutures or balloon tamponades fail, bilateral uterine artery ligation should be considered as a next step treatment approach.
- If the bleeding is still poorly controlled, the next step should be the ligation of the bilateral utero-ovarian artery.
- If the bleeding continues, ligation of the internal iliac artery should be considered.
- If all the abovementioned procedures are not successful for the bleeding control (might be considered at an earlier step for patients without fertility desires), hysterectomy (total or supracervical) should be considered as a life-saving measure.
Possible complications of hysterectomy include infections of the female genitourinary system, venous thromboembolism, ileus, postoperative hemorrhage, Clostridium difficile infection, bowel injuries, urinary tract injuries, vaginal cuff dehiscence, urinary incontinence, sexual dysfunction, hormonal changes, anorectal injuries, and nerve injuries with neuropathies.
- Possible complications of hysterectomy include infections of the female genitourinary system, venous thromboembolism, ileus, postoperative hemorrhage, Clostridium difficile infection, bowel injuries, urinary tract injuries, vaginal cuff dehiscence, urinary incontinence, sexual dysfunction, hormonal changes, anorectal injuries, and nerve injuries with neuropathies.
## Prevention
For the prevention of postpartum hemorrhage, click here.
|
Uterine atony
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adnan Ezici, M.D[2]
Synonyms and keywords:
# Overview
Physiologically, contraction of the myometrium occurs in response to oxytocin, therefore, mediates the uterine hemostasis by mechanically compressing the blood vessels supplying the placenta. The uterine atony is caused by inadequate contraction of the myometrium following the delivery. Uterine atony must be differentiated from other diseases that cause postpartum hemorrhage, such as retained placental tissue, obstetric lacerations, placenta accreta spectrum (placenta accreta, increta, and percreta), uterine inversion, maternal coagulation defects, and disseminated intravascular coagulation (DIC). Uterine atony is responsible for up to 80% of cases of postpartum hemorrhage, and approximately 25% of maternal deaths are due to postpartum hemorrhage, which is the leading cause of maternal deaths. The presence of a large, soft and boggy uterus on physical examination is highly suggestive of uterine atony. The mainstay of treatment for uterine atony is bimanual uterine massage with the administration of oxytocin (IV or IM) simultaneously. If oxytocin fails, second-line pharmacologic agents (methylergonovine or carboprost) should be considered. If medical therapy fails, surgical procedures such as uterine compression sutures (brace sutures) should be considered.
# Historical Perspective
In 1953, Du Vigneaud et al. were the first to discover the aminoacid sequence of oxytocin and its biochemical synthesis. Following his discoveries about polypeptide hormones, The Nobel Prize for chemistry was awarded to Vincent du Vigneaud in 1955.[1][2]
# Classification
There is no established system for the classification of uterine atony.
# Pathophysiology
It is thought that the uterine atony is caused by inadequate contraction of the myometrium following the delivery. Physiologically, contraction of the myometrium occurs in response to oxytocin, therefore, mediates the uterine hemostasis by mechanically compressing the blood vessels supplying the placenta.[3]
# Causes and Risk Factors
Common risk factors in the development of uterine atony include:[4][5][6]
- Uterine overdistention
Polyhydramnios
Multiple pregnancy
Macrosomia
- Polyhydramnios
- Multiple pregnancy
- Macrosomia
- Intrinsic factors
Advanced maternal age
Obesity
Maternal race/ethnicity (Hispanic and non-Hispanic white)
Previous postpartum hemorrhage
Anemia
Preeclampsia
Fibroids
- Advanced maternal age
- Obesity
- Maternal race/ethnicity (Hispanic and non-Hispanic white)
- Previous postpartum hemorrhage
- Anemia
- Preeclampsia
- Fibroids
- Delivery-related factors
Prolonged labor
Precipitate labor
Prolonged use of oxytocin
Induction of labor
Manual removal of placenta
- Prolonged labor
- Precipitate labor
- Prolonged use of oxytocin
- Induction of labor
- Manual removal of placenta
- Chorioamnionitis
- Administration of magnesium sulfate
- Administration of inhaled anesthetic agents
# Differentiating Uterine Atony from other Diseases
Uterine atony must be differentiated from other diseases that cause postpartum hemorrhage, such as retained placental tissue, obstetric lacerations, placenta accreta spectrum (placenta accreta, increta, and percreta), uterine inversion, maternal coagulation defects, and disseminated intravascular coagulation (DIC)[7]
- Detection of the uterine atony might be challenging in the presence of uterine inversion which causes the absence of typical findings of uterine atony such as soft and boggy uterus. The specific finding of uterine inversion is a visible protruding mass through the vagina.[3]
# Epidemiology and Demographics
Uterine atony is responsible for up to 80% of cases of postpartum hemorrhage, and approximately 25% of maternal deaths are due to postpartum hemorrhage, which is the leading cause of maternal deaths.[4][8]
# Screening
There is insufficient evidence to recommend routine screening for uterine atony. However, identifying the risk factors might provide a better prediction of women at risk for uterine atony, therefore, planning and preparation might be provided more sufficiently.[4]
# Natural History, Complications, and Prognosis
- Previous history of postpartum hemorrhage increases the risk of recurrence by up to 15% in the next pregnancy.[3]
- Common complications of uterine atony include:[9][10][3]
Postpartum anemia
Hypovolemic shock
Disseminated intravascular coagulation (DIC)
Transfusion-associated morbidities (transfusion-related acute lung injury (TRALI), transfusion-associated volume overload)
Acute respiratory distress syndrome (ARDS)
Uterine necrosis
Sheehan syndrome
- Postpartum anemia
- Hypovolemic shock
- Disseminated intravascular coagulation (DIC)
- Transfusion-associated morbidities (transfusion-related acute lung injury (TRALI), transfusion-associated volume overload)
- Acute respiratory distress syndrome (ARDS)
- Uterine necrosis
- Sheehan syndrome
# Diagnosis
## Diagnostic Study of Choice
For the diagnostic definition of postpartum hemorrhage, click here.
## History and Symptoms
- A detailed prenatal history is important for the detection of risk factors in the development of uterine atony.[3]
- The hallmark of postpartum hemorrhage is hypovolemia. For more symptoms of postpartum hemorrhage, click here.
## Physical Examination
Abdominal examination by palpation is one of the main methods of physical examination in the diagnosis of uterine atony. Palpation of the uterus might be either direct (following the cesarean delivery) or indirect (bimanual examination after the vaginal delivery).[3]
- The presence of a large, soft and boggy uterus on physical examination is highly suggestive of uterine atony.[11]
- In case of focal localized atony of the uterine lower segments with normal contraction of uterine fundus, it might be challenging to detect the uterine atony with abdominal examination. Thus, manual exploration of the uterine cavity or ultrasound imaging might be useful in suspected cases.
## Laboratory Findings
Laboratory findings consistent with the diagnosis of uterine atony include a decreased concentration of hemoglobin and hematocrit.[12]
- Severe anemia (Hb ⩽ 7 g/dl) might decrease the ability of contraction of the myometrium. Therefore, low maternal hemoglobin levels at the beginning of the delivery might predict the possibility and the severity of the uterine atony.[13]
## Electrocardiogram
There are no ECG findings associated with uterine atony.
## X-ray
There are no x-ray findings associated with uterine atony.
## Ultrasound
Ultrasound may be helpful in the diagnosis of uterine atony. Findings on ultrasound suggestive of uterine atony include echogenic endometrial stripe and intrauterine blood clots with no intrinsic vascularity.[14]
- On the other hand, findings on ultrasound suggestive of retained products of conception, which is another cause of postpartum hemorrhage, include intrauterine mass with intrinsic vascularity.
## CT scan
Dynamic CT (dCT) scan may be helpful in the detection of intractable uterine atony. Findings on dCT scan suggestive of intractable uterine atony include arterial contrast extravasation and significant difference of size and shape between the upper and lower uterine cavity.[15]
- The eventual requirement of embolization might be predicted by the presence of arterial contrast extravasation on dynamic CT scan.
## MRI
There are no MRI findings associated with uterine atony.
## Other Imaging Findings
There are no other imaging findings associated with uterine atony.
## Other Diagnostic Studies
There are no other diagnostic studies associated with uterine atony.
# Treatment
## Medical Therapy
The mainstay of treatment for uterine atony is bimanual uterine massage with the administration of oxytocin (IV or IM) simultaneously.[9]
- It is thought that the stimulation of uterine contractions can be mediated by bimanual uterine massage by the secretion of endogenous prostaglandins.
If oxytocin fails, second-line pharmacologic agents (methylergonovine or carboprost) should be considered.
- Methylergonovine is generally preferred as a second-line pharmacologic treatment. However, it should be avoided in patients with hypertension and cardiovascular diseases.
- Carboprost should be avoided in patients with asthma, cardiovascular diseases, hepatic diseases, and renal diseases.
If pharmacotherapy fails, uterine compression sutures or placement of a uterine balloon tamponade (success rate >85%) such as Bakri balloon tamponade may be considered.
## Surgery
Surgery is not the first-line treatment option for patients with uterine atony. Surgery is usually reserved for patients with bleeding resistant to the medical therapy.[9]
- Uterine compression sutures (brace sutures) such as the B-Lynch method is recommended in patients with uterine atony resistant to the medical therapy (bimanual uterine massage, administration of uterotonic agents, etc.).
Possible complications of uterine compression sutures include intrauterine synechiae and uterine necrosis.
- Possible complications of uterine compression sutures include intrauterine synechiae and uterine necrosis.
- If uterine compression sutures or balloon tamponades fail, bilateral uterine artery ligation should be considered as a next step treatment approach.
- If the bleeding is still poorly controlled, the next step should be the ligation of the bilateral utero-ovarian artery.
- If the bleeding continues, ligation of the internal iliac artery should be considered.
- If all the abovementioned procedures are not successful for the bleeding control (might be considered at an earlier step for patients without fertility desires), hysterectomy (total or supracervical) should be considered as a life-saving measure.
Possible complications of hysterectomy include infections of the female genitourinary system, venous thromboembolism, ileus, postoperative hemorrhage, Clostridium difficile infection, bowel injuries, urinary tract injuries, vaginal cuff dehiscence, urinary incontinence, sexual dysfunction, hormonal changes, anorectal injuries, and nerve injuries with neuropathies.[16]
- Possible complications of hysterectomy include infections of the female genitourinary system, venous thromboembolism, ileus, postoperative hemorrhage, Clostridium difficile infection, bowel injuries, urinary tract injuries, vaginal cuff dehiscence, urinary incontinence, sexual dysfunction, hormonal changes, anorectal injuries, and nerve injuries with neuropathies.[16]
## Prevention
For the prevention of postpartum hemorrhage, click here.
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https://www.wikidoc.org/index.php/Uterine_atony
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4cb76cac616ac03b831aaa42bd667a5af12a1025
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wikidoc
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Uterine polyp
|
Uterine polyp
# Overview
An endometrial polyp or uterine polyp is a polyp or lesion in the lining of the uterus (endometrium) that takes up space within the uterine cavity. Commonly occurring, they are experienced by up to 10% of women. They may have a large flat base (sessile) or be attached to the uterus by an elongated pedicle (pedunculated). Pedunculated polyps are more common than sessile ones. They range in size from a few millimeters to several centimeters. If pedunculated, they can protrude through the cervix into the vagina. Small blood vessels may be present, particularly in large polyps.
# Cause and symptoms
No definitive cause of endometrial polyps is known, but they appear to be affected by hormone levels and grow in response to circulating estrogen. They often cause no symptoms. Where they occur, symptoms include irregular menstrual bleeding, bleeding between menstrual periods, excessively heavy menstrual bleeding (menorrhagia), and vaginal bleeding after menopause. Bleeding from the blood vessels of the polyp contributes to an increase of blood loss during menstruation and blood "spotting" between menstrual periods, or after menopause. If the polyp protrudes through the cervix into the vagina, pain (dysmenorrhea) may result.
# Diagnosis
Endometrial polyps can be detected by vaginal ultrasound (sonohysterography), hysteroscopy and dilation and curettage. Detection by ultrasonography can be difficult, particularly when there is endometrial hyperplasia (excessive thickening of the endometrium). Larger polyps may be missed by curettage.
# Treatment
Polyps can be surgically removed using curettage or hysterescopy. When curettage is performed, polyps may be missed. To reduce this risk, the uterus can be first explored using grasping forceps at the beginning of the curettage procedure. During hysterescopy, the polyp can be visualized and removed through the cervix. If it is a large polyp, it can be cut into sections before each section is removed. If cancerous cells are discovered, a hysterectomy may be performed. A hysterectomy would usually not be considered if cancer has been ruled out. Whichever method is used, polyps are usually treated under general anesthetic.
# Prognosis and complications
Endometrial polyps are usually benign although some may be precancerous or cancerous. About 0.5% of endometrial polyps contain adenocarcinoma cells. Polyps can increase the risk of miscarriage in women undergoing IVF treatment. If they develop near the fallopian tubes, they may lead to difficulty in becoming pregnant. Although treatments such as hysterescopy usually cure the polyp concerned, recurrence of endometrial polyps is frequent. Untreated, small polyps may regress on their own.
# Risk factors and epidemiology
Endometrial polyps usually occur in women in their 40s and 50s. Risk factors include obesity, high blood pressure and a history of cervical polyps. Taking tamoxifen or hormone replacement therapy can also increase the risk of uterine polyps. The use of an IntraUterine System containing levonorgestrel in women taking Tamoxifen may reduce the incidence of polyps. Endometrial polyps occur in up to 10% of women. It is estimated that they are present in 25% of women with abnormal vaginal bleeding.
# Structure
Endometrial polyps can be solitary or occur with others. They are round or oval and measure between a few millimeters to several centimeters in diameter. They are usually the same red/brown color of the surrounding endometrium although large ones can appear to be a darker red. The polyps consist of dense, fibrous tissue (stroma), blood vessels and glandlike spaces lined with endometrial epithelium. If they are pedunculated, they are attached by a thin stalk (pedicle). If they are sessile, they are connected by a flat base to the uterine wall. Pedunculated polyps are more common than sessile ones.
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Uterine polyp
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
An endometrial polyp or uterine polyp is a polyp or lesion in the lining of the uterus (endometrium) that takes up space within the uterine cavity. Commonly occurring, they are experienced by up to 10% of women.[1] They may have a large flat base (sessile) or be attached to the uterus by an elongated pedicle (pedunculated).[1][2] Pedunculated polyps are more common than sessile ones.[3] They range in size from a few millimeters to several centimeters.[2] If pedunculated, they can protrude through the cervix into the vagina.[1][4] Small blood vessels may be present, particularly in large polyps.[1]
# Cause and symptoms
No definitive cause of endometrial polyps is known, but they appear to be affected by hormone levels and grow in response to circulating estrogen.[2] They often cause no symptoms.[3] Where they occur, symptoms include irregular menstrual bleeding, bleeding between menstrual periods, excessively heavy menstrual bleeding (menorrhagia), and vaginal bleeding after menopause.[2][5] Bleeding from the blood vessels of the polyp contributes to an increase of blood loss during menstruation and blood "spotting" between menstrual periods, or after menopause.[6] If the polyp protrudes through the cervix into the vagina, pain (dysmenorrhea) may result.[4]
# Diagnosis
Endometrial polyps can be detected by vaginal ultrasound (sonohysterography), hysteroscopy and dilation and curettage.[2] Detection by ultrasonography can be difficult, particularly when there is endometrial hyperplasia (excessive thickening of the endometrium).[1] Larger polyps may be missed by curettage.[7]
# Treatment
Polyps can be surgically removed using curettage or hysterescopy.[8] When curettage is performed, polyps may be missed. To reduce this risk, the uterus can be first explored using grasping forceps at the beginning of the curettage procedure.[6] During hysterescopy, the polyp can be visualized and removed through the cervix. If it is a large polyp, it can be cut into sections before each section is removed.[6] If cancerous cells are discovered, a hysterectomy may be performed.[2] A hysterectomy would usually not be considered if cancer has been ruled out.[6] Whichever method is used, polyps are usually treated under general anesthetic.[7]
# Prognosis and complications
Endometrial polyps are usually benign although some may be precancerous or cancerous.[2] About 0.5% of endometrial polyps contain adenocarcinoma cells.[9] Polyps can increase the risk of miscarriage in women undergoing IVF treatment.[2] If they develop near the fallopian tubes, they may lead to difficulty in becoming pregnant.[2] Although treatments such as hysterescopy usually cure the polyp concerned, recurrence of endometrial polyps is frequent.[6] Untreated, small polyps may regress on their own.[10]
# Risk factors and epidemiology
Endometrial polyps usually occur in women in their 40s and 50s.[2] Risk factors include obesity, high blood pressure and a history of cervical polyps.[2] Taking tamoxifen or hormone replacement therapy can also increase the risk of uterine polyps.[2][11] The use of an IntraUterine System containing levonorgestrel in women taking Tamoxifen may reduce the incidence of polyps.[12] Endometrial polyps occur in up to 10% of women.[1] It is estimated that they are present in 25% of women with abnormal vaginal bleeding.[11]
# Structure
Endometrial polyps can be solitary or occur with others.[13] They are round or oval and measure between a few millimeters to several centimeters in diameter.[13][6] They are usually the same red/brown color of the surrounding endometrium although large ones can appear to be a darker red.[6] The polyps consist of dense, fibrous tissue (stroma), blood vessels and glandlike spaces lined with endometrial epithelium.[6] If they are pedunculated, they are attached by a thin stalk (pedicle). If they are sessile, they are connected by a flat base to the uterine wall.[13] Pedunculated polyps are more common than sessile ones.[3]
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https://www.wikidoc.org/index.php/Uterine_polyp
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673d8524def51304b5caf280f5947aec75ad0490
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wikidoc
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VEGF receptor
|
VEGF receptor
VEGF receptors are receptors for vascular endothelial growth factor (VEGF). There are three main subtypes of VEGFR, numbered 1, 2 and 3. Also, they may be membrane-bound (mbVEGFR) or soluble (sVEGFR), depending on alternative splicing.
Inhibitors of VEGFR are used in the treatment of cancer.
# VEGF
Vascular endothelial growth factor (VEGF) is an important signaling protein involved in both vasculogenesis (the formation of the circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature). As its name implies, VEGF activity is restricted mainly to cells of the vascular endothelium, although it does have effects on a limited number of other cell types (e.g. stimulation monocyte/macrophage migration). In vitro, VEGF has been shown to stimulate endothelial cell mitogenesis and cell migration. VEGF also enhances microvascular permeability and is sometimes referred to as vascular permeability factor.
# Receptor biology
All members of the VEGF family stimulate cellular responses by binding to tyrosine kinase receptors (the VEGFRs) on the cell surface, causing them to dimerize and become activated through transphosphorylation. The VEGF receptors have an extracellular portion consisting of 7 immunoglobulin-like domains, a single transmembrane spanning region and an intracellular portion containing a split tyrosine-kinase domain.
VEGF-A binds to VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF. The function of VEGFR-1 is less well defined, although it is thought to modulate VEGFR-2 signaling. Another function of VEGFR-1 is to act as a dummy/decoy receptor, sequestering VEGF from VEGFR-2 binding (this appears to be particularly important during vasculogenesis in the embryo). In fact, an alternatively spliced form of VEGFR-1 (sFlt1) is not a membrane bound protein but is secreted and functions primarily as a decoy. A third receptor has been discovered (VEGFR-3), however, VEGF-A is not a ligand for this receptor. VEGFR-3 mediates lymphangiogenesis in response to VEGF-C and VEGF-D.
In addition to binding to VEGFRs, TACO VEGF binds to receptor complexes consisting of both neuropilins and VEGFRs. This receptor complex has increased VEGF signalling activity in endothelial cells (blood vessels). Neuropilins (NRP) are pleitrophic receptors and therefore other molecules may interfere with the signalling of the NRP/VEGFR receptor complexes. For example, Class 3 semaphorins compete with VEGF165 for NRP binding and could therefore regulate VEGF-mediated angiogenesis.
# VEGFR antagonists
Some VEGFR antagonists (inhibitors) (for example lenvatinib, motesanib) are under investigation for treating various cancers. Pazopanib was approved for renal cell carcinoma in 2009. Regorafenib was approved for colorectal cancer in Sept 2012.
|
VEGF receptor
VEGF receptors are receptors for vascular endothelial growth factor (VEGF).[1][2] There are three main subtypes of VEGFR, numbered 1, 2 and 3. Also, they may be membrane-bound (mbVEGFR) or soluble (sVEGFR), depending on alternative splicing.[3]
Inhibitors of VEGFR are used in the treatment of cancer.
# VEGF
Vascular endothelial growth factor (VEGF) is an important signaling protein involved in both vasculogenesis (the formation of the circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature). As its name implies, VEGF activity is restricted mainly to cells of the vascular endothelium, although it does have effects on a limited number of other cell types (e.g. stimulation monocyte/macrophage migration). In vitro, VEGF has been shown to stimulate endothelial cell mitogenesis and cell migration. VEGF also enhances microvascular permeability and is sometimes referred to as vascular permeability factor.
# Receptor biology
All members of the VEGF family stimulate cellular responses by binding to tyrosine kinase receptors (the VEGFRs) on the cell surface, causing them to dimerize and become activated through transphosphorylation. The VEGF receptors have an extracellular portion consisting of 7 immunoglobulin-like domains, a single transmembrane spanning region and an intracellular portion containing a split tyrosine-kinase domain.
VEGF-A binds to VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF.[1] The function of VEGFR-1 is less well defined, although it is thought to modulate VEGFR-2 signaling. Another function of VEGFR-1 is to act as a dummy/decoy receptor, sequestering VEGF from VEGFR-2 binding (this appears to be particularly important during vasculogenesis in the embryo). In fact, an alternatively spliced form of VEGFR-1 (sFlt1) is not a membrane bound protein but is secreted and functions primarily as a decoy.[6] A third receptor has been discovered (VEGFR-3), however, VEGF-A is not a ligand for this receptor. VEGFR-3 mediates lymphangiogenesis in response to VEGF-C and VEGF-D.
In addition to binding to VEGFRs, TACO VEGF binds to receptor complexes consisting of both neuropilins and VEGFRs. This receptor complex has increased VEGF signalling activity in endothelial cells (blood vessels).[7][8] Neuropilins (NRP) are pleitrophic receptors and therefore other molecules may interfere with the signalling of the NRP/VEGFR receptor complexes. For example, Class 3 semaphorins compete with VEGF165 for NRP binding and could therefore regulate VEGF-mediated angiogenesis.[9]
# VEGFR antagonists
Some VEGFR antagonists (inhibitors) (for example lenvatinib, motesanib) are under investigation for treating various cancers. Pazopanib was approved for renal cell carcinoma in 2009. Regorafenib was approved for colorectal cancer in Sept 2012.
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https://www.wikidoc.org/index.php/VEGF_receptor
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08974df99a505cb874c2bf4946666aa961260ae7
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wikidoc
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VLDL receptor
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VLDL receptor
The very-low-density-lipoprotein receptor (VLDLR) is a transmembrane lipoprotein receptor of the low-density-lipoprotein (LDL) receptor family. VLDLR shows considerable homology with the members of this lineage. Discovered in 1992 by T. Yamamoto, VLDLR is widely distributed throughout the tissues of the body, including the heart, skeletal muscle, adipose tissue, and the brain, but is absent from the liver. This receptor has an important role in cholesterol uptake, metabolism of apoprotein-E-containing triacylglycerol-rich lipoproteins, and neuronal migration in the developing brain. In humans, VLDLR is encoded by the VLDLR gene. Mutations of this gene may lead to a variety of symptoms and diseases, which include type I lissencephaly, cerebellar hypoplasia, and atherosclerosis.
# Protein structure
VLDLR is a member of the low-density-lipoprotein (LDL) receptor family, which is entirely composed of type I transmembrane lipoprotein receptors.
All members of this family share five highly conserved structural domains: an extracellular N-terminal ligand-binding domain with cysteine-rich repeats (also called ligand-binding repeats), an epidermal growth factor (EGF), an O-linked glycosylation sugar domain, a single transmembrane sequence, and a cytoplasmic domain which contains an NPxY sequence. The NPxY motif functions in signal transduction and the targeting of receptors to coated pits and consists of the sequence Asparagine-Proline-X-Tyrosine, where X can be any amino acid. Mimicking this general structure, VLDLR has eight, 40 amino acid long cysteine-rich repeats in its extracellular N-terminal ligand-binding domain. This is the main difference from the main member of the LDL receptor family, LDLR, which has only seven cysteine-rich repeats which are also 40 amino acids long. Each of these cysteine-rich repeats, in both VLDLR and LDLR, has three disulfide bonds and a coordinated Ca2+ ion. The N-terminus also consists of a glycine residue followed by 27 hydrophobic residues that constitute the signal peptide. Following this region is an EGF repeat, a β-propeller segment that plays a role in the pH-dependent dissociation of the ligand-receptor complex, and two more EGF repeats. The VLDLR O-linked glycosylation domain, next in the sequence, has many threonine and serine residues and totals 46 amino acids. The transmembrane domain, which functions in anchoring the receptors to the membrane, is 22 amino acids long. Final in the sequence is the 54 amino acid cytoplasmic domain, which contains the NPxY motif.
## Isoforms
The full-length human VLDLR genome is located on locus 9p24 on chromosome 9. It consists of a 40 kb segment that includes 19 exon-coding sequences, which is one more exon than encoded by LDLR. This extra exon in the VLDLR gene accounts for the extra cysteine-binding repeat not found in LDLR. Together, the exons making up the VLDLR gene encode a protein that is 873 amino acid residues long. VLDLR is known to exist as four different protein isoforms: type I, II, III, and IV. These different isoforms result from variations in alternative splicing. The transcript of type I VLDLR (VLDLR-I) is composed of all 19 exons. VLDLR-II, on the other hand, lacks exon 16, which encodes for the O-glycosylation domain between sugar regions. VLDLR-III lacks exon 4 that encodes the third ligand-binding repeat. Finally, VLDLR-IV transcripts lack both exon 16 and exon 4. It has been shown that 75% of VLDLR transcripts exist as isoform type II in mouse brain models. This shows that most VLDLRs in the brain are not glycosylated, as type II lacks exon 16 which encodes the O-glycosylation domain. Isoform type IV is known to be the second most prominent.
## Evolutionary conservation
There is a high level of conservation within the LDL receptor family. In particular, there is 50% overall sequence homology between VLDLR and ApoER2, another lipoprotein receptor of this family. Comparing LDLR and VLDLR, it was found that their primary structures are 55% identical within their ligand-binding regions. The modular structures of these two proteins are almost superimposable, with the only difference being the additional cysteine-rich repeat in VLDLR. This is demonstrated through the alignment of the two receptors according to their linker region; in LDLR, the linker region is located between cysteine-rich repeats four and five of its seven repeats while in VLDLR, the linker region appears to be between repeats five and six of its eight repeats.
VLDLR also shows high homology among various species. VLDLR of humans, mice, rats, and rabbits have been identified as 95% identical. Furthermore, there is approximately 84% conservation with the respective protein in chickens. This level of homology between species is much higher than that found for LDLR. Hence, these gene comparisons suggest that VLDLR and LDLR diverged before the LDLRs did among vertebrates.
# Ligand binding
VLDLR binds compounds containing apolipoprotein E (apoE). These ligands attach to the cysteine binding repeats in the N-terminus end. The difference in cysteine-rich repeats between the members of the LDL receptor family lead to the differences in binding affinity. VLDLR, in particular, binds VLDL and intermediate-density lipoprotein (IDL), but not LDL. This inability to bind LDL is due to VLDLR's incapability to bind apolipoprotein B (apoB), which is present in LDL.
## Inhibitors
Receptor-associated protein (RAP) and thrombospondin-1 (THBS1) have been identified as compounds that bind VLDLR. In many cases, these compounds exhibit inhibitory effects. THBS1 binds VLDLR and blocks ligand binding. This plays an important role in the reelin pathway, as THBS1 can block the attachment of reelin, while simultaneously stimulating the transcription factors normally activated by reelin. This binding of THBS1, however, does not induce the subsequent degradation of these transcription factors, as reelin does, and can thus lead to greatly amplified effects. The RAP protein acts similarly by blocking reelin from binding VLDLR. However, in this case phosphorylation of transcription factors, usually performed by reelin, is also blocked.
# Tissue distribution and expression
VLDLR is found throughout the body, with particularly high expression in fatty acid tissues due to their high level of triglycerides, VLDLR’s primary ligand. These tissues include those of the heart, skeletal muscle, and adipose layer. In addition, the receptor is found in macrophages, endothelial cells of capillaries, and in the brain, where it has a very different function from that found in the rest of the body. There is a preferred expression for VLDLR type I in the heart, skeletal muscle and brain, as opposed to type II, which is mainly expressed in non-muscular tissues including the cerebrum, cerebellum, kidney, spleen, and aortic endothelial cells. The highest expression of VLDLR is found in the brain. Although VLDLR is found in almost all regions of the brain, its highest expression is restricted to the cortex and cerebellum. Here, the receptor can be found on resting or activated microglia that are associated with senile plaques and cortical neurons, neuroblasts, matrix cells, Cajal-Retzius cells, glioblasts, astrocytes, oligodendrocytes, and region-specific pyramidal neurons. Despite its major role in cholesterol and fatty acid metabolism, VLDLR is not found in the liver. This phenomenon is mainly attributed to the very high levels of LDLR in these areas. In addition, it has been uncovered that this receptor is found, sub-cellularly, in the non-lipid raft sections of cell membranes.
## Regulation
Unlike LDLR, VLDLR does not exhibit any feedback mechanism, and hence intracellular lipoproteins are incapable of regulating it. This phenomenon is due to a difference in the sterol regulatory element-1 (SRE-1) of VLDLR. Normal SRE-1 sequences, like those found in LDLR, are characterized by two repeats of the codon CAC separated by two intervening C nucleotides (5’-CACCCCAC-3’). The sterol regulatory element-binding protein-1 (SREBP-1), a transcription factor, targets the CAC repeats of SRE-1 to regulate the protein’s transcription. However, the VLDLR gene is encoded by two SRE-1-like sequences that contain single nucleotide polymorphisms. These polymorphisms disrupt the SREBP-1 binding to the CAC repeats, and hence eliminate the feedback mechanism seen in other proteins.
VLDLR expression is regulated by peroxisome proliferator-activated receptor-gamma (PPAR-γ). A 2010 study showed that the prescription drug Pioglitazone, an agonist of PPAR-γ, increases VLDLR mRNA expression and protein levels in experiments using mouse fibroblasts. The Pioglitazone treated mice exhibited a higher conversion rate of plasma triglycerides into epididymal fats. As expected, mice deficient in VLDLR did not show this same response. These results suggest that VLDLR is important in fat accumulation.
Many other hormones and dietary factors also regulate VLDLR expression. Thyroid hormone positively regulates VLDLR expression in skeletal muscles of rats, but not in adipose or heart tissues. In rabbits, VLDLR expression in heart muscle is up-regulated by estrogen and down-regulated by granulocyte-macrophage colony-stimulating factor. In trophoblast-derived cell lines, up-regulated VLDLR expression occurs when cells are incubated with hypolipidemic agents such as insulin and clofibrate. In contrast, 8-bromoadenosine 3',5'-cyclic monophosphate (8-bromo-cAMP) down-regulates VLDLR expression. Finally, VLDLR is affected by the presence of apoE and LDLR. The presence of apoE is required for VLDLR expression regulation, while the absence of LDLR alters the sterol-regulatory-element-1-like sequences of VLDLR to make them functional in only heart and skeletal muscle.
# Function
## Beyond the nervous system
VLDLR is a peripheral lipoprotein receptor that functions in lipoprotein metabolism, cardiac fatty acid metabolism, and fat deposition. In effect, VLDLR will allow cholesterol to reach tissues from the bloodstream, where it may be used in cellular membranes. In addition, it will allow fatty acids to get into cells where they may be used as an energy source. Overall, VLDLR primarily modulates the extra-hepatic metabolism of triglyceride-rich lipoproteins.
### Lipoprotein uptake
VLDLR only plays a discrete role in lipid metabolism, but is more significant in stressed situations. Mice with double knockouts in VLDLR and LDLR have higher serum triglyceride levels than those with only a knockout in the LDLR gene. In addition, LDLR knockout mice overexpressing VLDLR have decreased serum triglyceride levels. Although fat deposition is close to normal without VLDLR, its role gains importance when LDLR is deficient. Despite this knowledge on its role in lipoprotein uptake, the complete mechanism of lipid metabolism performed by VLDLR is not fully understood.
VLDLR is known to employ endocytosis, although the exact mechanism of this process is unknown for this protein. Endocytosis is mediated through NPxY sequences known to signal for receptor internalization through clathrin-coated pits. The presence of this sequence in the cytoplasmic tail of VLDLR makes endocytosis possible. In general, lipoprotein receptors undergo a process by which they are endocytosed with their ligand into clathrin-coated pits. From here, they are together transported to early and late endosomes until reaching the lysosome. At this point, hydrolysis occurs and lipoprotein is released into the cytoplasm while the receptors are recycled back to the cell surface. It is not yet confirmed if VLDLR follows this exact mechanism, but one closely related to it is likely.
## In the nervous system
In addition to its role throughout the body, VLDLR has a unique role in the brain. It is a key component of the reelin pathway, which functions in neuronal migration. VLDLR links the reelin protein to an intracellular signaling protein, Dab1, that tells the individual neurons where to go within the anatomy of the brain. Mutations in VLDLR often do not lead to major disorganization as seen in reelin mutations. However, a VLDLR mutation does lead to some disorganization primarily located in the cerebellum, where VLDLR is believed to be most prominent.
### Neuronal migration
VLDLR is expressed on migrating neurons to help guide them to their proper location in the brain. This process is part of the reelin pathway, which is responsible for the inside-out formation of the six-layered neocortex. Despite the discovery of this pathway, many of the specifics and molecular mechanisms of this process are still being debated. The presence of two reelin receptors, VLDLR and ApoER2, has made it difficult to distinguish each protein’s specific function.
VLDLR is primarily responsible for the correct layering of pyramidal cells into layer 1 of the cerebral cortex. In particular, the absence of VLDLR may lead to ectopic accumulation of pyramidal cells in this region. VLDLR does not affect the migration of early born cells into an organized layer, but since its absence results in the invasion of these neuroblasts into the marginal zone, it is theorized that VLDLR may encode a “stop signal.” This is supported by the fact that VLDLR is primarily expressed in the cortical plate adjacent to reelin-expressing cells, Cajal–Retzius cells, and in the intermediate zone. However, definitive evidence has not yet been found. In general, reelin binds VLDLR and undergoes endocytosis via clathrin-coated vesicles. Meanwhile, an intracellular protein, Dab1, has a PI/PTB domain that interacts with the NPxY sequence found in the cytoplasmic tail of VLDLR. As a result, Dab1 is tyrosine phosphorylated and reelin is degraded. Finally, phosphorylated Dab1 activates an intracellular signaling cascade that directs neuroblasts to their proper location through the alteration of the cytoskeleton. Many of the specifics of this pathway are still being investigated. It is not yet known if Dab1 is phosphorylated as a result of the endocytosis of reelin, or if there is another mechanism at play. In addition to the organization of the neocortex, VLDLR also plays a role in neuronal migration of the hippocampus and the Purkinje cells of the cerebellum. Yet, much information on this process is still unknown.
# Associated disorders
Mutations within the VLDLR gene lead to a multitude of disorders of varying severities. These disorders are usually associated with cholesterol homeostasis or a disorganization of neuron ordering in the brain due to disruption of the reelin pathway. The most prominent of these diseases are type I lissencephaly, VLDR-associated cerebellar hypoplasia, and atherosclerosis. In contrast to causing diseases, VLDLR has also been identified as a possible remedy for some disorders. Implementation of VLDLR into the liver may cure familial hypercholesterolemia (FH) in patients who either have defective LDLR or have defective immune systems that attack this protein. Since VLDLR is non-immunogenic it does not initiate an immune response, thus it is able to function normally under defective immune systems. In addition, being that apoE, a major ligand of VLDLR, is a leading genetic risk factor for Alzheimer’s disease, VLDLR may play a role in modulating the risk of this disorder. VLDLR has also been shown to reduce the chances of premature heart disease and stroke because VLDLR clears out lipoprotein A (Lp(a)), a major inherited risk factor for these diseases.
## Type 1 lissencephaly
Type I lissencephaly, or agyria-pachygyria, is a rare developmental disorder characterized by the absence of gyri and sulci in the brain. These severe malformations are a result of aberrant neuronal migration. In classical type I lissencephaly, neuronal migration begins but is unable to continue to completion. This process is likely disrupted by alterations to several genes, including the VLDLR, DCX, ARX, TUBA1A, RELN and LIS1. The severity of type I lissencephaly therefore varies with the mutation type. A homozygous deletion affecting the VLDLR gene results in a low degree of cortical thickening and absence of a cell-sparse zone. The cell-sparse zone describes the region between the outer and inner cortical layers of arrested neurons. In addition, type 1 lissencephaly is closely associated with cerebellar hypoplasia.
## VLDLR-associated cerebellar hypoplasia
Disequilibrium syndrome (DES) was first described in the 1970s as a non-progressive, neurological disorder. In a 2005 study, DES was renamed as VLDLR-associated cerebellar hypoplasia (VLDLRCH) after its cause was linked to a disruption in the VLDLR gene. At least six mutations affecting the homozygous recessive allele of the VLDLR gene have been identified and found to cause VLDLRCH. Several of these mutations have been localized to specific exons encoding the gene. One such mutation is a cytosine to thymine transition at base pair 1342 in exon 10 that causes a substitution at Arg448 for a termination signal. Likewise, there is evidence of a cytosine to thymine transition at base pair number 769 in exon 5 that causes a substitution at Arg257 for a termination signal. A third known mutation is caused by a homozygous 1-base pair deletion in exon 17 that causes a frameshift and premature termination in the O-linked sugar domain. All such alterations to the VLDLR gene prevent the production of VLDLR and are therefore termed loss-of-function mutations. The recognized symptoms of VLDLRCH are moderate-to-severe intellectual disability, seizures, dysarthria, strabismus and delayed locomotion. In some cases, children with VLDLRCH learn to walk very late in development after the age of six years, or never learn to walk independently. The frequency of this disorder is unknown because early diagnosis of VLDLRCH is difficult using imaging techniques. It is associated with parental consanguinity and found in secluded communities such as the Hutterites and inbred families from Iran and Turkey.
## Atherosclerosis
Atherosclerosis is marked by an excessive accumulation of cholesterol by macrophages, leading to their transformation into foam cells. This accumulation of cholesterol is caused by dysregulation of cholesterol influx and efflux. Since macrophages do not have the ability to limit the influx of cholesterol, the balance is completely dependent on efflux pathways. VLDLR is expressed by macrophages, and functions in the uptake of native lipoproteins. Uniquely, VLDLR does not respond to cholesterol loading, likely due to its lack of feedback mechanisms. The inability to control its uptake of native lipoproteins makes VLDLR a pro-atherogenic factor. This characteristic is supported by results from a 2005 study, in which reintroduction of VLDLR into VLDLR knockout mice led to greatly increased atherosclerotic lesion development.
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VLDL receptor
The very-low-density-lipoprotein receptor (VLDLR) is a transmembrane lipoprotein receptor of the low-density-lipoprotein (LDL) receptor family. VLDLR shows considerable homology with the members of this lineage. Discovered in 1992 by T. Yamamoto, VLDLR is widely distributed throughout the tissues of the body, including the heart, skeletal muscle, adipose tissue, and the brain, but is absent from the liver.[1] This receptor has an important role in cholesterol uptake, metabolism of apoprotein-E-containing triacylglycerol-rich lipoproteins, and neuronal migration in the developing brain. In humans, VLDLR is encoded by the VLDLR gene. Mutations of this gene may lead to a variety of symptoms and diseases, which include type I lissencephaly, cerebellar hypoplasia, and atherosclerosis.
# Protein structure
VLDLR is a member of the low-density-lipoprotein (LDL) receptor family, which is entirely composed of type I transmembrane lipoprotein receptors.
All members of this family share five highly conserved structural domains: an extracellular N-terminal ligand-binding domain with cysteine-rich repeats (also called ligand-binding repeats), an epidermal growth factor (EGF), an O-linked glycosylation sugar domain, a single transmembrane sequence, and a cytoplasmic domain which contains an NPxY sequence. The NPxY motif functions in signal transduction and the targeting of receptors to coated pits and consists of the sequence Asparagine-Proline-X-Tyrosine, where X can be any amino acid.[2] Mimicking this general structure, VLDLR has eight, 40 amino acid long cysteine-rich repeats in its extracellular N-terminal ligand-binding domain.[2] This is the main difference from the main member of the LDL receptor family, LDLR, which has only seven cysteine-rich repeats which are also 40 amino acids long.[3] Each of these cysteine-rich repeats, in both VLDLR and LDLR, has three disulfide bonds and a coordinated Ca2+ ion. The N-terminus also consists of a glycine residue followed by 27 hydrophobic residues that constitute the signal peptide.[2] Following this region is an EGF repeat, a β-propeller segment that plays a role in the pH-dependent dissociation of the ligand-receptor complex,[4] and two more EGF repeats.[5] The VLDLR O-linked glycosylation domain, next in the sequence, has many threonine and serine residues and totals 46 amino acids. The transmembrane domain, which functions in anchoring the receptors to the membrane, is 22 amino acids long.[2] Final in the sequence is the 54 amino acid cytoplasmic domain, which contains the NPxY motif.[4]
## Isoforms
The full-length human VLDLR genome is located on locus 9p24 on chromosome 9. It consists of a 40 kb segment that includes 19 exon-coding sequences, which is one more exon than encoded by LDLR. This extra exon in the VLDLR gene accounts for the extra cysteine-binding repeat not found in LDLR.[3] Together, the exons making up the VLDLR gene encode a protein that is 873 amino acid residues long. VLDLR is known to exist as four different protein isoforms: type I, II, III, and IV. These different isoforms result from variations in alternative splicing. The transcript of type I VLDLR (VLDLR-I) is composed of all 19 exons. VLDLR-II, on the other hand, lacks exon 16, which encodes for the O-glycosylation domain between sugar regions. VLDLR-III lacks exon 4 that encodes the third ligand-binding repeat. Finally, VLDLR-IV transcripts lack both exon 16 and exon 4. It has been shown that 75% of VLDLR transcripts exist as isoform type II in mouse brain models. This shows that most VLDLRs in the brain are not glycosylated, as type II lacks exon 16 which encodes the O-glycosylation domain. Isoform type IV is known to be the second most prominent.[2]
## Evolutionary conservation
There is a high level of conservation within the LDL receptor family. In particular, there is 50% overall sequence homology between VLDLR and ApoER2, another lipoprotein receptor of this family.[2] Comparing LDLR and VLDLR, it was found that their primary structures are 55% identical within their ligand-binding regions. The modular structures of these two proteins are almost superimposable, with the only difference being the additional cysteine-rich repeat in VLDLR. This is demonstrated through the alignment of the two receptors according to their linker region; in LDLR, the linker region is located between cysteine-rich repeats four and five of its seven repeats while in VLDLR, the linker region appears to be between repeats five and six of its eight repeats.[6]
VLDLR also shows high homology among various species. VLDLR of humans, mice, rats, and rabbits have been identified as 95% identical. Furthermore, there is approximately 84% conservation with the respective protein in chickens. This level of homology between species is much higher than that found for LDLR. Hence, these gene comparisons suggest that VLDLR and LDLR diverged before the LDLRs did among vertebrates.[6]
# Ligand binding
VLDLR binds compounds containing apolipoprotein E (apoE). These ligands attach to the cysteine binding repeats in the N-terminus end. The difference in cysteine-rich repeats between the members of the LDL receptor family lead to the differences in binding affinity. VLDLR, in particular, binds VLDL and intermediate-density lipoprotein (IDL), but not LDL. This inability to bind LDL is due to VLDLR's incapability to bind apolipoprotein B (apoB), which is present in LDL.[7]
## Inhibitors
Receptor-associated protein (RAP) and thrombospondin-1 (THBS1) have been identified as compounds that bind VLDLR. In many cases, these compounds exhibit inhibitory effects. THBS1 binds VLDLR and blocks ligand binding.[7] This plays an important role in the reelin pathway, as THBS1 can block the attachment of reelin, while simultaneously stimulating the transcription factors normally activated by reelin. This binding of THBS1, however, does not induce the subsequent degradation of these transcription factors, as reelin does, and can thus lead to greatly amplified effects.[2] The RAP protein acts similarly by blocking reelin from binding VLDLR. However, in this case phosphorylation of transcription factors, usually performed by reelin, is also blocked.[8]
# Tissue distribution and expression
VLDLR is found throughout the body, with particularly high expression in fatty acid tissues due to their high level of triglycerides, VLDLR’s primary ligand. These tissues include those of the heart, skeletal muscle, and adipose layer. In addition, the receptor is found in macrophages, endothelial cells of capillaries,[4] and in the brain, where it has a very different function from that found in the rest of the body. There is a preferred expression for VLDLR type I in the heart, skeletal muscle and brain, as opposed to type II, which is mainly expressed in non-muscular tissues including the cerebrum, cerebellum, kidney, spleen, and aortic endothelial cells.[3][7] The highest expression of VLDLR is found in the brain. Although VLDLR is found in almost all regions of the brain, its highest expression is restricted to the cortex and cerebellum. Here, the receptor can be found on resting or activated microglia that are associated with senile plaques and cortical neurons, neuroblasts, matrix cells, Cajal-Retzius cells, glioblasts, astrocytes, oligodendrocytes, and region-specific pyramidal neurons.[2] Despite its major role in cholesterol and fatty acid metabolism, VLDLR is not found in the liver. This phenomenon is mainly attributed to the very high levels of LDLR in these areas.[3] In addition, it has been uncovered that this receptor is found, sub-cellularly, in the non-lipid raft sections of cell membranes.[2]
## Regulation
Unlike LDLR, VLDLR does not exhibit any feedback mechanism, and hence intracellular lipoproteins are incapable of regulating it. This phenomenon is due to a difference in the sterol regulatory element-1 (SRE-1) of VLDLR. Normal SRE-1 sequences, like those found in LDLR, are characterized by two repeats of the codon CAC separated by two intervening C nucleotides (5’-CACCCCAC-3’). The sterol regulatory element-binding protein-1 (SREBP-1), a transcription factor, targets the CAC repeats of SRE-1 to regulate the protein’s transcription. However, the VLDLR gene is encoded by two SRE-1-like sequences that contain single nucleotide polymorphisms. These polymorphisms disrupt the SREBP-1 binding to the CAC repeats, and hence eliminate the feedback mechanism seen in other proteins.[3]
VLDLR expression is regulated by peroxisome proliferator-activated receptor-gamma (PPAR-γ). A 2010 study showed that the prescription drug Pioglitazone, an agonist of PPAR-γ, increases VLDLR mRNA expression and protein levels in experiments using mouse fibroblasts. The Pioglitazone treated mice exhibited a higher conversion rate of plasma triglycerides into epididymal fats. As expected, mice deficient in VLDLR did not show this same response.[4] These results suggest that VLDLR is important in fat accumulation.[4]
Many other hormones and dietary factors also regulate VLDLR expression. Thyroid hormone positively regulates VLDLR expression in skeletal muscles of rats, but not in adipose or heart tissues. In rabbits, VLDLR expression in heart muscle is up-regulated by estrogen and down-regulated by granulocyte-macrophage colony-stimulating factor. In trophoblast-derived cell lines, up-regulated VLDLR expression occurs when cells are incubated with hypolipidemic agents such as insulin and clofibrate. In contrast, 8-bromoadenosine 3',5'-cyclic monophosphate (8-bromo-cAMP) down-regulates VLDLR expression. Finally, VLDLR is affected by the presence of apoE and LDLR. The presence of apoE is required for VLDLR expression regulation, while the absence of LDLR alters the sterol-regulatory-element-1-like sequences of VLDLR to make them functional in only heart and skeletal muscle.[3]
# Function
## Beyond the nervous system
VLDLR is a peripheral lipoprotein receptor that functions in lipoprotein metabolism, cardiac fatty acid metabolism, and fat deposition. In effect, VLDLR will allow cholesterol to reach tissues from the bloodstream, where it may be used in cellular membranes. In addition, it will allow fatty acids to get into cells where they may be used as an energy source.[3] Overall, VLDLR primarily modulates the extra-hepatic metabolism of triglyceride-rich lipoproteins.[4]
### Lipoprotein uptake
VLDLR only plays a discrete role in lipid metabolism, but is more significant in stressed situations. Mice with double knockouts in VLDLR and LDLR have higher serum triglyceride levels than those with only a knockout in the LDLR gene. In addition, LDLR knockout mice overexpressing VLDLR have decreased serum triglyceride levels. Although fat deposition is close to normal without VLDLR, its role gains importance when LDLR is deficient. Despite this knowledge on its role in lipoprotein uptake, the complete mechanism of lipid metabolism performed by VLDLR is not fully understood.[7]
VLDLR is known to employ endocytosis, although the exact mechanism of this process is unknown for this protein. Endocytosis is mediated through NPxY sequences known to signal for receptor internalization through clathrin-coated pits. The presence of this sequence in the cytoplasmic tail of VLDLR makes endocytosis possible.[7] In general, lipoprotein receptors undergo a process by which they are endocytosed with their ligand into clathrin-coated pits. From here, they are together transported to early and late endosomes until reaching the lysosome. At this point, hydrolysis occurs and lipoprotein is released into the cytoplasm while the receptors are recycled back to the cell surface. It is not yet confirmed if VLDLR follows this exact mechanism, but one closely related to it is likely.[4]
## In the nervous system
In addition to its role throughout the body, VLDLR has a unique role in the brain. It is a key component of the reelin pathway, which functions in neuronal migration. VLDLR links the reelin protein to an intracellular signaling protein, Dab1, that tells the individual neurons where to go within the anatomy of the brain. Mutations in VLDLR often do not lead to major disorganization as seen in reelin mutations. However, a VLDLR mutation does lead to some disorganization primarily located in the cerebellum, where VLDLR is believed to be most prominent.[2]
### Neuronal migration
VLDLR is expressed on migrating neurons to help guide them to their proper location in the brain. This process is part of the reelin pathway, which is responsible for the inside-out formation of the six-layered neocortex.[2] Despite the discovery of this pathway, many of the specifics and molecular mechanisms of this process are still being debated. The presence of two reelin receptors, VLDLR and ApoER2, has made it difficult to distinguish each protein’s specific function.[9]
VLDLR is primarily responsible for the correct layering of pyramidal cells into layer 1 of the cerebral cortex. In particular, the absence of VLDLR may lead to ectopic accumulation of pyramidal cells in this region.[9] VLDLR does not affect the migration of early born cells into an organized layer, but since its absence results in the invasion of these neuroblasts into the marginal zone, it is theorized that VLDLR may encode a “stop signal.” This is supported by the fact that VLDLR is primarily expressed in the cortical plate adjacent to reelin-expressing cells, Cajal–Retzius cells, and in the intermediate zone. However, definitive evidence has not yet been found.[2] In general, reelin binds VLDLR and undergoes endocytosis via clathrin-coated vesicles.[2] Meanwhile, an intracellular protein, Dab1, has a PI/PTB domain that interacts with the NPxY sequence found in the cytoplasmic tail of VLDLR.[8] As a result, Dab1 is tyrosine phosphorylated and reelin is degraded. Finally, phosphorylated Dab1 activates an intracellular signaling cascade that directs neuroblasts to their proper location through the alteration of the cytoskeleton.[8][10] Many of the specifics of this pathway are still being investigated. It is not yet known if Dab1 is phosphorylated as a result of the endocytosis of reelin, or if there is another mechanism at play. In addition to the organization of the neocortex, VLDLR also plays a role in neuronal migration of the hippocampus and the Purkinje cells of the cerebellum. Yet, much information on this process is still unknown.[2]
# Associated disorders
Mutations within the VLDLR gene lead to a multitude of disorders of varying severities. These disorders are usually associated with cholesterol homeostasis or a disorganization of neuron ordering in the brain due to disruption of the reelin pathway. The most prominent of these diseases are type I lissencephaly, VLDR-associated cerebellar hypoplasia, and atherosclerosis. In contrast to causing diseases, VLDLR has also been identified as a possible remedy for some disorders. Implementation of VLDLR into the liver may cure familial hypercholesterolemia (FH) in patients who either have defective LDLR or have defective immune systems that attack this protein. Since VLDLR is non-immunogenic it does not initiate an immune response, thus it is able to function normally under defective immune systems.[3] In addition, being that apoE, a major ligand of VLDLR, is a leading genetic risk factor for Alzheimer’s disease, VLDLR may play a role in modulating the risk of this disorder.[2] VLDLR has also been shown to reduce the chances of premature heart disease and stroke because VLDLR clears out lipoprotein A (Lp(a)), a major inherited risk factor for these diseases.[3]
## Type 1 lissencephaly
Type I lissencephaly, or agyria-pachygyria, is a rare developmental disorder characterized by the absence of gyri and sulci in the brain. These severe malformations are a result of aberrant neuronal migration. In classical type I lissencephaly, neuronal migration begins but is unable to continue to completion. This process is likely disrupted by alterations to several genes, including the VLDLR, DCX, ARX, TUBA1A, RELN and LIS1. The severity of type I lissencephaly therefore varies with the mutation type. A homozygous deletion affecting the VLDLR gene results in a low degree of cortical thickening and absence of a cell-sparse zone. The cell-sparse zone describes the region between the outer and inner cortical layers of arrested neurons.[11] In addition, type 1 lissencephaly is closely associated with cerebellar hypoplasia.
## VLDLR-associated cerebellar hypoplasia
Disequilibrium syndrome (DES) was first described in the 1970s as a non-progressive, neurological disorder.[12] In a 2005 study, DES was renamed as VLDLR-associated cerebellar hypoplasia (VLDLRCH) after its cause was linked to a disruption in the VLDLR gene.[13] At least six mutations affecting the homozygous recessive allele of the VLDLR gene have been identified and found to cause VLDLRCH. Several of these mutations have been localized to specific exons encoding the gene. One such mutation is a cytosine to thymine transition at base pair 1342 in exon 10 that causes a substitution at Arg448 for a termination signal. Likewise, there is evidence of a cytosine to thymine transition at base pair number 769 in exon 5 that causes a substitution at Arg257 for a termination signal. A third known mutation is caused by a homozygous 1-base pair deletion in exon 17 that causes a frameshift and premature termination in the O-linked sugar domain.[14] All such alterations to the VLDLR gene prevent the production of VLDLR and are therefore termed loss-of-function mutations. The recognized symptoms of VLDLRCH are moderate-to-severe intellectual disability, seizures, dysarthria, strabismus and delayed locomotion. In some cases, children with VLDLRCH learn to walk very late in development after the age of six years, or never learn to walk independently. The frequency of this disorder is unknown because early diagnosis of VLDLRCH is difficult using imaging techniques. It is associated with parental consanguinity and found in secluded communities such as the Hutterites and inbred families from Iran and Turkey.[15]
## Atherosclerosis
Atherosclerosis is marked by an excessive accumulation of cholesterol by macrophages, leading to their transformation into foam cells. This accumulation of cholesterol is caused by dysregulation of cholesterol influx and efflux. Since macrophages do not have the ability to limit the influx of cholesterol, the balance is completely dependent on efflux pathways. VLDLR is expressed by macrophages, and functions in the uptake of native lipoproteins. Uniquely, VLDLR does not respond to cholesterol loading, likely due to its lack of feedback mechanisms. The inability to control its uptake of native lipoproteins makes VLDLR a pro-atherogenic factor.[16] This characteristic is supported by results from a 2005 study, in which reintroduction of VLDLR into VLDLR knockout mice led to greatly increased atherosclerotic lesion development.[16]
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https://www.wikidoc.org/index.php/VLDL_receptor
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a20956853b17c5d38ecfcd0d782e26b14b53504f
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wikidoc
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Vaccenic acid
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Vaccenic acid
Vaccenic acid is a trans fat found in the fat of ruminants and in dairy products. Its IUPAC name is trans-7-octadecenoic acid, and its lipid shorthand name is 18:1 trans-11.
The name was derived from the Latin vacca (cow).
Vaccenic acid was discovered in 1928 in animal fats and butter. It is the main trans fatty acid isomer present in milk fat.
Mammals convert it into rumenic acid, a conjugated linoleic acid,
where it shows anticarcinogenic properties.
Its stereoisomer, Cis-Vaccenic acid is an Omega-7 fatty acid found in Sea Buckthorn (Hippophae rhamnoides) oil. Its IUPAC name is cis-7-octadecenoic acid, and its lipid shorthand name is 18:1 cis-11.
# Old Person Smell
In the April 2001 issue of THE JOURNAL OF INVESTIGATIVE DERMATOLOGY, Shinichiro Haze et al published an article entitled: "2-Nonenal, Newly Found in Human Body Odor Tends to Increase with Aging".
In this article it was suggested that omega-7 unsaturated fatty acids, such as palmitoleic acid and vaccenic acid, found on the skin surface may be the cause of the phenomenon commonly known as "old person smell".
|
Vaccenic acid
Vaccenic acid is a trans fat found in the fat of ruminants and in dairy products. Its IUPAC name is trans-7-octadecenoic acid, and its lipid shorthand name is 18:1 trans-11.
The name was derived from the Latin vacca (cow).[1]
Vaccenic acid was discovered in 1928 in animal fats and butter. It is the main trans fatty acid isomer present in milk fat.[1]
Mammals convert it into rumenic acid, a conjugated linoleic acid,[2][3]
where it shows anticarcinogenic properties.[4]
Its stereoisomer, Cis-Vaccenic acid is an Omega-7 fatty acid found in Sea Buckthorn (Hippophae rhamnoides) oil. [5] Its IUPAC name is cis-7-octadecenoic acid, and its lipid shorthand name is 18:1 cis-11.
# Old Person Smell
In the April 2001 issue of THE JOURNAL OF INVESTIGATIVE DERMATOLOGY, Shinichiro Haze et al published an article entitled: "2-Nonenal, Newly Found in Human Body Odor Tends to Increase with Aging". [6]
In this article it was suggested that omega-7 unsaturated fatty acids, such as palmitoleic acid and vaccenic acid, found on the skin surface may be the cause of the phenomenon commonly known as "old person smell".
|
https://www.wikidoc.org/index.php/Vaccenic_acid
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225948746e6bac8c3de569c3355bb97d3ee6c87b
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wikidoc
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Vacuous truth
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Vacuous truth
Vacuous truth is a special topic of first-order logic. A conditional assertion is vacuously true if the assertion can already be shown to be true (often by the use of axioms) and the condition is logically unrelated to the assertion.
This notion has relevance in pure mathematics. One example is the empty product—the fact that the result of multiplying no numbers at all is 1—which is useful in a variety of mathematical fields including probability theory, combinatorics, and power series. Another example is that the elementary symmetric polynomial in no variables at all is 1. Yet another is the discovery that the Euler characteristic is one of the finitely additive "measures" treated in Hadwiger’s theorem.
Outside of mathematics, statements which can be characterized informally as vacuously true can be misleading. Such statements make reasonable assertions about qualified objects which do not actually exist. For example, a child might tell his parents "I ate every vegetable on my plate," when there were no vegetables on the child’s plate.
Compare: tautology, counterfactual.
# Scope of the concept
The term "vacuously true" is generally applied to a statement S if S has a form similar to:
- P \Rightarrow Q, where P is false.
- \forall x, P(x) \Rightarrow Q(x), where it is the case that \forall x, \neg P(x).
- \forall x \in A, Q(x), where the set A is empty.
- \forall \xi, Q(\xi), where the symbol \xi is restricted to a type that has no representatives.
The first instance is the most basic one; the other three can be reduced to the first with suitable transformations.
Vacuous truth is usually applied in classical logic, which in particular is two-valued, and most of the arguments in the next section will be based on this assumption.
However, vacuous truth also appears in, for example, intuitionistic logic in the same situations given above.
Indeed, the first 2 forms above will yield vacuous truth in any logic that uses material conditional, but there are other logics which do not.
# Arguments of the semantic "truth" of vacuously true logical statements
This is a complex question and, for simplicity of exposition, we will here consider only vacuous truth as concerns logical implication, i.e., the case when S has the form P \Rightarrow Q, and P is false. This case strikes many people as odd, and it’s not immediately obvious whether all such statements are true, all such statements are false, some are true while others are false, or what.
## Arguments that at least some vacuously true statements are true
Consider the implication "if I am in Massachusetts, then I am in North America", which we might alternatively express as, "if I were in Massachusetts, then I would be in North America". There is something inherently reasonable about this claim, even if one is not currently in Massachusetts. It seems that someone in Europe, for example, would still have good reason to assert this proposition. Thus at least one vacuously true statement seems to actually be true.
### Arguments against taking all vacuously true statements to be false
Second, the most obvious alternative to taking all vacuously true statements to be true — i.e., taking all vacuously true statements to be false — has some unsavory consequences. Suppose we are willing to accept that P \Rightarrow Q should be true when both P and Q are true, and false when P is true but Q is false. That is, suppose we accept this as a partial truth table for implies:
Suppose we decide that the unknown values should be F. In this case, then implies turns out to be logically equivalent to logical AND (\land), as we can see in the following table:
Intuitively this is odd, because it certainly seems like "if" and "and" ought to have different meanings; if they didn’t, then it’s confusing why we should have a separate logical symbol for each one.
Perhaps more disturbing, we must also accept that the following arguments are logically valid:
- P \Rightarrow Q
- P \land Q
- P
and
- P \Rightarrow Q
- P \land Q
- Q
That is, we can conclude that P is true (or that Q is true) based solely on the logical connection of the two.
Picking "true" as the truth value makes many mathematical propositions that people tend to think are true come out as true. For example, most people would say that the statement
is true. Now suppose that we decide to say that all vacuously true statements are false. In that case, the vacuously true statement
is false. But in this case, there is an integer value for x (namely, x=3), for which it does not hold that
Therefore our first statement isn’t true, as we said before, but false. This doesn’t seem to be how people use language, however.
First, calling vacuously true sentences false may extend the term "lying" to too many different situations. Note that lying could be defined as knowingly making a false statement. Now suppose two male friends, Peter and Ned, read this very article on some June 4, and both (perhaps unwisely) concluded that "vacuously true" sentences, despite their name, are actually false. Suppose the same day, Peter tells Ned the following statement S:
Suppose June 5 goes by without Ned getting his new house. Now according to Peter and Ned’s common understanding that vacuously true sentences are false, S is a false statement. Moreover, since Peter knew that he was not female when he uttered S, we can assume he knew, at that time, that S was vacuously true, and hence false. But if this is true, then Ned has every right to accuse Peter of having lied to him. This doesn’t seem right, however.
## Arguments for taking all vacuously true statements to be true
The main argument that all vacuously true statements are true is as follows: As explained in the article on logical conditionals, the axioms of propositional logic entail that if P is false, then P \Rightarrow Q is true. That is, if we accept those axioms, we must accept that vacuously true statements are indeed true. For many people, the axioms of propositional logic are obviously truth-preserving. These people, then, really ought to accept that vacuously true statements are indeed true. On the other hand, if one is willing to question whether all vacuously true statements are indeed true, one may also be quite willing to question the validity of the propositional calculus, in which case this argument begs the question.
## Arguments that only some vacuously true statements are true
One objection to saying that all vacuously true statements are true is that this makes the following deduction valid:
- \neg P
- P \Rightarrow Q
Many people have trouble with or are bothered by this because, unless we know about some a priori connection between P and Q, what should the truth of P have to do with the implication of P and Q? Shouldn’t the truth value of P in this situation be irrelevant? Logicians bothered by this have developed alternative logics (e.g. relevant logic) where this sort of deduction is valid only when P is known a priori to be relevant to the truth of Q.
Note that this "relevance" objection really applies to logical implication as a whole, and not merely to the case of vacuous truth. For example, it’s commonly accepted that the sun is made of gas, on one hand, and that 3 is a prime number, on the other. By the standard definition of implication, we can conclude that: the sun’s being made of gas implies that 3 is a prime number. Note that since the premise is indeed true, this is not a case of vacuous truth. Nonetheless, there seems to be something fishy about this assertion.
## Summary
So there are a number of justifications for saying that vacuously true statements are indeed true.
Nonetheless, there is still something odd about the choice.
There seems to be no direct reason to pick true; it’s just that things blow up in our face if we don’t.
Thus we say S is vacuously true; it is true, but in a way that doesn’t seem entirely free from arbitrariness.
Furthermore, the fact that S is true doesn’t really provide us with any information, nor can we make useful deductions from it; it is only a choice we made about how our logical system works, and can’t represent any fact of the real
world.
# Difficulties with the use of vacuous truth
Both of these seemingly contradictory statements are true using classical or two-valued logic – so long as the set of pink rhinoceros remains empty. (See also Present King of France.)
Certainly, one would think it should be easy to avoid falling into the trap of employing vacuously true statements in rigorous proofs, but the history of mathematics contains many ‘proofs’ based on the negation of some accepted truth and subsequently demonstrating how this leads to a contradiction.
One fundamental problem with such ‘demonstrations’ is the uncertainty of the truth-value of any of the statements which follow (or even whether they do follow) when our initial supposition is false. Stated another way, we should ask ourselves which rules of mathematics or inference should still be applicable after we first suppose that pi is an integer.
The problem occurs when it is not immediately obvious that we are dealing with a vacuous truth. For example, if we have two propositions, neither of which implies the other, then we can reasonably conclude that they are different; counter-intuitively, we can also conclude that the two propositions are the same. The reason for this is that (P \Rightarrow Q)\lor(Q \Rightarrow P) is a tautology in classical logic, so every assertion that is made about "two propositions, neither of which implies the other" is an assertion about nothing, hence vacuously true. Although such a fact that "two propositions, neither of which implies the other, are both different and the same" poses no theoretical problems, it can easily be disturbing to the human mind.
Avoidance of such paradox is the impetus behind the development of non-classical systems of logic relevant logic and paraconsistent logic which refuse to admit the validity of one or two of the axioms of classical logic. Unfortunately the resulting systems are often too weak to prove anything but the most trivial of truths.
# Vacuous truths in mathematics
Vacuous truths occur commonly in mathematics. For instance, when making a general statement about arbitrary sets, said statement ought to hold for all sets including the empty set. But for the empty set the statement may very well reduce to a vacuous truth. So by taking this vacuous truth to be true, our general statement stands and we are not forced to make an exception for the empty set.
For example, consider the property of being an antisymmetric relation. A relation R on a set S is antisymmetric if, for any a and b in S with a\mathrel{R}b and b\mathrel{R}a, it is true that a=b. The less-than-or-equal-to relation \leq on the real numbers is an example of an antisymmetric relation, because whenever a\leq b and b\leq a, it is true that a=b. The less-than relation is also antisymmetric, and vacuously so, because there are no numbers a and b for which both a and b, and so the conclusion, that a=b whenever this occurs, is vacuously true.
An even simpler example concerns the theorem that says that for any set X, the empty set \varnothing is a subset of X. This is equivalent to asserting that every element of \varnothing is an element of X, which is vacuously true since there are no elements of \varnothing.
There are however vacuous truths that even most mathematicians will outright dismiss as "nonsense" and would never publish in a mathematical journal (even if grudgingly admitting that they are true). An example would be the true statement
More disturbing are generalizations of obviously "nonsensical" statements which are likewise true, but not vacuously so:
Since no infinite subset of any set has seven elements, we may be tempted to conclude that this statement is obviously false. But this is wrong, because we’ve failed to consider the possibility of sets that have no infinite subsets at all (as in the previous example—in fact, any finite set will do). It is this sort of "hidden" vacuous truth that can easily invalidate a proof when not treated with care.
# Further reading
- When is truth vacuous? Is infinity a bunch of nothing?: a transcript of a discussion in which some professional and amateur mathematicians try to find a definition for vacuous truth and debate its properties
- Null set uniqueness theorem: A proof of the uniqueness of the null set in standard set theory demonstrates the utility of ‘vacuous truth’.
|
Vacuous truth
Vacuous truth is a special topic of first-order logic. A conditional assertion is vacuously true if the assertion can already be shown to be true (often by the use of axioms) and the condition is logically unrelated to the assertion.
This notion has relevance in pure mathematics. One example is the empty product—the fact that the result of multiplying no numbers at all is 1—which is useful in a variety of mathematical fields including probability theory, combinatorics, and power series. Another example is that the elementary symmetric polynomial in no variables at all is 1. Yet another is the discovery that the Euler characteristic is one of the finitely additive "measures" treated in Hadwiger’s theorem.[1]
Outside of mathematics, statements which can be characterized informally as vacuously true can be misleading. Such statements make reasonable assertions about qualified objects which do not actually exist. For example, a child might tell his parents "I ate every vegetable on my plate," when there were no vegetables on the child’s plate.
Compare: tautology, counterfactual.
# Scope of the concept
The term "vacuously true" is generally applied to a statement <math>S</math> if <math>S</math> has a form similar to:
- <math>P \Rightarrow Q</math>, where <math>P</math> is false.
- <math>\forall x, P(x) \Rightarrow Q(x)</math>, where it is the case that <math>\forall x, \neg P(x)</math>.
- <math>\forall x \in A, Q(x)</math>, where the set <math>A</math> is empty.
- <math>\forall \xi, Q(\xi)</math>, where the symbol <math>\xi</math> is restricted to a type that has no representatives.
The first instance is the most basic one; the other three can be reduced to the first with suitable transformations.
Vacuous truth is usually applied in classical logic, which in particular is two-valued, and most of the arguments in the next section will be based on this assumption.
However, vacuous truth also appears in, for example, intuitionistic logic in the same situations given above.
Indeed, the first 2 forms above will yield vacuous truth in any logic that uses material conditional, but there are other logics which do not.
# Arguments of the semantic "truth" of vacuously true logical statements
This is a complex question and, for simplicity of exposition, we will here consider only vacuous truth as concerns logical implication, i.e., the case when <math>S</math> has the form <math>P \Rightarrow Q</math>, and <math>P</math> is false. This case strikes many people as odd, and it’s not immediately obvious whether all such statements are true, all such statements are false, some are true while others are false, or what.
## Arguments that at least some vacuously true statements are true
Consider the implication "if I am in Massachusetts, then I am in North America", which we might alternatively express as, "if I were in Massachusetts, then I would be in North America". There is something inherently reasonable about this claim, even if one is not currently in Massachusetts. It seems that someone in Europe, for example, would still have good reason to assert this proposition. Thus at least one vacuously true statement seems to actually be true.
### Arguments against taking all vacuously true statements to be false
Second, the most obvious alternative to taking all vacuously true statements to be true — i.e., taking all vacuously true statements to be false — has some unsavory consequences. Suppose we are willing to accept that <math>P \Rightarrow Q</math> should be true when both <math>P</math> and <math>Q</math> are true, and false when <math>P</math> is true but <math>Q</math> is false. That is, suppose we accept this as a partial truth table for implies:
Suppose we decide that the unknown values should be <math>F</math>. In this case, then implies turns out to be logically equivalent to logical AND (<math>\land</math>), as we can see in the following table:
Intuitively this is odd, because it certainly seems like "if" and "and" ought to have different meanings; if they didn’t, then it’s confusing why we should have a separate logical symbol for each one.
Perhaps more disturbing, we must also accept that the following arguments are logically valid:
- <math>P \Rightarrow Q</math>
- <math>P \land Q</math>
- <math>P</math>
and
- <math>P \Rightarrow Q</math>
- <math>P \land Q</math>
- <math>Q</math>
That is, we can conclude that <math>P</math> is true (or that <math>Q</math> is true) based solely on the logical connection of the two.
Picking "true" as the truth value makes many mathematical propositions that people tend to think are true come out as true. For example, most people would say that the statement
is true. Now suppose that we decide to say that all vacuously true statements are false. In that case, the vacuously true statement
is false. But in this case, there is an integer value for <math>x</math> (namely, <math>x=3</math>), for which it does not hold that
Therefore our first statement isn’t true, as we said before, but false. This doesn’t seem to be how people use language, however.
First, calling vacuously true sentences false may extend the term "lying" to too many different situations. Note that lying could be defined as knowingly making a false statement. Now suppose two male friends, Peter and Ned, read this very article on some June 4, and both (perhaps unwisely) concluded that "vacuously true" sentences, despite their name, are actually false. Suppose the same day, Peter tells Ned the following statement <math>S</math>:
Suppose June 5 goes by without Ned getting his new house. Now according to Peter and Ned’s common understanding that vacuously true sentences are false, <math>S</math> is a false statement. Moreover, since Peter knew that he was not female when he uttered <math>S</math>, we can assume he knew, at that time, that <math>S</math> was vacuously true, and hence false. But if this is true, then Ned has every right to accuse Peter of having lied to him. This doesn’t seem right, however.
## Arguments for taking all vacuously true statements to be true
The main argument that all vacuously true statements are true is as follows: As explained in the article on logical conditionals, the axioms of propositional logic entail that if <math>P</math> is false, then <math>P \Rightarrow Q</math> is true. That is, if we accept those axioms, we must accept that vacuously true statements are indeed true. For many people, the axioms of propositional logic are obviously truth-preserving. These people, then, really ought to accept that vacuously true statements are indeed true. On the other hand, if one is willing to question whether all vacuously true statements are indeed true, one may also be quite willing to question the validity of the propositional calculus, in which case this argument begs the question.
## Arguments that only some vacuously true statements are true
One objection to saying that all vacuously true statements are true is that this makes the following deduction valid:
- <math>\neg P</math>
- <math>P \Rightarrow Q</math>
Many people have trouble with or are bothered by this because, unless we know about some a priori connection between <math>P</math> and <math>Q</math>, what should the truth of <math>P</math> have to do with the implication of <math>P</math> and <math>Q</math>? Shouldn’t the truth value of <math>P</math> in this situation be irrelevant? Logicians bothered by this have developed alternative logics (e.g. relevant logic) where this sort of deduction is valid only when <math>P</math> is known a priori to be relevant to the truth of <math>Q</math>.
Note that this "relevance" objection really applies to logical implication as a whole, and not merely to the case of vacuous truth. For example, it’s commonly accepted that the sun is made of gas, on one hand, and that 3 is a prime number, on the other. By the standard definition of implication, we can conclude that: the sun’s being made of gas implies that 3 is a prime number. Note that since the premise is indeed true, this is not a case of vacuous truth. Nonetheless, there seems to be something fishy about this assertion.
## Summary
So there are a number of justifications for saying that vacuously true statements are indeed true.
Nonetheless, there is still something odd about the choice.
There seems to be no direct reason to pick true; it’s just that things blow up in our face if we don’t.
Thus we say <math>S</math> is vacuously true; it is true, but in a way that doesn’t seem entirely free from arbitrariness.
Furthermore, the fact that <math>S</math> is true doesn’t really provide us with any information, nor can we make useful deductions from it; it is only a choice we made about how our logical system works, and can’t represent any fact of the real
world.
# Difficulties with the use of vacuous truth
Both of these seemingly contradictory statements are true using classical or two-valued logic – so long as the set of pink rhinoceros remains empty. (See also Present King of France.)
Certainly, one would think it should be easy to avoid falling into the trap of employing vacuously true statements in rigorous proofs, but the history of mathematics contains many ‘proofs’ based on the negation of some accepted truth and subsequently demonstrating how this leads to a contradiction.
One fundamental problem with such ‘demonstrations’ is the uncertainty of the truth-value of any of the statements which follow (or even whether they do follow) when our initial supposition is false. Stated another way, we should ask ourselves which rules of mathematics or inference should still be applicable after we first suppose that pi is an integer.
The problem occurs when it is not immediately obvious that we are dealing with a vacuous truth. For example, if we have two propositions, neither of which implies the other, then we can reasonably conclude that they are different; counter-intuitively, we can also conclude that the two propositions are the same. The reason for this is that <math>(P \Rightarrow Q)\lor(Q \Rightarrow P)</math> is a tautology in classical logic, so every assertion that is made about "two propositions, neither of which implies the other" is an assertion about nothing, hence vacuously true. Although such a fact that "two propositions, neither of which implies the other, are both different and the same" poses no theoretical problems, it can easily be disturbing to the human mind.
Avoidance of such paradox is the impetus behind the development of non-classical systems of logic relevant logic and paraconsistent logic which refuse to admit the validity of one or two of the axioms of classical logic. Unfortunately the resulting systems are often too weak to prove anything but the most trivial of truths.
# Vacuous truths in mathematics
Vacuous truths occur commonly in mathematics. For instance, when making a general statement about arbitrary sets, said statement ought to hold for all sets including the empty set. But for the empty set the statement may very well reduce to a vacuous truth. So by taking this vacuous truth to be true, our general statement stands and we are not forced to make an exception for the empty set.
For example, consider the property of being an antisymmetric relation. A relation <math>R</math> on a set <math>S</math> is antisymmetric if, for any <math>a</math> and <math>b</math> in <math>S</math> with <math>a\mathrel{R}b</math> and <math>b\mathrel{R}a</math>, it is true that <math>a=b</math>. The less-than-or-equal-to relation <math>\leq</math> on the real numbers is an example of an antisymmetric relation, because whenever <math>a\leq b</math> and <math>b\leq a</math>, it is true that <math>a=b</math>. The less-than relation <math><</math> is also antisymmetric, and vacuously so, because there are no numbers <math>a</math> and <math>b</math> for which both <math>a< b</math> and <math>b< a</math>, and so the conclusion, that <math>a=b</math> whenever this occurs, is vacuously true.
An even simpler example concerns the theorem that says that for any set <math>X</math>, the empty set <math>\varnothing</math> is a subset of <math>X</math>. This is equivalent to asserting that every element of <math>\varnothing</math> is an element of <math>X</math>, which is vacuously true since there are no elements of <math>\varnothing</math>.
There are however vacuous truths that even most mathematicians will outright dismiss as "nonsense" and would never publish in a mathematical journal (even if grudgingly admitting that they are true). An example would be the true statement
More disturbing are generalizations of obviously "nonsensical" statements which are likewise true, but not vacuously so:
Since no infinite subset of any set has seven elements, we may be tempted to conclude that this statement is obviously false. But this is wrong, because we’ve failed to consider the possibility of sets that have no infinite subsets at all (as in the previous example—in fact, any finite set will do). It is this sort of "hidden" vacuous truth that can easily invalidate a proof when not treated with care.
# Further reading
- When is truth vacuous? Is infinity a bunch of nothing?: a transcript of a discussion in which some professional and amateur mathematicians try to find a definition for vacuous truth and debate its properties
- Null set uniqueness theorem: A proof of the uniqueness of the null set in standard set theory demonstrates the utility of ‘vacuous truth’.
# External links
- Conditional Assertions: Vacuous truth
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https://www.wikidoc.org/index.php/Vacuous_truth
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18e2c2bdfbbd051df6ead438ea3f21f72345c6ec
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wikidoc
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Vaginal flora
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Vaginal flora
The human vaginal region has a higher concentration of bacteria, than any other part of the body, save the colon . The bacteria of the vaginal flora were discovered by the gynecologist Albert Döderlein in 1892. Primarily, these bacteria consist of lactobacilli , and are collectively referred to as the vaginal flora. The amount and type of bacteria present have significant implications for a woman's overall health. These bacteria and the lactic acid they produce, in combination with fluids secreted during sexual arousal, are greatly responsible for the characteristic odor associated with the vaginal area.
# Menstruation
During menstruation, the concentration of vaginal flora is observed to decline. The effect of tampon use on vaginal flora is debated, but safe application of sterile tampons appears not to significantly modify the balance of bacterial presence.
# Disease Prevention
A healthy vaginal flora aids in the prevention of yeast infections and other possible problems by occupying the chemical resources otherwise utilized by pathogen organisms. However, harmful bacteria or an imbalance in bacteria can lead to infection.
One method of reducing the risk of infection in the local area of the urethra is to urinate immediately after sex. Additionally, exclusive use of sterile contraceptives can assist in prevention of infection.
|
Vaginal flora
The human vaginal region has a higher concentration of bacteria, than any other part of the body, save the colon [1]. The bacteria of the vaginal flora were discovered by the gynecologist Albert Döderlein in 1892. Primarily, these bacteria consist of lactobacilli [2], and are collectively referred to as the vaginal flora. The amount and type of bacteria present have significant implications for a woman's overall health. These bacteria and the lactic acid they produce, in combination with fluids secreted during sexual arousal, are greatly responsible for the characteristic odor associated with the vaginal area.
# Menstruation
During menstruation, the concentration of vaginal flora is observed to decline. [3] The effect of tampon use on vaginal flora is debated, but safe application of sterile tampons appears not to significantly modify the balance of bacterial presence.
# Disease Prevention
A healthy vaginal flora aids in the prevention of yeast infections and other possible problems by occupying the chemical resources otherwise utilized by pathogen organisms. [4] However, harmful bacteria or an imbalance in bacteria can lead to infection.
One method of reducing the risk of infection in the local area of the urethra is to urinate immediately after sex. Additionally, exclusive use of sterile contraceptives can assist in prevention of infection.
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https://www.wikidoc.org/index.php/Vaginal_flora
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1952ab6cedc40b1eac8761b452fa8f32c82bff83
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Varicosavirus
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Varicosavirus
# Overview
The viral genus Varicosavirus is a plant virus associated with the swelling it causes in plant vein tissues. It is a double stranded RNA virus with no specific assigned family. Infection occurs through soil by the spores of the fungus Olpidium brassicae.
# Genome
The genome consists of a bi-segmented linear, double-stranded RNA. The segments are distributed among two particle types of the RNA. The first segment is about 6350-7000 nucleotides in length; the second, about 5630-6500 nucleotides in length .
# Structure
Virions consist of a non-enveloped rod-shaped capsid, having a helical symmetry of 120-360 nm in length, and a width of 18-30 nm.
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Varicosavirus
# Overview
The viral genus Varicosavirus is a plant virus associated with the swelling it causes in plant vein tissues. It is a double stranded RNA virus with no specific assigned family. Infection occurs through soil by the spores of the fungus Olpidium brassicae.
# Genome
The genome consists of a bi-segmented linear, double-stranded RNA. The segments are distributed among two particle types of the RNA. The first segment is about 6350-7000 nucleotides in length; the second, about 5630-6500 nucleotides in length [1].
# Structure
Virions consist of a non-enveloped rod-shaped capsid, having a helical symmetry of 120-360 nm in length, and a width of 18-30 nm.
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https://www.wikidoc.org/index.php/Varicosavirus
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a6c9e74544703c85095351dd4005d784a255de7a
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wikidoc
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Vascular ring
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Vascular ring
# Overview
A vascular ring is a congenital defect in which there is an abnormal formation of the aorta and/or its surrounding blood vessels. The trachea and esophagus are completely encircled and sometimes compressed by a "ring" formed by these vessels, which can lead to breathing and digestive difficulties.
# Pathophysiology
Most often this is because of persistence of the double aortic arch after the second month of fetal life. A less common ring is present with a right aortic arch instead of the usual left-sided aortic arch which compresses the esophagus and trachea because of the persistence of a ductal ligament (from fetal circulation) that may connect between the aorta on the front and the left subclavian artery posteriorly going to the left arm.
# Diagnosis
## Symptoms
The two arches surround the esophagus and trachea which if sufficiently constrictive cause the breathing or swallowing difficulties.
# Additional Resources
- Moss and Adams' Heart Disease in Infants, Children, and Adolescents Hugh D. Allen, Arthur J. Moss, David J. Driscoll, Forrest H. Adams, Timothy F. Feltes, Robert E. Shaddy, 2007 ISBN 0781786843
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Vascular ring
For patient information click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editors-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]; Keri Shafer, M.D. [3]
# Overview
A vascular ring is a congenital defect in which there is an abnormal formation of the aorta and/or its surrounding blood vessels. The trachea and esophagus are completely encircled and sometimes compressed by a "ring" formed by these vessels, which can lead to breathing and digestive difficulties.
# Pathophysiology
Most often this is because of persistence of the double aortic arch after the second month of fetal life. A less common ring is present with a right aortic arch instead of the usual left-sided aortic arch which compresses the esophagus and trachea because of the persistence of a ductal ligament (from fetal circulation) that may connect between the aorta on the front and the left subclavian artery posteriorly going to the left arm.
# Diagnosis
## Symptoms
The two arches surround the esophagus and trachea which if sufficiently constrictive cause the breathing or swallowing difficulties.
# Additional Resources
- Moss and Adams' Heart Disease in Infants, Children, and Adolescents Hugh D. Allen, Arthur J. Moss, David J. Driscoll, Forrest H. Adams, Timothy F. Feltes, Robert E. Shaddy, 2007 ISBN 0781786843
Template:WikiDoc Sources
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https://www.wikidoc.org/index.php/Vascular_ring
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f652cc203c58b757baa770a69e04769e333b0251
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wikidoc
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Vasovasostomy
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Vasovasostomy
Vasovasostomy (literally connection of the vas to the vas) is the surgery by which vasectomies are reversed in males.
In most cases the vas deferens can be reattached but, in many cases, fertility is not achieved. There are several reasons for this, including blockages in the vas deferens, and the presence of autoantibodies which disrupt normal sperm activity. If blockage at the level of the epididymis is suspected, a vaso-epidymostomy (connecting the vas to the epididymis) can be performed.
Return of sperm to the ejaculate ranges from roughly 30 to 90 percent, and may depend greatly on the length of time from the vasectomy. Generally, the shorter the interval, the higher the chance of success. The likelihood of pregnancy is somewhat lower (30 to 60 percent), and can depend on female partner factors.
Over half of men who have undergone a vasectomy develop anti-sperm antibodies. The effects of anti-sperm antibodies continue to be debated in the medical literature but, there is agreement that antibodies reduce sperm motility.
The procedure is typically performed by urologists. Most urologists specializing in the field of male infertility perform vasovasostomies using an operative microscope for magnification, under general or regional anesthesia.
Vasovasostomy is typically an out-patient procedure (patient goes home the same day).
Prognosis
Determining the prognosis for each patient may involve a pre-operative examination of the vasectomy sites and consideration of the time interval between vasectomy and reversal. If there are no granulomas at either vasectomy site, the prognosis may then be based on the time interval since the vasectomy. If the interval since the vasectomy is less than fifteen years, the prognosis will likely be 70% or better.
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Vasovasostomy
Template:Interventions infobox
Vasovasostomy (literally connection of the vas to the vas) is the surgery by which vasectomies are reversed in males.
In most cases the vas deferens can be reattached but, in many cases, fertility is not achieved. There are several reasons for this, including blockages in the vas deferens, and the presence of autoantibodies which disrupt normal sperm activity. If blockage at the level of the epididymis is suspected, a vaso-epidymostomy (connecting the vas to the epididymis) can be performed.
Return of sperm to the ejaculate ranges from roughly 30 to 90 percent, and may depend greatly on the length of time from the vasectomy. Generally, the shorter the interval, the higher the chance of success. The likelihood of pregnancy is somewhat lower (30 to 60 percent), and can depend on female partner factors.
Over half of men who have undergone a vasectomy develop anti-sperm antibodies. The effects of anti-sperm antibodies continue to be debated in the medical literature but, there is agreement that antibodies reduce sperm motility.
The procedure is typically performed by urologists. Most urologists specializing in the field of male infertility perform vasovasostomies using an operative microscope for magnification, under general or regional anesthesia.
Vasovasostomy is typically an out-patient procedure (patient goes home the same day).
Prognosis
Determining the prognosis for each patient may involve a pre-operative examination of the vasectomy sites and consideration of the time interval between vasectomy and reversal. If there are no granulomas at either vasectomy site, the prognosis may then be based on the time interval since the vasectomy. If the interval since the vasectomy is less than fifteen years, the prognosis will likely be 70% or better.[citation needed]
# External links
- Vasectomy Reversal American Urological Association sponsored site.
Template:Urogenital surgical procedures
de:Vasovasostomie
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https://www.wikidoc.org/index.php/Vasovasostomy
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f761cbe83107d6be4504f6478073c9f34abb33c1
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Vegas Cubanas
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Vegas Cubanas
Vegas Cubanas is a brand of hand-made premium cigar owned by El Rey de los Habanos, Inc.
# History and Background
This brand was created by José "Pepin" Garcia and is manufactured at the El Rey de los Habanos factory in Little Havana, Miami, Florida. It was introduced into national distribution in 2005.
# Description
A Nicaraguan puro, the wrapper is a corojo leaf, colorado maduro in color. It is a mild- to medium-bodied smoke available, uncellophaned, in boxes of 25. Cigars are aged for a minimum of one year before shipping.
# Models/Vitolas
# Notes
- ↑ Catalogue blurb
# See Also
Perelman, Richard B., comp. Perelman's Pocket Cyclopedia of Cigars, 2006 edn. Philadelphia: Perelman, Pioneer & Co., (2005). p. 545-546.
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Vegas Cubanas
Vegas Cubanas is a brand of hand-made premium cigar owned by El Rey de los Habanos, Inc.
# History and Background
This brand was created by José "Pepin" Garcia and is manufactured at the El Rey de los Habanos factory in Little Havana, Miami, Florida. It was introduced into national distribution in 2005.
# Description
A Nicaraguan puro, the wrapper is a corojo leaf, colorado maduro in color. It is a mild- to medium-bodied smoke available, uncellophaned, in boxes of 25. Cigars are aged for a minimum of one year before shipping.[1]
# Models/Vitolas
# Notes
- ↑ Catalogue blurb
# See Also
Perelman, Richard B., comp. Perelman's Pocket Cyclopedia of Cigars, 2006 edn. Philadelphia: Perelman, Pioneer & Co., (2005). p. 545-546.
Template:WikiDoc Sources
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https://www.wikidoc.org/index.php/Vegas_Cubanas
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9df6614d092eedb1a8f01776a3cb816d880a5ac0
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wikidoc
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Veggie burger
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Veggie burger
A veggie burger is a vegetarian hamburger. The patty of a veggie burger can be made from vegetables, nuts, dairy, mushrooms, textured vegetable protein (TVP), or a combination of these. They are sometimes vegan.
Veggie burgers are available in a growing number of fast-food restaurants in the U.S., but availability may vary geographically or even among particular restaurants of the same franchise. As of April 2005, veggie burgers were available in all Burger King restaurants (although, not vegan : ), and certain Subway restaurants. Many "greasy spoon" cafes as well as top-of-the-range eateries also offer veggie burgers as an option. In places like India where vegetarianism is popular, McDonald's serves veggie burgers as it is one of the primary hot sellers.
Non-meat burgers made by Boca, Gardenburger, and Morningstar Farms are sold extensively in supermarkets across America.
The first veggie burger was created, in London, by Gregory Sams in 1982, calling it the 'VegeBurger'. Gregory and his brother Craig had run a famous natural food restaurant in Paddington since the 1960s. A Carrefour hypermarket in Southampton sold 2000 packets in three weeks after its launch, which was reported in The Observer newspaper on February 27, 1983.
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Veggie burger
A veggie burger is a vegetarian hamburger. The patty of a veggie burger can be made from vegetables, nuts, dairy, mushrooms, textured vegetable protein (TVP), or a combination of these. They are sometimes vegan.
Veggie burgers are available in a growing number of fast-food restaurants in the U.S., but availability may vary geographically or even among particular restaurants of the same franchise. As of April 2005, veggie burgers were available in all Burger King restaurants (although, not vegan : http://www.vegparadise.com/news15.html)[citation needed], and certain Subway restaurants. Many "greasy spoon" cafes as well as top-of-the-range eateries also offer veggie burgers as an option. In places like India where vegetarianism is popular, McDonald's serves veggie burgers as it is one of the primary hot sellers.
Non-meat burgers made by Boca, Gardenburger, and Morningstar Farms are sold extensively in supermarkets across America.
The first veggie burger was created, in London, by Gregory Sams in 1982, calling it the 'VegeBurger'. Gregory and his brother Craig had run a famous natural food restaurant in Paddington since the 1960s.[1] A Carrefour hypermarket in Southampton sold 2000 packets in three weeks after its launch, which was reported in The Observer newspaper on February 27, 1983.[2]
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https://www.wikidoc.org/index.php/Veggie_burger
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55142a110331c94e55a495d1daf781867c9a88f7
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wikidoc
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Vinyl bromide
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Vinyl bromide
# Overview
Vinyl bromide is a simple vinyl halide. It is soluble in chloroform, ethanol, diethyl ether, acetone and benzene.
# Uses
Vinyl bromide is used to manufacture bromopolymers and mainly polyvinyl bromide. Further it is used as a flame retardant and as an alkylation agent.
# Safety precautions
Vinyl bromide is highly flammable liquid and reacts violently with oxidizers.
It is listed in List of IARC Group 2A carcinogens as a suspected human carcinogen.
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Vinyl bromide
Template:Chembox new
# Overview
Vinyl bromide is a simple vinyl halide. It is soluble in chloroform, ethanol, diethyl ether, acetone and benzene.
# Uses
Vinyl bromide is used to manufacture bromopolymers and mainly polyvinyl bromide. Further it is used as a flame retardant and as an alkylation agent.
# Safety precautions
Vinyl bromide is highly flammable liquid and reacts violently with oxidizers.
It is listed in List of IARC Group 2A carcinogens as a suspected human carcinogen.
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https://www.wikidoc.org/index.php/Vinyl_bromide
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1805ae44aa7a516530947c2f1910163f0c6438f3
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wikidoc
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Virtual image
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Virtual image
In optics, a virtual image is an image in which the outgoing rays from a point on the object never actually intersect at a point. A simple example is a flat mirror where the image of oneself is perceived at twice the distance from yourself to the mirror. That is, if you are half a meter in front of the mirror, your image will appear at a distance of half a meter inside or behind the mirror.
To contrast, a real image is an image in which the outgoing rays from a point on the object pass through a single point. It is easiest to observe real images when projected on an opaque screen. A screen is not necessary for the image to form.
- When we look through a diverging lens (at least one concave surface) or look into a convex mirror, what we see is a virtual image. However, if we observe a focused image on a screen inside or behind a converging lens (at least one convex side) or in front of a concave mirror what we see on the screen is a real image because the image really is at the screen's location. If we position ourselves so that the screen is directly between ourselves and the optical device (mirror, lens, etc.), we can remove the screen and still observe the image. It is also important to note that a converging lens and concave mirror are also capable of producing virtual images if the object is within the focal length.
- For example, a plane or convex mirror forms a virtual image positioned behind the mirror. Although rays of light seem to come from behind the mirror, light from the source spreads and exists only in front of the mirror. In drawings of optical systems, virtual rays are conventionally represented by dotted lines. Optical rays represent paths on which light actually travels. A virtual ray (the dotted lines) represent perceived paths as seen by an observer looking into the optical device. The light rays do not travel on these dotted paths. A point on the image is located where the virtual rays intersect.
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Virtual image
In optics, a virtual image is an image in which the outgoing rays from a point on the object never actually intersect at a point. A simple example is a flat mirror where the image of oneself is perceived at twice the distance from yourself to the mirror. That is, if you are half a meter in front of the mirror, your image will appear at a distance of half a meter inside or behind the mirror.
To contrast, a real image is an image in which the outgoing rays from a point on the object pass through a single point. It is easiest to observe real images when projected on an opaque screen. A screen is not necessary for the image to form.[1]
- When we look through a diverging lens (at least one concave surface) or look into a convex mirror, what we see is a virtual image. However, if we observe a focused image on a screen inside or behind a converging lens (at least one convex side) or in front of a concave mirror what we see on the screen is a real image because the image really is at the screen's location. If we position ourselves so that the screen is directly between ourselves and the optical device (mirror, lens, etc.), we can remove the screen and still observe the image. It is also important to note that a converging lens and concave mirror are also capable of producing virtual images if the object is within the focal length.
- For example, a plane or convex mirror forms a virtual image positioned behind the mirror. Although rays of light seem to come from behind the mirror, light from the source spreads and exists only in front of the mirror. In drawings of optical systems, virtual rays are conventionally represented by dotted lines. Optical rays represent paths on which light actually travels. A virtual ray (the dotted lines) represent perceived paths as seen by an observer looking into the optical device. The light rays do not travel on these dotted paths. A point on the image is located where the virtual rays intersect.
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https://www.wikidoc.org/index.php/Virtual_image
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9251e7af1886a3b4a98f3899d09501c0f84cb264
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Vitrification
|
Vitrification
Vitrification is a process of converting a material into a glass-like amorphous solid that is free from any crystalline structure, either by the quick removal or addition of heat, or by mixing with an additive. Solidification of a vitreous solid occurs at the glass transition temperature (which is lower than melting temperature, Tm, due to supercooling).
When the starting material is solid, vitrification usually involves heating the substances to very high temperatures. Many ceramics are produced in such a manner. Vitrification may also occur naturally when lightning strikes sand, where the extreme and immediate heat can create hollow, branching rootlike structures of glass, called fulgurite. When applied to whiteware ceramics, vitreous means the material has an extremely low permeability to liquids, often but not always water, when determined by a specified test regime. The microstructure of whiteware ceramics frequently contain both amorphous and crystalline phases.
# Examples
When sucrose is cooled slowly, the result is crystal sugar (or rock candy), but, when cooled rapidly, the result can be in the form of syrupy cotton candy (candyfloss). Vitrification can also occur when starting with a liquid such as water, usually through very rapid cooling or the introduction of agents that suppress the formation of ice crystals. Additives used in cryobiology or produced naturally by organisms living in polar regions are called cryoprotectants. Arctic frogs and some other ectotherms naturally produce glycerol or glucose in their livers to reduce ice formation. When glucose is used as a cryoprotectant by Arctic frogs, massive amounts of glucose are released at low temperature, and a special form of insulin allows for this extra glucose to enter the cells. When the frog rewarms during spring, the extra glucose must be rapidly removed from the cells and recycled via renal excretion and storage in the bladder. Arctic insects also use sugars as cryoprotectants. Arctic fish use antifreeze proteins, sometimes appended with sugars, as cryoprotectants.
# Applications
Ordinary soda-lime glass, used in windows and drinking containers, is created by the addition of sodium carbonate and lime (calcium oxide) to silicon dioxide. Without these additives, silicon dioxide will (with slow cooling) form sand or quartz crystal, not glass.
Vitrification is a proven technique in the disposal and long-term storage of nuclear waste or other hazardous wastes. Waste is mixed with glass-forming chemicals to form molten glass that then solidifies, immobilizing the waste. The final waste form resembles obsidian and is a non-leaching, durable material that effectively traps the waste inside. The waste can be stored for relatively long periods in this form without concern for air or groundwater contamination. Bulk vitrification uses electrodes to melt soil and wastes where they lay buried. The hardened waste may then be disinterred with less danger of widespread contamination. According to the Pacific Northwest National Labs, "Vitrification locks dangerous materials into a stable glass form that will last for thousands of years."
Ethylene glycol is used as automotive antifreeze and propylene glycol has been used to reduce ice crystals in ice cream, making it smoother.
For years, glycerol has been used in cryobiology as a cryoprotectant for blood cells and bull sperm, allowing storage at liquid nitrogen temperatures. However, glycerol cannot be used to protect whole organs from damage. Instead, many biotechnology companies are currently researching the development of other cryoprotectants more suitable for such uses. A successful discovery may eventually make possible the bulk cryogenic storage (or "banking") of transplantable human and xenobiotic organs. A substantial step in that direction has already occurred. At the July 2005 annual conference of the Society for Cryobiology, Twenty-First Century Medicine announced the vitrification of a rabbit kidney to -135°C with their proprietary vitrification cocktail. Upon rewarming, the kidney was successfully transplanted into a rabbit, with complete functionality and viability.
In the context of cryonics, especially in preservation of the human brain, vitrification of tissue is thought to be necessary to prevent destruction of the tissue or information encoded in the brain. At present, vitrification techniques have only been applied to brains (neurovitrification) by Alcor and to the upper body by the Cryonics Institute, but research is in progress by both organizations to apply vitrification to the whole body.
|
Vitrification
Vitrification is a process of converting a material into a glass-like amorphous solid that is free from any crystalline structure, either by the quick removal or addition of heat, or by mixing with an additive. Solidification of a vitreous solid occurs at the glass transition temperature (which is lower than melting temperature, Tm, due to supercooling).
When the starting material is solid, vitrification usually involves heating the substances to very high temperatures. Many ceramics are produced in such a manner. Vitrification may also occur naturally when lightning strikes sand, where the extreme and immediate heat can create hollow, branching rootlike structures of glass, called fulgurite. When applied to whiteware ceramics, vitreous means the material has an extremely low permeability to liquids, often but not always water, when determined by a specified test regime. The microstructure of whiteware ceramics frequently contain both amorphous and crystalline phases.
# Examples
When sucrose is cooled slowly, the result is crystal sugar (or rock candy), but, when cooled rapidly, the result can be in the form of syrupy cotton candy (candyfloss). Vitrification can also occur when starting with a liquid such as water, usually through very rapid cooling or the introduction of agents that suppress the formation of ice crystals. Additives used in cryobiology or produced naturally by organisms living in polar regions are called cryoprotectants. Arctic frogs and some other ectotherms naturally produce glycerol or glucose in their livers to reduce ice formation. When glucose is used as a cryoprotectant by Arctic frogs, massive amounts of glucose are released at low temperature[1], and a special form of insulin allows for this extra glucose to enter the cells. When the frog rewarms during spring, the extra glucose must be rapidly removed from the cells and recycled via renal excretion and storage in the bladder. Arctic insects also use sugars as cryoprotectants. Arctic fish use antifreeze proteins, sometimes appended with sugars, as cryoprotectants.
# Applications
Ordinary soda-lime glass, used in windows and drinking containers, is created by the addition of sodium carbonate and lime (calcium oxide) to silicon dioxide. Without these additives, silicon dioxide will (with slow cooling) form sand or quartz crystal, not glass.
Vitrification is a proven technique in the disposal and long-term storage of nuclear waste or other hazardous wastes[2]. Waste is mixed with glass-forming chemicals to form molten glass that then solidifies, immobilizing the waste. The final waste form resembles obsidian and is a non-leaching, durable material that effectively traps the waste inside. The waste can be stored for relatively long periods in this form without concern for air or groundwater contamination. Bulk vitrification uses electrodes to melt soil and wastes where they lay buried. The hardened waste may then be disinterred with less danger of widespread contamination. According to the Pacific Northwest National Labs, "Vitrification locks dangerous materials into a stable glass form that will last for thousands of years."[3]
Ethylene glycol is used as automotive antifreeze and propylene glycol has been used to reduce ice crystals in ice cream, making it smoother.
For years, glycerol has been used in cryobiology as a cryoprotectant for blood cells and bull sperm, allowing storage at liquid nitrogen temperatures. However, glycerol cannot be used to protect whole organs from damage. Instead, many biotechnology companies are currently researching the development of other cryoprotectants more suitable for such uses. A successful discovery may eventually make possible the bulk cryogenic storage (or "banking") of transplantable human and xenobiotic organs. A substantial step in that direction has already occurred. At the July 2005 annual conference of the Society for Cryobiology[4], Twenty-First Century Medicine announced the vitrification of a rabbit kidney to -135°C with their proprietary vitrification cocktail. Upon rewarming, the kidney was successfully transplanted into a rabbit, with complete functionality and viability.
In the context of cryonics, especially in preservation of the human brain, vitrification of tissue is thought to be necessary to prevent destruction of the tissue or information encoded in the brain. At present, vitrification techniques have only been applied to brains (neurovitrification) by Alcor and to the upper body by the Cryonics Institute, but research is in progress by both organizations to apply vitrification to the whole body.
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https://www.wikidoc.org/index.php/Vitrification
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1ba3b5895c01c11cd44572a31fa460cdc9d0e205
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wikidoc
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Vitruvian Man
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Vitruvian Man
The Vitruvian Man is a world-renowned drawing with accompanying notes created by Leonardo da Vinci around the year 1487 as recorded in one of his journals. It depicts a nude male figure in two superimposed positions with his arms and legs apart and simultaneously inscribed in a circle and square. The drawing and text are sometimes called the Canon of Proportions or, less often, Proportions of Man. It is stored in the Gallerie dell'Accademia in Venice, Italy, but is only displayed on special occasions.
# Description
Da Vinci based his drawing on some hints at correlations of ideal human proportions with geometry in Book III of the treatise De Architectura by the ancient Roman architect Vitruvius, thus its name. Other artists had attempted to realize the conception, with less success. Vitruvius described as the principal source of proportion among the orders of architecture the proportion of the human figure.
This image exemplifies the blend of art and science during the Renaissance and provides the perfect example of da Vinci's keen interest in proportion. In addition, this picture represents a cornerstone of Da Vinci's attempts to relate man to nature. Encyclopaedia Britannica online states, "Leonardo envisaged the great picture chart of the human body he had produced through his anatomical drawings and Vitruvian Man as a cosmografia del minor mondo (cosmography of the microcosm). He believed the workings of the human body to be an analogy for the workings of the universe." It is also believed by some that Leonardo symbolized the material existence by the square and spiritual existence by the circle. Thus he attempted to depict the correlation between these two aspects of human existence.
According to Leonardo's notes in the accompanying text, written in mirror writing, it was made as a study of the proportions of the (male) human body as described in Vitruvius, who wrote that in the human body:
- a palm is the width of four fingersTemplate:Vitruvian Man Measurements
- a foot is the width of four palms (i.e. 12 inches)
- a cubit is the width of six palms
- a man's height is four cubits (and thus 24 palms)
- a pace is four cubits
- the length of a man's outspread arms is equal to his height
- the distance from the hairline to the bottom of the chin is one-tenth of a man's height
- the distance from the top of the head to the bottom of the chin is one-eighth of a man's height
- the maximum width of the shoulders is a quarter of a man's height
- the distance from the elbow to the tip of the hand is one-fifth of a man's height
- the distance from the elbow to the armpit is one-eighth of a man's height
- the length of the hand is one-tenth of a man's height
- the distance from the bottom of the chin to the nose is one-third of the length of the head
- the distance from the hairline to the eyebrows is one-third of the length of the face
- the length of the ear is one-third of the length of the face
Da Vinci is clearly illustrating Vitruvius' De architectura 3.1.3 which reads:
The multiple viewpoint that set in with Romanticism has convinced us that there is no such thing as a universal set of proportions for the human body. The field of anthropometry was created in order to describe these individual variations. Vitruvius' statements may be interpreted as statements about average proportions. Vitruvius goes through some trouble to give a precise mathematical definition of what he means by saying that the navel is the center of the body, but other definitions lead to different results; for example, the center of mass of the human body depends on the position of the limbs, and in a standing posture is typically about 10 cm lower than the navel, near the top of the hip bones.
Note that Leonardo's drawing combines a careful reading of the ancient text, combined with his own observation of actual human bodies. In drawing the circle and square he correctly observes that the square cannot have the same center as the circle, the navel, but is somewhat lower in the anatomy. This adjustment is the innovative part of Leonardo's drawing and what distinguishes it from earlier illustrations. He also departs from Vitruvius by drawing the arms raised to a position in which the fingertips are level with the top of the head, rather than Vitruvius's much higher angle, in which the arms form lines passing through the navel.
The drawing itself is often used as an implied symbol of the essential symmetry of the human body, and by extension, to the universe as a whole.
It may be noticed by examining the drawing that the combination of arm and leg positions actually creates sixteen different poses. The pose with the arms straight out and the feet together is seen to be inscribed in the superimposed square. On the other hand, the "spread-eagle" pose is seen to be inscribed in the superimposed circle.
The drawing was in the collection of Giuseppe Bossi, who illustrated it in his monograph on Leonardo's The Last Supper, Del Cenacolo di Leonardo Da Vinci libri quattro (Milan 1810). The following year he excerpted the section of his monograph concerned with Leonardo's "Vitruvian Man" and published it as Delle opinioni di Leonardo da Vinci intorno alla simmetria de'Corpi Umani (Milan: Stamperia Reale, 1811), with a dedication to his friend Antonio Canova.
Dedicated by the author to his friend, the neoclassical sculptor Antonio Canova, this discussion of Leonardo's theory of human proportions is extracted from Bossi monograph on the Last Supper, pp. 202-26 (No. 318).
After his death in 1815 it was acquired with the bulk of his drawings by the Accademia, and later acquired by Microsoft founder Bill Gates.
# Representations in modern times
The Vitruvian Man is now used as a contemporary symbol of medical professionals and medical establishments. Many medical companies have adopted this artwork as their symbol of their group, company and or organization.
The medical profession and the Vitruvian Man has become somewhat synonymous with modern medical practices. The United States, Saudi Arabia, India and Germany are the countries which have widely accepted and adopted the Vitruvian Man as a symbol of medical professionalism.
The Vitruvian Man remains one of the most referenced and reproduced artistic images in the world today. The proportions for the human body, as proposed by Vitruvius, have inspired many other artists in drawing their version of the Vitruvian Man:
- Cesare Ceasariano (1521) who edited the important 1521 edition of “De Archtectura” of Vitruvius (Leonardo da Vinci is supposed to have provided the illustrations for this edition).
- Albrecht Dürer (1528) in his book Vier Bücher von menschlicher Proportion (Four books on human proportions)
- Pietro di Giacomo Cataneo (1554)
- Heinrich Lautensack (1618)
- William Blake (1795) “Glad Day” (now known as "Albion rose"). This representation is without the circle and square.
As well as its use by the medical profession, the Vitruvian Man has been used in a variety of fictional and non-fictional media, for various symbolic purposes. For example, the image appears on the national side of Italian 1 euro coins, chosen by the Economy minister (and later President of the Italian Republic) Carlo Azeglio Ciampi for its high symbolic meaning of "man as a measure of all things".
Particularly when used in fiction, the image of the Vitruvian Man is commonly modified to suit the setting by featuring a character, a skeleton or a non-human (such as a robot in science fiction or an animal). The easily-recognisable image lends itself to being referenced.
Canadian heavy metal band Triumph used the image, only altered to adapt as the 'Study Of Man' in the 21st century, making it robotic and adding two heads. This image appeared as the cover of the bands seventh album, Thunder Seven
The cover of the In Flames album Clayman features the Vitruvian man with the band's logo, the Jesterhead, as the background.
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Vitruvian Man
The Vitruvian Man is a world-renowned drawing with accompanying notes created by Leonardo da Vinci around the year 1487[1] as recorded in one of his journals. It depicts a nude male figure in two superimposed positions with his arms and legs apart and simultaneously inscribed in a circle and square. The drawing and text are sometimes called the Canon of Proportions or, less often, Proportions of Man. It is stored in the Gallerie dell'Accademia in Venice, Italy, but is only displayed on special occasions.[2][3]
# Description
Da Vinci based his drawing on some hints at correlations of ideal human proportions with geometry in Book III of the treatise De Architectura by the ancient Roman architect Vitruvius, thus its name. Other artists had attempted to realize the conception, with less success. Vitruvius described as the principal source of proportion among the orders of architecture the proportion of the human figure.
This image exemplifies the blend of art and science during the Renaissance and provides the perfect example of da Vinci's keen interest in proportion. In addition, this picture represents a cornerstone of Da Vinci's attempts to relate man to nature. Encyclopaedia Britannica online states, "Leonardo envisaged the great picture chart of the human body he had produced through his anatomical drawings and Vitruvian Man as a cosmografia del minor mondo (cosmography of the microcosm). He believed the workings of the human body to be an analogy for the workings of the universe." It is also believed by some that Leonardo symbolized the material existence by the square and spiritual existence by the circle. Thus he attempted to depict the correlation between these two aspects of human existence.[4]
According to Leonardo's notes in the accompanying text, written in mirror writing, it was made as a study of the proportions of the (male) human body as described in Vitruvius, who wrote that in the human body:
- a palm is the width of four fingersTemplate:Vitruvian Man Measurements
- a foot is the width of four palms (i.e. 12 inches)
- a cubit is the width of six palms
- a man's height is four cubits (and thus 24 palms)
- a pace is four cubits
- the length of a man's outspread arms is equal to his height
- the distance from the hairline to the bottom of the chin is one-tenth of a man's height
- the distance from the top of the head to the bottom of the chin is one-eighth of a man's height
- the maximum width of the shoulders is a quarter of a man's height
- the distance from the elbow to the tip of the hand is one-fifth of a man's height
- the distance from the elbow to the armpit is one-eighth of a man's height
- the length of the hand is one-tenth of a man's height
- the distance from the bottom of the chin to the nose is one-third of the length of the head
- the distance from the hairline to the eyebrows is one-third of the length of the face
- the length of the ear is one-third of the length of the face
Da Vinci is clearly illustrating Vitruvius' De architectura 3.1.3 which reads:
The multiple viewpoint that set in with Romanticism has convinced us that there is no such thing as a universal set of proportions for the human body. The field of anthropometry was created in order to describe these individual variations. Vitruvius' statements may be interpreted as statements about average proportions. Vitruvius goes through some trouble to give a precise mathematical definition of what he means by saying that the navel is the center of the body, but other definitions lead to different results; for example, the center of mass of the human body depends on the position of the limbs, and in a standing posture is typically about 10 cm lower than the navel, near the top of the hip bones.
Note that Leonardo's drawing combines a careful reading of the ancient text, combined with his own observation of actual human bodies. In drawing the circle and square he correctly observes that the square cannot have the same center as the circle, the navel, but is somewhat lower in the anatomy. This adjustment is the innovative part of Leonardo's drawing and what distinguishes it from earlier illustrations. He also departs from Vitruvius by drawing the arms raised to a position in which the fingertips are level with the top of the head, rather than Vitruvius's much higher angle, in which the arms form lines passing through the navel.
The drawing itself is often used as an implied symbol of the essential symmetry of the human body, and by extension, to the universe as a whole.
It may be noticed by examining the drawing that the combination of arm and leg positions actually creates sixteen different poses. The pose with the arms straight out and the feet together is seen to be inscribed in the superimposed square. On the other hand, the "spread-eagle" pose is seen to be inscribed in the superimposed circle.
The drawing was in the collection of Giuseppe Bossi, who illustrated it in his monograph on Leonardo's The Last Supper, Del Cenacolo di Leonardo Da Vinci libri quattro (Milan 1810).[5] The following year he excerpted the section of his monograph concerned with Leonardo's "Vitruvian Man" and published it as Delle opinioni di Leonardo da Vinci intorno alla simmetria de'Corpi Umani (Milan: Stamperia Reale, 1811), with a dedication to his friend Antonio Canova.[6]
Dedicated by the author to his friend, the neoclassical sculptor Antonio Canova, this discussion of Leonardo's theory of human proportions is extracted from Bossi monograph on the Last Supper, pp. 202-26 (No. 318).
After his death in 1815 it was acquired with the bulk of his drawings by the Accademia, and later acquired by Microsoft founder Bill Gates.
# Representations in modern times
The Vitruvian Man is now used as a contemporary symbol of medical professionals and medical establishments. Many medical companies have adopted this artwork as their symbol of their group, company and or organization.
The medical profession and the Vitruvian Man has become somewhat synonymous with modern medical practices. The United States, Saudi Arabia, India and Germany are the countries which have widely accepted and adopted the Vitruvian Man as a symbol of medical professionalism.
The Vitruvian Man remains one of the most referenced and reproduced artistic images in the world today. The proportions for the human body, as proposed by Vitruvius, have inspired many other artists in drawing their version of the Vitruvian Man:
- Cesare Ceasariano (1521) who edited the important 1521 edition of “De Archtectura” of Vitruvius (Leonardo da Vinci is supposed to have provided the illustrations for this edition).
- Albrecht Dürer (1528) in his book Vier Bücher von menschlicher Proportion (Four books on human proportions)
- Pietro di Giacomo Cataneo (1554)
- Heinrich Lautensack (1618)
- William Blake (1795) “Glad Day” (now known as "Albion rose"). This representation is without the circle and square.
As well as its use by the medical profession, the Vitruvian Man has been used in a variety of fictional and non-fictional media, for various symbolic purposes. For example, the image appears on the national side of Italian 1 euro coins, chosen by the Economy minister (and later President of the Italian Republic) Carlo Azeglio Ciampi for its high symbolic meaning of "man as a measure of all things".
Particularly when used in fiction, the image of the Vitruvian Man is commonly modified to suit the setting by featuring a character[7], a skeleton or a non-human[8] (such as a robot[9] in science fiction or an animal). The easily-recognisable image lends itself to being referenced.[10]
Canadian heavy metal band Triumph used the image, only altered to adapt as the 'Study Of Man' in the 21st century, making it robotic and adding two heads. This image appeared as the cover of the bands seventh album, Thunder Seven
The cover of the In Flames album Clayman features the Vitruvian man with the band's logo, the Jesterhead, as the background.
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Voltage clamp
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Voltage clamp
The voltage clamp is used by electrophysiologists to measure the ion currents across a neuronal membrane while holding the membrane voltage at a set level. Neuronal membranes contain many different kinds of ion channels, some of which are voltage gated. The voltage clamp allows the membrane voltage to be manipulated independently of the ionic currents, allowing the current-voltage relationships of membrane channels to be studied.
The concept of the voltage clamp is due to Kenneth Cole and George Marmount in the 1940s. Cole discovered that it was possible to use two electrodes and a feedback circuit to keep the cell's membrane potential at a level set by the experimenter.
Alan Hodgkin realized that, to understand ion flux across the membrane, it was necessary to eliminate differences in membrane potential. After experiments with the voltage clamp, Hodgkin and Andrew Huxley outlined the ionic causes of the action potential in 1952, for which they shared the Nobel Prize for Physiology or Medicine in 1963.
# Technique
The voltage clamp is a current generator with two electrodes. Transmembrane voltage is recorded through a "voltage electrode", relative to ground, and a "current electrode" passes current into the cell. The experimenter sets a "holding voltage", or "command potential", and the voltage clamp uses negative feedback to maintain the cell at this voltage. The electrodes are connected to an amplifier, which measures membrane potential and feeds the signal into a feedback amplifier. This amplifier also gets an input from the signal generator that determines the command potential, and it subtracts the membrane potential from the command potential (Vcommand - Vm), magnifies any difference, and sends an output to the current electrode. Whenever the cell deviates from the holding voltage, the operational amplifier generates an "error signal", that is the difference between the command potential and the actual voltage of the cell. The feedback circuit passes current into the cell to reduce the error signal to zero. Thus, the clamp circuit produces a current equal and opposite to the ionic current. This can be measured, giving an accurate reproduction of the currents flowing across the membrane.
Cole developed the voltage clamp technique before the era of microelectrodes, so his two electrodes consisted of fine wires twisted around an insulating rod. Because this type of electrode could be inserted into only the largest cells, early electrophysiological experiments were conducted almost exclusively on squid axons. Squid squirt jets of water when they need to move quickly, as when escaping a predator. To make this escape as fast as possible, they have an axon that can reach 1 mm in diameter (signals propagate more quickly down large axons). The squid giant axon was the first preparation that could be used to voltage clamp a transmembrane current, and it was the basis of Hodgkin and Huxley's pioneering experiments on the properties of the action potential.
# Variations of the voltage clamp technique
A more detailed discussion of the below techniques can be found in the Axon Guide. The book is now out of print but can be downloaded in PDF form from Axon Instruments.
### Two-electrode voltage clamp using microelectrodes
This works on the same principle, but the two electrodes are glass pipettes with very fine tips (smaller than 1 micrometer), allowing for clamping of cells smaller than the squid axon. However, microelectrodes are much poorer conductors than the wires used by Cole, and sometimes cannot pass current rapidly enough to compensate for cellular current. The faster the kinetics of the current (onset and offset), the more likely it is that the clamp will be unable to "follow" it faithfully. Another disadvantage involves "space clamp" issues. Cole's voltage clamp used a long wire that clamped the squid axon uniformly along its entire length. Microelectrodes can provide only a spatial point source of current that might not uniformly affect different parts of an irregularly shaped cell.
### Single-electrode voltage clamp
In this, an electrode is placed inside a cell, and serves both the voltage-recording and current-passing duties.
### Continuous single-electrode clamp (SEVC-c)
The "patch-clamp" technique allows the study of individual ion channels. It uses an electrode with a relatively large tip (> 1 micrometer) which has a smooth surface (rather than a sharp tip). This is a "patch-clamp electrode" (as distinct from a "sharp electrode" used to impale cells). This electrode is pressed against a cell membrane and suction is applied to pull the cell's membrane inside the electrode tip. The suction causes the cell to form a tight seal with the electrode (a "gigaohm seal", as the resistance is more than a gigaohm).
SEV-c has the advantage is that you can record from small cells that would be impossible to impale with two electrodes. However:
1) Microelectrodes are imperfect conductors; they generally have a resistance of more than a million ohms. They rectify (i.e. change their resistance with voltage, often in an irregular manner), they sometimes have unstable resistance if clogged by cell contents. Thus they will not faithfully record the voltage of the cell, especially when it is changing quickly, nor will they faithfully pass current.
2) Voltage and current errors: SEV-c circuitry does not actually measure the voltage of the cell being clamped (as does a two-electrode clamp). The patch-clamp amplifier is like a two-electrode clamp, except the voltage measuring and current passing circuits are connected (in the two-electrode clamp, they are connected through the cell). The electrode is attached to a wire that contacts the current/voltage loop inside the amplifier. Thus the electrode has only an indirect influence on the feedback circuit. The amplifier reads only the voltage at the top of the electrode, and feeds back current to compensate. But, if the electrode is an imperfect conductor, the clamp circuity has only a distorted view of the membrane potential. Similarly, when the circuit passes back current to compensate for that (distorted) voltage, the current will be distorted by the electrode before it reaches the cell. To compensate for this, the electrophysiologist uses the lowest resistance electrode possible, makes sure that the electrode characteristics don't change during an experiment (so the errors will be constant), and avoids recording currents with kinetics likely to be too fast for the clamp to follow accurately. The accuracy of SEV-c goes up the slower and smaller are the voltage changes it is trying to clamp.
3) Series resistance errors: The currents passed to the cell must go to ground to complete the circuit. The voltages are recorded by the amplifier relative to ground. When a cell is clamped at its natural resting potential, there is no problem; the clamp is not passing current and the voltage is being generated only by the cell. But when clamping at a different potential, series resistance errors become a concern; the cell will pass current across its membrane in an attempt to return to its natural resting potential. The clamp amplifier opposes this by passing current to maintain the holding potential. A problem arises because the electrode is between the amplifier and the cell, i.e. the electrode is in series with the resistor that is the cell's membrane. Thus, when passing current through the electrode and the cell, Ohm's Law tells us that this will cause a voltage to form across both the cell's and the electrode's resistance. As these resistors are in series, the voltage drops will add. If the electrode and the cell membrane have equal resistances (which they usually do not), and if the experimenter command a 40mV change from the resting potential, the amplifier will pass enough current until it reads that it has achieved that 40mV change. However, in this example, half of that voltage drop is across the electrode. The experimenter thinks he or she has moved the cell voltage by 40mV, but has moved it only by 20mV. The difference is the "series resistance error". Modern patch-clamp amplifiers have circuity to compensate for this error, but these compensate only 70-80% of it. The electrophysiologist can further reduce the error by recording at or near the cell's natural resting potential, and by using as low a resistance electrode as possible.
4) Capacitance errors. Microelectrodes are capacitors, and are particularly troublesome because they are non-linear. The capacitance arises because the electrolyte inside the electrode is separated by an insulator (glass) from the solution outside. This is, by definition and function, a capacitor. Worse, as the thickness of the glass changes the farther you get from the tip, the time constant of the capacitor will vary. This produces a distorted record of membrane voltage or current whenever they are changing. Amplifiers can compensate for this, but not entirely because the capacitance has many time-constants. The experimenter can reduce the problem by keeping the cell's bathing solution shallow (exposing less glass surface to liquid) and by coating the electrode with silicone, resin, paint, or another substance that will increase the distance between the inside and outside solutions.
5) Space clamp errors. A single electrode is a point source of current. In distant parts of the cell, the current passed through the electrode will be less influential than at nearby parts of the cell. This is particularly a problem when recording from neurons with elaborate dendritic structures. There is nothing one can do about space clamp errors except to temper the conclusions of the experiment.
### Discontinuous single-electrode voltage-clamp
A single-electrode voltage clamp — discontinuous, or SEVC-d, has some advantages over SEVC-c for “whole-cell” recording. In this, a different approach is taken for passing current and recording voltage. An SEVC-d amplifier oscillates between passing current and measuring voltage. One oscillation is a “duty cycle”. During a cycle, the amplifier measures the membrane potential and compares it with the holding potential. An operational amplifier measures the difference, and generates an error signal. This current is a mirror image of the current generated by the cell. The amplifier outputs feature sample and hold circuits, so each briefly sampled voltage is then held on the output until the next measurement in the next cycle. Specifically, the amplifier measures voltage in the first few milliseconds of the cycle, generates the error signal, and spends the rest of the cycle passing current to reduce that error. At the start of the next cycle, voltage is measured again, a new error signal generated, current passed etc. The experimenter sets the cycle length, and it is possible to sample every 500-333 microseconds.
For this to work, the cell capacitance must be higher than the electrode capacitance by at least an order of magnitude. Capacitance slows the kinetics (the rise and fall times) of currents. If the electrode capacitance is much less than that of the cell, then when current is passed through the electrode, the electrode voltage will change faster than the cell voltage. Thus when you inject current and then turn it off (at the end of a duty cycle), the electrode voltage will decay faster than the cell voltage. As soon as the electrode voltage asymptotes to the cell voltage, the voltage can be sampled (again) and the next bolus of current applied. Thus the frequency of the duty cycle is limited to the speed at which the electrode voltage rises and decays while passing current. The lower the electrode capacitance, the faster one can cycle.
SEVC-d has a major advantage over SEVC-c in allowing the experimenter to measure membrane potential, and as it obviates passing current and measuring voltage at the same time, there is never a series resistance error. The main disadvantages are that the time resolution is limited, and the amplifier is unstable. If it passes too much current, so that the goal voltage is over-shot, it reverses the polarity of the current in the next duty cycle. This causes it to undershoot the target voltage, so the next cycle reverses the polarity of the injected current again. This error can grow with each cycle until the amplifier oscillates out of control (“ringing”); this usually results in the destruction of the cell being recorded. The investigator wants a short duty cycle to improve temporal resolution; the amplifier has adjustable compensators that will make the electrode voltage decay faster, but if these are set too high the amplifier will ring, so the investigator is always trying to “tune” the amplifier as close to the edge of uncontrolled oscillation as possible, in which case small changes in recording conditions can cause ringing. There are two solutions: to “back off” the amplifier settings into a safe range, or to be alert for signs that the amplifier is about to ring.
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Voltage clamp
The voltage clamp is used by electrophysiologists to measure the ion currents across a neuronal membrane while holding the membrane voltage at a set level. Neuronal membranes contain many different kinds of ion channels, some of which are voltage gated. The voltage clamp allows the membrane voltage to be manipulated independently of the ionic currents, allowing the current-voltage relationships of membrane channels to be studied.[1]
The concept of the voltage clamp is due to Kenneth Cole[2] and George Marmount[3] in the 1940s. Cole discovered that it was possible to use two electrodes and a feedback circuit to keep the cell's membrane potential at a level set by the experimenter.
Alan Hodgkin realized that, to understand ion flux across the membrane, it was necessary to eliminate differences in membrane potential.[4] After experiments with the voltage clamp, Hodgkin and Andrew Huxley outlined the ionic causes of the action potential in 1952, for which they shared the Nobel Prize for Physiology or Medicine in 1963.[4]
# Technique
The voltage clamp is a current generator with two electrodes. Transmembrane voltage is recorded through a "voltage electrode", relative to ground, and a "current electrode" passes current into the cell. The experimenter sets a "holding voltage", or "command potential", and the voltage clamp uses negative feedback to maintain the cell at this voltage. The electrodes are connected to an amplifier, which measures membrane potential and feeds the signal into a feedback amplifier. This amplifier also gets an input from the signal generator that determines the command potential, and it subtracts the membrane potential from the command potential (Vcommand - Vm), magnifies any difference, and sends an output to the current electrode. Whenever the cell deviates from the holding voltage, the operational amplifier generates an "error signal", that is the difference between the command potential and the actual voltage of the cell. The feedback circuit passes current into the cell to reduce the error signal to zero. Thus, the clamp circuit produces a current equal and opposite to the ionic current. This can be measured, giving an accurate reproduction of the currents flowing across the membrane.
Cole developed the voltage clamp technique before the era of microelectrodes, so his two electrodes consisted of fine wires twisted around an insulating rod. Because this type of electrode could be inserted into only the largest cells, early electrophysiological experiments were conducted almost exclusively on squid axons. Squid squirt jets of water when they need to move quickly, as when escaping a predator. To make this escape as fast as possible, they have an axon that can reach 1 mm in diameter (signals propagate more quickly down large axons). The squid giant axon was the first preparation that could be used to voltage clamp a transmembrane current, and it was the basis of Hodgkin and Huxley's pioneering experiments on the properties of the action potential.
# Variations of the voltage clamp technique
A more detailed discussion of the below techniques can be found in the Axon Guide. The book is now out of print but can be downloaded in PDF form from Axon Instruments.
### Two-electrode voltage clamp using microelectrodes
This works on the same principle, but the two electrodes are glass pipettes with very fine tips (smaller than 1 micrometer), allowing for clamping of cells smaller than the squid axon. However, microelectrodes are much poorer conductors than the wires used by Cole, and sometimes cannot pass current rapidly enough to compensate for cellular current. The faster the kinetics of the current (onset and offset), the more likely it is that the clamp will be unable to "follow" it faithfully. Another disadvantage involves "space clamp" issues. Cole's voltage clamp used a long wire that clamped the squid axon uniformly along its entire length. Microelectrodes can provide only a spatial point source of current that might not uniformly affect different parts of an irregularly shaped cell.
### Single-electrode voltage clamp
In this, an electrode is placed inside a cell, and serves both the voltage-recording and current-passing duties.
### Continuous single-electrode clamp (SEVC-c)
The "patch-clamp" technique allows the study of individual ion channels. It uses an electrode with a relatively large tip (> 1 micrometer) which has a smooth surface (rather than a sharp tip). This is a "patch-clamp electrode" (as distinct from a "sharp electrode" used to impale cells). This electrode is pressed against a cell membrane and suction is applied to pull the cell's membrane inside the electrode tip. The suction causes the cell to form a tight seal with the electrode (a "gigaohm seal", as the resistance is more than a gigaohm).
SEV-c has the advantage is that you can record from small cells that would be impossible to impale with two electrodes. However:
1) Microelectrodes are imperfect conductors; they generally have a resistance of more than a million ohms. They rectify (i.e. change their resistance with voltage, often in an irregular manner), they sometimes have unstable resistance if clogged by cell contents. Thus they will not faithfully record the voltage of the cell, especially when it is changing quickly, nor will they faithfully pass current.
2) Voltage and current errors: SEV-c circuitry does not actually measure the voltage of the cell being clamped (as does a two-electrode clamp). The patch-clamp amplifier is like a two-electrode clamp, except the voltage measuring and current passing circuits are connected (in the two-electrode clamp, they are connected through the cell). The electrode is attached to a wire that contacts the current/voltage loop inside the amplifier. Thus the electrode has only an indirect influence on the feedback circuit. The amplifier reads only the voltage at the top of the electrode, and feeds back current to compensate. But, if the electrode is an imperfect conductor, the clamp circuity has only a distorted view of the membrane potential. Similarly, when the circuit passes back current to compensate for that (distorted) voltage, the current will be distorted by the electrode before it reaches the cell. To compensate for this, the electrophysiologist uses the lowest resistance electrode possible, makes sure that the electrode characteristics don't change during an experiment (so the errors will be constant), and avoids recording currents with kinetics likely to be too fast for the clamp to follow accurately. The accuracy of SEV-c goes up the slower and smaller are the voltage changes it is trying to clamp.
3) Series resistance errors: The currents passed to the cell must go to ground to complete the circuit. The voltages are recorded by the amplifier relative to ground. When a cell is clamped at its natural resting potential, there is no problem; the clamp is not passing current and the voltage is being generated only by the cell. But when clamping at a different potential, series resistance errors become a concern; the cell will pass current across its membrane in an attempt to return to its natural resting potential. The clamp amplifier opposes this by passing current to maintain the holding potential. A problem arises because the electrode is between the amplifier and the cell, i.e. the electrode is in series with the resistor that is the cell's membrane. Thus, when passing current through the electrode and the cell, Ohm's Law tells us that this will cause a voltage to form across both the cell's and the electrode's resistance. As these resistors are in series, the voltage drops will add. If the electrode and the cell membrane have equal resistances (which they usually do not), and if the experimenter command a 40mV change from the resting potential, the amplifier will pass enough current until it reads that it has achieved that 40mV change. However, in this example, half of that voltage drop is across the electrode. The experimenter thinks he or she has moved the cell voltage by 40mV, but has moved it only by 20mV. The difference is the "series resistance error". Modern patch-clamp amplifiers have circuity to compensate for this error, but these compensate only 70-80% of it. The electrophysiologist can further reduce the error by recording at or near the cell's natural resting potential, and by using as low a resistance electrode as possible.
4) Capacitance errors. Microelectrodes are capacitors, and are particularly troublesome because they are non-linear. The capacitance arises because the electrolyte inside the electrode is separated by an insulator (glass) from the solution outside. This is, by definition and function, a capacitor. Worse, as the thickness of the glass changes the farther you get from the tip, the time constant of the capacitor will vary. This produces a distorted record of membrane voltage or current whenever they are changing. Amplifiers can compensate for this, but not entirely because the capacitance has many time-constants. The experimenter can reduce the problem by keeping the cell's bathing solution shallow (exposing less glass surface to liquid) and by coating the electrode with silicone, resin, paint, or another substance that will increase the distance between the inside and outside solutions.
5) Space clamp errors. A single electrode is a point source of current. In distant parts of the cell, the current passed through the electrode will be less influential than at nearby parts of the cell. This is particularly a problem when recording from neurons with elaborate dendritic structures. There is nothing one can do about space clamp errors except to temper the conclusions of the experiment.
### Discontinuous single-electrode voltage-clamp
A single-electrode voltage clamp — discontinuous, or SEVC-d, has some advantages over SEVC-c for “whole-cell” recording. In this, a different approach is taken for passing current and recording voltage. An SEVC-d amplifier oscillates between passing current and measuring voltage. One oscillation is a “duty cycle”. During a cycle, the amplifier measures the membrane potential and compares it with the holding potential. An operational amplifier measures the difference, and generates an error signal. This current is a mirror image of the current generated by the cell. The amplifier outputs feature sample and hold circuits, so each briefly sampled voltage is then held on the output until the next measurement in the next cycle. Specifically, the amplifier measures voltage in the first few milliseconds of the cycle, generates the error signal, and spends the rest of the cycle passing current to reduce that error. At the start of the next cycle, voltage is measured again, a new error signal generated, current passed etc. The experimenter sets the cycle length, and it is possible to sample every 500-333 microseconds.
For this to work, the cell capacitance must be higher than the electrode capacitance by at least an order of magnitude. Capacitance slows the kinetics (the rise and fall times) of currents. If the electrode capacitance is much less than that of the cell, then when current is passed through the electrode, the electrode voltage will change faster than the cell voltage. Thus when you inject current and then turn it off (at the end of a duty cycle), the electrode voltage will decay faster than the cell voltage. As soon as the electrode voltage asymptotes to the cell voltage, the voltage can be sampled (again) and the next bolus of current applied. Thus the frequency of the duty cycle is limited to the speed at which the electrode voltage rises and decays while passing current. The lower the electrode capacitance, the faster one can cycle.
SEVC-d has a major advantage over SEVC-c in allowing the experimenter to measure membrane potential, and as it obviates passing current and measuring voltage at the same time, there is never a series resistance error. The main disadvantages are that the time resolution is limited, and the amplifier is unstable. If it passes too much current, so that the goal voltage is over-shot, it reverses the polarity of the current in the next duty cycle. This causes it to undershoot the target voltage, so the next cycle reverses the polarity of the injected current again. This error can grow with each cycle until the amplifier oscillates out of control (“ringing”); this usually results in the destruction of the cell being recorded. The investigator wants a short duty cycle to improve temporal resolution; the amplifier has adjustable compensators that will make the electrode voltage decay faster, but if these are set too high the amplifier will ring, so the investigator is always trying to “tune” the amplifier as close to the edge of uncontrolled oscillation as possible, in which case small changes in recording conditions can cause ringing. There are two solutions: to “back off” the amplifier settings into a safe range, or to be alert for signs that the amplifier is about to ring.
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a8316bd3101fa34de73e7e59a702289821081a2a
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Volume status
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Volume status
# Overview
In medicine, volume status refers to the volume of blood in a patient's circulatory system. This is related to the patient's state of hydration, but is not identical to it. For instance, volume depletion can exist in an adequately hydrated person if there is loss of water into interstitial tissue (e.g. due to hyponatremia or liver failure).
# Clinical assessment
### Volume depletion
Signs of volume depletion (low blood volume) include, in order of severity:
- A fast pulse
- Infrequent urination
- Dry mucous membranes (e.g. a dry tongue)
- Poor capillary refill (e.g. when the patient's fingertip is pressed, the skin turns white, but upon release, the skin does not return to pink as fast as it should)
- Decreased skin turgor (e.g. the skin remains "tented" when it is pinched)
- A weak pulse
- Orthostatic hypotension (dizziness upon standing up from a seated or reclining position, due to a drop in cerebral blood pressure)
- Cool extremities (e.g. cool fingers)
### Volume overload
Signs of volume overload (high blood volume) include:
- An elevated Jugular venous pressure (JVP)
# Pathophysiology
### Volume depletion
The most common cause of volume depletion is diarrhea or vomiting. The other causes are usually divided into renal and extrarenal causes. Renal causes include overuse of diuretics, or trauma or disease of the kidney. Extrarenal causes include bleeding, burns, and any causes of edema (e.g. congestive heart failure, liver failure, etc.).
Volume depletion is divided into three types based on the blood sodium level:
- Isonatremic (normal blood sodium levels) Example: a child with diarrhea, because both water and sodium are lost in diarrhea.
- Hyponatremic (abnormally low blood sodium levels). Example: a child with diarrhea who has been given tap water to replete diarrheal losses. Water is replenished, but sodium is not, so water flows out of the vasculature into the interstitial tissue.
- Hypernatremic (abnormally high blood sodium levels). Example: a child with diarrhea who has been given salty soup to drink, or insufficiently diluted infant formula. Here sodium has been replenished, but not enough water has been provided with it.
### Volume overload
Volume overload can occur during surgery, if water rather than isotonic saline is used to wash the incision. It can also occur if there is inadequate urination, e.g. with certain kidney diseases.
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Volume status
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In medicine, volume status refers to the volume of blood in a patient's circulatory system. This is related to the patient's state of hydration, but is not identical to it. For instance, volume depletion can exist in an adequately hydrated person if there is loss of water into interstitial tissue (e.g. due to hyponatremia or liver failure).
# Clinical assessment
### Volume depletion
Signs of volume depletion (low blood volume) include, in order of severity:
- A fast pulse
- Infrequent urination
- Dry mucous membranes (e.g. a dry tongue)
- Poor capillary refill (e.g. when the patient's fingertip is pressed, the skin turns white, but upon release, the skin does not return to pink as fast as it should)
- Decreased skin turgor (e.g. the skin remains "tented" when it is pinched)
- A weak pulse
- Orthostatic hypotension (dizziness upon standing up from a seated or reclining position, due to a drop in cerebral blood pressure)
- Cool extremities (e.g. cool fingers)
### Volume overload
Signs of volume overload (high blood volume) include:
- An elevated Jugular venous pressure (JVP)
# Pathophysiology
### Volume depletion
The most common cause of volume depletion is diarrhea or vomiting. The other causes are usually divided into renal and extrarenal causes. Renal causes include overuse of diuretics, or trauma or disease of the kidney. Extrarenal causes include bleeding, burns, and any causes of edema (e.g. congestive heart failure, liver failure, etc.).
Volume depletion is divided into three types based on the blood sodium level:
- Isonatremic (normal blood sodium levels) Example: a child with diarrhea, because both water and sodium are lost in diarrhea.
- Hyponatremic (abnormally low blood sodium levels). Example: a child with diarrhea who has been given tap water to replete diarrheal losses. Water is replenished, but sodium is not, so water flows out of the vasculature into the interstitial tissue.
- Hypernatremic (abnormally high blood sodium levels). Example: a child with diarrhea who has been given salty soup to drink, or insufficiently diluted infant formula. Here sodium has been replenished, but not enough water has been provided with it.
### Volume overload
Volume overload can occur during surgery, if water rather than isotonic saline is used to wash the incision. It can also occur if there is inadequate urination, e.g. with certain kidney diseases.
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https://www.wikidoc.org/index.php/Volume_status
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ee8fd4f38e4a40cb3241ae729afd87021a27d061
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WAGR syndrome
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WAGR syndrome
Synonyms and keywords: WAGR complex; Wilms tumor-aniridia syndrome; aniridia-Wilms tumor syndrome; Wilms tumor - aniridia - genitourinary anomalies - mental retardation
# Overview
WAGR syndrome is a rare genetic syndrome in which affected children are predisposed to develop Wilms tumor (a tumor of the kidneys), Aniridia (absence of the colored part of the eye, the iris), Genitourinary anomalies, and mental Retardation. The G is sometimes instead given as "gonadoblastoma," since the genitourinary anomalies are tumors of the gonads (testes or ovaries).
A subset of WAGR syndrome patients shows severe childhood obesity; the acronym WAGRO (O for obesity) has been used to describe this category.
The condition results from a deletion on chromosome 11 resulting in the loss of several genes. As such, it is one of the best studied examples of a condition caused by loss of neighbouring (contiguous) genes.
# Historical Perspective
WAGR syndrome was first described by Miller et al.
# Pathophysiology
WAGR syndrome is caused by a mutation on chromosome 11 in the 11p13 region. Specifically, several genes in this area are deleted, including the PAX6 ocular development gene and the Wilms' tumor gene (WT1). Abnormalities in WT1 may also cause genitourinary anomalies. Mutations in the PAX6 gene have recently been shown to not only cause ocular abnormalities, but also problems in the brain and pancreas.
# Diagnosis
Newborn children with WAGR syndrome are soon noted to have aniridia.
The clinical suspicion for WAGR may be increased with the presence of other genital anomalies. It must be noted that genitourinary anomalies are not always present, particularly in girls.
In older children, clinical diagnosis of the syndrome can be made when aniridia and one of the other features are present. It must be noted that while aniridia is rarely absent in WAGR syndrome, cases have been reported without it. Other common eye defects include cataracts and ptosis.
About 50% of patients develop Wilms' tumor.
Females with WAGR syndrome may have streak ovaries, which can increase their risk for gonadoblastoma. Malformations of the vagina and/or uterus may also be present.
Chromosomal analysis is necessary for definitive diagnosis.
# Treatment
Children with WAGR syndrome receive regular (3-4 monthly) kidney surveillance for Wilm's tumour until at least the age of 6–8 years and thereafter remain under some follow-up because of the risk of late onset nephropathy (40% of patients over the age of 12 years).
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WAGR syndrome
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: WAGR complex; Wilms tumor-aniridia syndrome; aniridia-Wilms tumor syndrome; Wilms tumor - aniridia - genitourinary anomalies - mental retardation
# Overview
WAGR syndrome is a rare genetic syndrome in which affected children are predisposed to develop Wilms tumor (a tumor of the kidneys), Aniridia (absence of the colored part of the eye, the iris), Genitourinary anomalies, and mental Retardation.[1] The G is sometimes instead given as "gonadoblastoma," since the genitourinary anomalies are tumors of the gonads (testes or ovaries).[2]
A subset of WAGR syndrome patients shows severe childhood obesity; the acronym WAGRO (O for obesity) has been used to describe this category.[3]
The condition results from a deletion on chromosome 11 resulting in the loss of several genes. As such, it is one of the best studied examples of a condition caused by loss of neighbouring (contiguous) genes.[3]
# Historical Perspective
WAGR syndrome was first described by Miller et al.[4]
# Pathophysiology
WAGR syndrome is caused by a mutation on chromosome 11 in the 11p13 region.[3] Specifically, several genes in this area are deleted, including the PAX6 ocular development gene and the Wilms' tumor gene (WT1).[5] Abnormalities in WT1 may also cause genitourinary anomalies. Mutations in the PAX6 gene have recently been shown to not only cause ocular abnormalities, but also problems in the brain and pancreas.[5][6][7][8]
# Diagnosis
Newborn children with WAGR syndrome are soon noted to have aniridia.
The clinical suspicion for WAGR may be increased with the presence of other genital anomalies. It must be noted that genitourinary anomalies are not always present, particularly in girls.
In older children, clinical diagnosis of the syndrome can be made when aniridia and one of the other features are present. It must be noted that while aniridia is rarely absent in WAGR syndrome, cases have been reported without it. Other common eye defects include cataracts and ptosis.
About 50% of patients develop Wilms' tumor.
Females with WAGR syndrome may have streak ovaries, which can increase their risk for gonadoblastoma. Malformations of the vagina and/or uterus may also be present.
Chromosomal analysis is necessary for definitive diagnosis.[9][1]
# Treatment
Children with WAGR syndrome receive regular (3-4 monthly) kidney surveillance for Wilm's tumour until at least the age of 6–8 years and thereafter remain under some follow-up because of the risk of late onset nephropathy (40% of patients over the age of 12 years).
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https://www.wikidoc.org/index.php/WAGR_Syndrome
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e024ee4a55f3ba336a9ee86eb8c28875a8f85dd3
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wikidoc
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WARG syndrome
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WARG syndrome
WAGR syndrome is a rare genetic syndrome in which affected children are predisposed to develop Wilms tumour (a tumour of the kidneys), Aniridia (absence of the coloured part of the eye, the iris), Genitourinary anomalies, and Retardation. The G is sometimes instead given as "gonadoblastoma," since the genitourinary anomalies are tumours of the gonads (testes or ovaries).
A subset of WAGR syndrome patients shows severe childhood obesity; the acronym WAGRO (O for obesity) has been used to describe this category.
The condition results from a deletion on chromosome 11 resulting in the loss of several genes. As such, it is one of the best studied examples of a condition caused by loss of neighbouring (contiguous) genes.
# Synonyms
WAGR complex, Wilms tumour-aniridia syndrome, aniridia-Wilms tumour syndrome.
# Clinical features and diagnosis
Newborn children with WAGR syndrome are soon noted to have aniridia. The clinical suspicion for WAGR may be increased with the presence of other genital anomalies, though genitourinary anomalies are not always present, particularly in girls.
In older children, clinical diagnosis of the syndrome can be made when aniridia and one of the other features are present. While aniridia is rarely absent in WAGR syndrome, cases have been reported without it. Chromosomal analysis is necessary for definitive diagnosis. Other common eye defects include cataracts and ptosis. About 50% of patients develop Wilms' tumour.
# Treatment
Children with WAGR syndrome receive regular (3-4 monthly) kidney surveillance for Wilms' tumour until at least the age of 6–8 years and thereafter remain under some follow-up because of the risk of late onset nephropathy (40% of patients over the age of 12 years). Females with WAGR syndrome may have streak ovaries, which can increase the risk for gonadoblastoma. Malformations of the vagina and/or uterus may also be present.
# Disease mechanism
WAGR syndrome is caused by a mutation on chromosome 11 in the 11p13 region. Specifically, several genes in this area are deleted, including the PAX6 ocular development gene and the Wilms' tumour gene (WT1). Abnormalities in WT1 may also cause genitourinary anomalies. Mutations in the PAX6 gene have recently been shown to not only cause ocular abnormalities, but also problems in the brain and pancreas.
The gene for brain-derived neurotrophic factor (BDNF), located on 11p14.1, has been proposed as a candidate gene for the obesity and excessive eating in a subset of WAGR patients. This strengthens the case for a role for BDNF in energy balance.
# History
WAGR syndrome was first described by Miller et al. in 1964.
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WARG syndrome
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
WAGR syndrome is a rare genetic syndrome in which affected children are predisposed to develop Wilms tumour (a tumour of the kidneys), Aniridia (absence of the coloured part of the eye, the iris), Genitourinary anomalies, and Retardation.[1] The G is sometimes instead given as "gonadoblastoma," since the genitourinary anomalies are tumours of the gonads (testes or ovaries).[2]
A subset of WAGR syndrome patients shows severe childhood obesity; the acronym WAGRO (O for obesity) has been used to describe this category.[3]
The condition results from a deletion on chromosome 11 resulting in the loss of several genes. As such, it is one of the best studied examples of a condition caused by loss of neighbouring (contiguous) genes.[3]
# Synonyms
WAGR complex, Wilms tumour-aniridia syndrome, aniridia-Wilms tumour syndrome.
# Clinical features and diagnosis
Newborn children with WAGR syndrome are soon noted to have aniridia. The clinical suspicion for WAGR may be increased with the presence of other genital anomalies, though genitourinary anomalies are not always present, particularly in girls.
In older children, clinical diagnosis of the syndrome can be made when aniridia and one of the other features are present. While aniridia is rarely absent in WAGR syndrome, cases have been reported without it. Chromosomal analysis is necessary for definitive diagnosis.[1][4] Other common eye defects include cataracts and ptosis. About 50% of patients develop Wilms' tumour.
# Treatment
Children with WAGR syndrome receive regular (3-4 monthly) kidney surveillance for Wilms' tumour until at least the age of 6–8 years and thereafter remain under some follow-up because of the risk of late onset nephropathy (40% of patients over the age of 12 years). Females with WAGR syndrome may have streak ovaries, which can increase the risk for gonadoblastoma. Malformations of the vagina and/or uterus may also be present.
# Disease mechanism
WAGR syndrome is caused by a mutation on chromosome 11 in the 11p13 region.[3] Specifically, several genes in this area are deleted, including the PAX6 ocular development gene and the Wilms' tumour gene (WT1).[5] Abnormalities in WT1 may also cause genitourinary anomalies. Mutations in the PAX6 gene have recently been shown to not only cause ocular abnormalities, but also problems in the brain and pancreas.[5][6][7][8]
The gene for brain-derived neurotrophic factor (BDNF), located on 11p14.1, has been proposed as a candidate gene for the obesity and excessive eating in a subset of WAGR patients.[9] This strengthens the case for a role for BDNF in energy balance.
# History
WAGR syndrome was first described by Miller et al. in 1964.[10]
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WBR mnemonics
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WBR mnemonics
1. Anatomy
# GI Anatomy
From proximal to distal:
- Duodenum
- Jejunum
- Ileum
- Appendix
- Colon
- Sigmoid
- Rectum
# Brachial Plexus Organization
- Roots
- Trunks
- Divisions
- Cords
- Branches
# Cranial Nerves
- I - olfactory
- II - optic
- III - oculomotor
- IV - trochlear
- V - trigeminal
- VI - abducens
- VII - facial
- VIII - acoustic (vestibulocochlear)
- IX - glossophrayngeal
- X - vagus
- XI - accessory
- XII - hypoglossal
# Extraocular Muscles Innervation
- LR 6 - Lateral Rectus by the VI cranial nerve (Abducens)
- SO 4 - Superior Oblique by the IV cranial nerve (Trochlear)
- 3 - The remaining by the III cranial nerve (Occulomotor)
- L - Lateral Rectus
- A - Abducens Nerve
- S - Superior Oblique
- T - Trochlear Nerve
# Facial Nerve Branches
- Temporal
- Zygomatic
- Buccal
- Mandibular
- Cervical
# Penis Innervation
- Parasympathetic causes erection
- Sympathetic causes ejaculation
- Innervation of the penis by branches of the pudendal nerve, derived from spinal cord levels S 2-4
# Aorta Branches
- Aortic arch gives off the:
- B - Bracheiocephalic trunk
- C - Left Common Carotid
- S - Left Subclavian artery
# Femoral Triangle Structures in Order
- Nerve
- Artery
- Vein
- Empty space
- Lymphatics
- Parenthesis includes things contained in the femoral sheath.
2. Cell Biology
# Cell Division Phases
- P - Prophase
- M - Metaphase
- A - Anaphase
- T - Telophase
# Cell Cycle Stages
- G1 phase - Growth phase 1
- S phase - DNA synthesis
- G2 phase - Growth phase 2
- M phase - Mitosis
- C phase - Cytokinesis
# Golgi Complex Functions
- Distributes proteins and lipids from ER
- Add mannose onto specific lysosome proteins
- Sulfation of sugars and slected tyrosine
- Proteoglycan assembly
- Add O-oligosugars to serine and threnonine
- Modify N-ologosugars on asparagine
# Collagen
- C - C-terminal propeptide (procollagen) / Covalent Cross links/ C vitamin/ Connective tissue/ Cartilage/Chondroblasts/Copper Cofactor (Covalent Cross linking)
- O - Outside the cell is where collagen normally functions/ Osteoblasts/ Osteogenesis imperfecta
- L - Lysyl hydroxylase / Lysyl oxidase (oxidatively deaminates lysyl and hydroxylysyl residues to form collagen cross links, last biosynthesis step)
- L - Long triple helical fibers / Ligaments
- A - Alpha chains / Attached by H bonds form triple helix / Ascorbate for hydroxylation of lysyl and prolyl residues of pro-Alpha chains
(postranslational modification)
- G - Gly in every third position / Glycosylation of hydroxyl group of hydroxylysine with Glucose and Galactose;GOlgi allows procollagen to GO outside of cell
- E - Extracellular matrix / Eye (cornea, sclera) / Ehlers-Danlos Syndrome
- N - N-terminal propeptide (procollagen) / Nonhelical terminal extensions
3. Molecular Biology
# Carbon Monoxide: Electron Transport Chain Target
Carbon monoxide (CO) blocks Cytochrome Oxidase (CO)
# Hemoglobin Binding Curve: Right Shift Causes
- C = Increase in carbon dioxide
- A = Acidosis (low ph)
- D = Increase in 2,3 DPG aka 2,3 BPG
- E = Exercise
- T = increase in temperature
# G-proteins Receptors
In alphabetical order
- Q: alpha 1
- I: alpha 2
- S: beta 1
- S: beta 2
- Q: M1
- I: M2
- Q: M3
# Adrenaline Mechanism
- Adrenaline--> activates
- Beta receptors--> increases
- Cyclic AMP
4. Biochemistry
# Enzymes Classification
- O - Oxidoreductases
- T - Transferases
- H - Hydrolases
- I - Isomerases
- L - Ligases
- L - Lyases
# Glycolysis Enzymes
- Hexokinase
- Phosphohexo isomerase
- Phosphofructokinase-1 (6-phosphofructo-1 kinase)
- Aldolase, Triose phosphate isomerase
- Glyceraldehyde 3-phosphate dehydrogenase
- Phosphoglycerate kinase
- Phosphoglycerate mutase
- Enolase
- Pyruvate kinase
# Glycolysis Steps
- Glucose
- Glucose-6-P
- Fructose-6-P
- Fructose-1,6-diP
- Dihydroxyacetone-P
- Glyceraldehyde-P
- 1,3-Biphosphoglycerate
- 3-Phosphoglycerate
- 2-Phosphoglycerate (to)
- Phosphoenolpyruvate Pyruvate - 'Did', 'By' and 'Pies' tell you the first part of those three: di-, bi-, and py-.
- 'PrEPare' tells location of PEP in the process.
5. Metabolism
# Metabolism Sites
- Heme synthesis
- Urea cycle
- Gluconeogenesis
These reactions occur in both cytoplasm and mitochondria
# AcetylCoA and AcetacetylCoA
Amino acids forming them:
- A=AcetylCoA or Acetoacetyl CoA
- Ly=Lysine
- Tr=Tryptophan
- Le=Leucine
- Is=Isoleucine
# Citric Acid Cycle Compounds
- Oxaloacetate
- Citrate
- Isocitrate
- alpha-Ketoglutarate
- Succinyl-CoA
- Succinate
- Fumarate
- Malate
- Citrate
- Isocitrate
- alpha-Ketogluterate
- Succinyl CoA
- Succinate
- Fumerate
- Malate
- Oxaloacetate
- Oxaloacetate
- Citrate
- Isocitrate, alpha-Ketoglutarate
- Succinyl CoA
- Succinate
- Fumarate
- Malate
# Citric Acid Cycle Enzymes
- Citrate synthatase
- Aconitase
- Isocitrate dehydrogenase
- Alpha ketogluturate dehydrogenase
- Succinyl CoA synthetase
- Succinate dehydrogenase
- Fumarase
- Malate Dehydrogenase
# Essential Amino Acids
- P - Phe
- V - Val
- T - Thr
- T - Trp
- I - Ile
- M - Met
- H - His
- A - Arg
- L - Leu
- L - Lys
- Pvt. is short for Private in the military
- Arg and His are considered semi-essential
- Alternatively: MATT VIL PHLy
# Creatine Phosphate: Amino Acid Precursors
- G - Glycine
- A - Arginine
- M - Methionine
# Branched Chain Amino Acids Catabolism Steps
- T - Transamination
- O - Oxidative decarboxylation
- D - Dehydrogenation
# Branched-chain Amino Acids Used by Skeletal Muscle (Fasting State)
- Leucine
- Isoleucine
- Valine
# Urea Cycle
- O - Ornithine
- C - Carbamoyl
- C - Citrulline
- A - Aspartate
- A - Arginosuccinate
- F - Fumarate
- A - Arginine
- U - Urea
# Pyrimidines Nucleotides
- Cytosine
- Uracil
- Thiamine
- The
- PYrimidines
6. Enzyme Deficiencies
# G6PD: Oxidant Drugs Inducing Hemolytic Anemia
- Antibiotic (eg: sufamethoxazole)
- Antimalarial (eg: primaquine)
- Antipyretics (eg: acetanilid, but not aspirin or acetaminophen)
# Pompe's Disease
- POmpe's disease is a LYSosomal storage disease (alpha 1,4 glucosidase)
# Galactosemia
- Galactose 1 Phosphate Uridyl Transferase
- There is an assay called the Galiput test for this
# Fabry's Disease
- F - Foam cells found in glomeruli and tubules / Febrile episodes
- A - Alpha galactosidase A deficiency / Angiokeratomas
- B - Burning pain in extremities / BUN increased in serum / Boys
- R - Renal failure
- Y - YX genotype (male, X linked recessive)
- S - Sphingolipidoses
# Hurler Syndrome Features
- Heptosplenomegaly
- Ugly facies
- Recessive (AR inheritance)
- L-iduronidase deficiency (alpha)
- Eyes clouded
- Retarded
- Stubby fingers/Short
# Acute Intermittent Porphyria
- Pain in abdomen
- Polyneuropathy
- Psychologial abnormalities
- Pink urine
- Precipitated by drugs (eg barbiturates, oral contraceptives, sulpha drugs)
7. Vitamins
# B Vitamins
In increasing order:
- T - Thiamine (B1)
- R - Riboflavin (B2)
- N - Niacin (B3)
- P - Pyridoxine (B6)
- C - Cobalamin (B12)
# Niacin Deficiency
- Diarrhea
- Dermatitis
- Dementia
- Death (if untreated)
Vitamin B3 (niacin, nicotinic acid) deficiency
- Dermatitis
- Diarrhea
- Dementia
# Folate Deficiency Causes
- Alcoholism
- Folic acid antagonists
- Oral contraceptives
- Low dietary intake
- Infection with Giardia
- Celiac sprue
- Dilatin
- Relative folate deficiency
- Old
- Pregnant
# Fat Soluble Vitamins
Fat soluble vitamins are A,D,E,K.'
# Hypervitaminosis A
- H - Headache / Hepatomegaly
- A - Anorexia / Alopecia
- R - Really painful bones
- D - Dry skin / Drowsiness
8. History Taking
# Alcoholism Screening
- Have you ever felt it necessary to CUT DOWN on your drinking?
- Have you ever been ANNOYED when people suggest you cut down on your drinking?
- Have you ever felt GUILTY about your drinking?
- Have you ever felt the need to have a drink in the morning for an EYE OPENER?
# Chief Complaint
- O - Onset of pain: what was the patient doing when the pain started?
- P - Palliative or Provocative factors for the pain
- Q - Quality of pain (burning, stabbing, aching, etc.)
- R - Radiation (up to jaw, down left arm, etc.)
- S - Severity of pain (usually 1 - 10 scale)
- T - Timing of pain (eg: after meals, in the morning, how long it lasts, etc.)
- S - Site of pain
- O - Onset of pain
- C - Character of pain: dull, sharp, aching, stabbing, tearing
- R - Radiation of pain: central abdominal pain radiating to Right Iliac Fossa
- A - Associated factors: eg. nausea/vomiting
- T - Timing of pain/duration
- E - Exacerbating/alleviating factors
- S - Severity of pain (1 - 10 scale)
- A - Aggravatiing and Alleviating factors
- S - Severity
- C - Character, quality
- L - Location
- A - Associated symptoms
- S - Setting
- T - Timing
NOTE: ASCLAST means let the patient talk first, then ask him/her specific questions.
# Hospital Admission Orders
- Diet
- Activity
- Vital signs: how often to monitor
- Excrement: test urine/stool
- Weight: how often to monitor
- I / O: monitor input/output
- Labs: which/how often
- Meds: which/route/interval
- I V fluids: what/at what rate
- Nursing care: e.g. position, wound care, up in chair, ostomy care
- General care: e.g. physical/respiratory therapy
- Tests: e.g. X-ray/EKG/EEG
- Observe for: reaction/seizure/neuro exams
- Notify parameters: e.g. Temperature > 100 F / respiration changes
After noting date and time of admission as well as diagnosis and condition (ADC), use the mnemonic to ensure all areas are addressed, but not all apply to every patient.
- Admit: 23 hours, full admit, service of attending
- Diagnosis
- Condition: "Stable"/"Guarded"
- Vitals: post-op, routine, q 1 hour
- Allergies
- Activities: strict bed rest/fall precautions/ad lib/bathroom privileges
- Nursing: strict I&O's/daily weights/call P.R.N.
- Diet: NPO/regular/clears/advance diet as tolerated/2000 cal ADA/renal
- IV fluids: D5, 1/2 NS, 20 KCL at 110 ml/hr, LR @ 100 ml/hr
- Meds: scheduled and PRN's
- Labs and X-ray: CBC in AM, PCXR in PACU
Note that IV fluids follows Diet. If one writes NPO, then all such patients get maintenance fluids (use the 4-2-1 rule).
# Post-Op Fever Causes
- Wind: pneumonia, atelectasis
- Wound: wound infections
- Water: urinary tract infection
- Walking: DVT/PE (walking can help reduce DVT/PE)
- Wonderdrugs: especially anesthesia
# Predisposing Conditions for Pulmonary Embolism
- T - Trauma
- O - Obesity
- M - Malignancy
- S - Surgery
- C - Cardiac disease
- H - Hospitalization
- P - Past history
- R - Rest (bed-bound)
- E - Estrogen, pregnancy, post-partum
- F - Fracture
- E - Elderly
- R - Road trip
# Compartment Syndrome Signs (Arterial Occlusion)
- Pain
- Pale (Pallor)
- Perishing with Cold (Poikilothermia)
- Pulseless
- Paresthesias
- Paralysis
9. Pathology
# Causes of Diseases
- Vascular
- Infectious
- Trauma
- Auto-immune
- Metabolic
- Idiopathic/Iatrogenic
- Neoplastic
- Congenital
# Signs of Inflammation
- Rubor: redness/erythema
- Calor: raised temperature
- Tumor: swelling
- Dolor: pain
- Functio Laesa: loss of function
- Described by Celsus
# Hypersentivity Reactions (Gell & Goombs Classification)
- Type I Anaphylaxis
- Type II Cytotoxic-mediated
- Type III Immune-complex
- Type IV Delayed hypersensitivity
# Multiple Endocrine Neoplasia (MEN)
Each of the MENs is a disease of three or two letters plus a feature; all are autosomal dominant.
- Pituitary
- Parathyroid
- Pancreas
- Plus Adrenal cortex
- Carcinoma of thyroid
- Catacholamines (pheochromocytoma)
- MEN IIA: parathyroid
- MEN IIB (MEN III): mucocutaneous neuromas for
# Acute Pneumonia Infiltrates
- Pyogenic bacteria: PMN infiltrate
- Miscellaneous microbes: Mononuclear infiltrate
# Takayasu's Disease/Pulseless Disease
# CBC Normal Differential
- Neutrophils: 60%
- Lymphocytes: 30%
- Monocytes: 6%
- Eosinophils: 3%
- Basophils: 1%
10. Causes
# Metabolic Acidosis Causes
- Methanol poisoning
- Uremia
- Diabetic Keto-acidosis
- Para-aldehyde ingestion
- Ischemia
- Lactic Acidosis
- Ethanol poisoning
- Salicylate ingestion
# Metabolic Acidosis (Normal Anion-Gap) Causes
## With Hyperkalemia
- RTA type 4
- Aldosterone or mineralocorticord deficiency
- Iatrogenic: NH4Cl, HCl
- "Stenosis": obstructive uropathy
- Early uremia
## With hypokalemia
- Renal TA type 1 and 2
- Diarrhoea
- Urine diversion into gut
- Carbonate anhydrase inhibitor
- Ex-hyperventilation
# BUN & Creatinine Elevation Causes
- A - Azotremia (pre-renal)
- B - Bleeding (GI)
- C - Catabolic status
- D - Diet (high protein parenteral nutrition)
# Hypercalcemia Causes
- Paget's Disease
- Amyloid
- Multiple Myeloma
- Sarcoid
- Cancer
- Hormomal (para-thyroid)
- Milk-alkali Syndrome
- Immobilization
- D-vitamin overdose
- Thyrotoxicosis
OR
- Malignancy
- Intoxication (hypervitaminosis)
- Sarcoidosis
- Hyperparathyroidism
- Alkali (Milk) syndrome
- Paget's Disease (bone)
Also consider Addison's disease, thiazide diuretics and simple lab error
# Acute Pancreatitis Causes
- Gall stones
- Ethanol
- Trauma
- Steroids
- Mumps
- Autoimmune disease
- Scorpion venom
- Hyperlipidemia
- ERCP (dye)
- Drugs (Azathioprine, Asparginase, Mercaptopurines, Pentamidine)
Alcohol and Gallstones are the most common causes.
# Back Pain Causes
- D-Degeneration: DJD, Osteoporosis, spondylosis
- I-Infection: UTI, PID, Potts, osteomyelitis, prostatitis, Injury/fracture, compression fracture
- S-Spondylitis, ankylosing Spondyloarthropathies (rheumatoid arthritis, Reiters, SLE)
- K-Kidney stones/infarction/infection (pyelo/abscess)
- M-Multiple myeloma, Metastasis from breast, prostate, lung, thyroid, kidney CA
- A-Aneurysm, Abdominal pain referred to the back (see acute abdominal pain)
- S-Slipped disk, Spondylolisthesis
- S-Strain, Scoliosis/lordosis, Skin: herpes zoster
11. Treatment
# Syncope Management
# Malignant Hyperthermia Treatment
- S- Stop all triggering agents, give 100% O2
- H- Hyperventillate
- D- Dantrolene 2.5 mg/kg
- B- Bicarbonate
- G- Glucose and Insulin
- I- IV Fluids, Cooling Blanket
- F- Fluid Output; Furosemide
- T- Tachycardia, be prepared to treat V Tach
12. Genetics
# Down Syndrome Features
- Congenital heart disease/ Cataracts
- Hypotonia/ Hypothyroidism
- Incure 5th finger/ Increased gap between 1st and 2nd toe
- Leukemia risk x2/ Lung problem
- Duodenal atresia/ Delayed development
- Hirshsprung's disease/ Hearing loss
- Alzheimer's disease/ Alantoaxial instability
- Squint/ Short neck
- Protruding tongue/ Palm crease
- Round face/ Rolling eye (nystagmus)
- Occiput flat/ Oblique eye fissure
- Brushfield spot/ Brachycephaly
- Low nasal bridge/ Language problem
- Epicanthic fold/ Ear folded
- Mental retardation/ Myoclonus
- Decreased alpha-fetoprotein and unconjugated estriol (maternal)
- One extra chromosome twenty-one
- Women of advanced age
- Non-disjunction during maternal meiosis
Chromosome 21
# Patau's Syndrome - Chromosome 13
# Edward's Syndrome - Chromosome 18
# DiGeorge (Velocardiofacial) Syndrome
- Cardiac abnormalities
- Abnormal facies
- Thymic aplasia
- Cleft palate
- Hypocalcemia
- 22q11 deletion
# Marfan Syndrome Features
- Mitral valve prolapse - MVP
- Aortic Aneurysm
- Retinal detachment
- Fibrillin
- Arachnodactyly
- Negative Nitroprusside test (differentiates from homocystinuria)
# Adult Polycystic Kidney Disease
Also, and is due to a defect on chromosome 16.
ADult Polycystic Kidney Disease is Autosomal Dominant
13. Pediatrics
# APGAR Score
- Appearance (color): blue/pale, trunk pink, all pink
- Pulse (heart rate): 0, <100, 100+
- Grimace (reflex irritability): 0, grimace, grimace+cough
- Activity (muscle tone): limp, some, active
- Respiration (respiratory effort): 0, irregular, regular
- Score 0-2 at 1 and 5 minutes in each of 5 categories, being 10 the perfect score.
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WBR mnemonics
1. Anatomy
# GI Anatomy
From proximal to distal:
- Duodenum
- Jejunum
- Ileum
- Appendix
- Colon
- Sigmoid
- Rectum
# Brachial Plexus Organization
- Roots
- Trunks
- Divisions
- Cords
- Branches
# Cranial Nerves
- I - olfactory
- II - optic
- III - oculomotor
- IV - trochlear
- V - trigeminal
- VI - abducens
- VII - facial
- VIII - acoustic (vestibulocochlear)
- IX - glossophrayngeal
- X - vagus
- XI - accessory
- XII - hypoglossal
# Extraocular Muscles Innervation
- LR 6 - Lateral Rectus by the VI cranial nerve (Abducens)
- SO 4 - Superior Oblique by the IV cranial nerve (Trochlear)
- 3 - The remaining by the III cranial nerve (Occulomotor)
- L - Lateral Rectus
- A - Abducens Nerve
- S - Superior Oblique
- T - Trochlear Nerve
# Facial Nerve Branches
- Temporal
- Zygomatic
- Buccal
- Mandibular
- Cervical
# Penis Innervation
- Parasympathetic causes erection
- Sympathetic causes ejaculation
- Innervation of the penis by branches of the pudendal nerve, derived from spinal cord levels S 2-4
# Aorta Branches
- Aortic arch gives off the:
- B - Bracheiocephalic trunk
- C - Left Common Carotid
- S - Left Subclavian artery
# Femoral Triangle Structures in Order
- Nerve
- Artery
- Vein
- Empty space
- Lymphatics
- Parenthesis includes things contained in the femoral sheath.
2. Cell Biology
# Cell Division Phases
- P - Prophase
- M - Metaphase
- A - Anaphase
- T - Telophase
# Cell Cycle Stages
- G1 phase - Growth phase 1
- S phase - DNA synthesis
- G2 phase - Growth phase 2
- M phase - Mitosis
- C phase - Cytokinesis
# Golgi Complex Functions
- Distributes proteins and lipids from ER
- Add mannose onto specific lysosome proteins
- Sulfation of sugars and slected tyrosine
- Proteoglycan assembly
- Add O-oligosugars to serine and threnonine
- Modify N-ologosugars on asparagine
# Collagen
- C - C-terminal propeptide (procollagen) / Covalent Cross links/ C vitamin/ Connective tissue/ Cartilage/Chondroblasts/Copper Cofactor (Covalent Cross linking)
- O - Outside the cell is where collagen normally functions/ Osteoblasts/ Osteogenesis imperfecta
- L - Lysyl hydroxylase / Lysyl oxidase (oxidatively deaminates lysyl and hydroxylysyl residues to form collagen cross links, last biosynthesis step)
- L - Long triple helical fibers / Ligaments
- A - Alpha chains / Attached by H bonds form triple helix / Ascorbate for hydroxylation of lysyl and prolyl residues of pro-Alpha chains
(postranslational modification)
- G - Gly in every third position / Glycosylation of hydroxyl group of hydroxylysine with Glucose and Galactose;GOlgi allows procollagen to GO outside of cell
- E - Extracellular matrix / Eye (cornea, sclera) / Ehlers-Danlos Syndrome
- N - N-terminal propeptide (procollagen) / Nonhelical terminal extensions
3. Molecular Biology
# Carbon Monoxide: Electron Transport Chain Target
Carbon monoxide (CO) blocks Cytochrome Oxidase (CO)
# Hemoglobin Binding Curve: Right Shift Causes
- C = Increase in carbon dioxide
- A = Acidosis (low ph)
- D = Increase in 2,3 DPG aka 2,3 BPG
- E = Exercise
- T = increase in temperature
# G-proteins Receptors
In alphabetical order
- Q: alpha 1
- I: alpha 2
- S: beta 1
- S: beta 2
- &
- Q: M1
- I: M2
- Q: M3
# Adrenaline Mechanism
- Adrenaline--> activates
- Beta receptors--> increases
- Cyclic AMP
4. Biochemistry
# Enzymes Classification
- O - Oxidoreductases
- T - Transferases
- H - Hydrolases
- I - Isomerases
- L - Ligases
- L - Lyases
# Glycolysis Enzymes
- Hexokinase
- Phosphohexo isomerase
- Phosphofructokinase-1 (6-phosphofructo-1 kinase)
- Aldolase, Triose phosphate isomerase
- Glyceraldehyde 3-phosphate dehydrogenase
- Phosphoglycerate kinase
- Phosphoglycerate mutase
- Enolase
- Pyruvate kinase
# Glycolysis Steps
- Glucose
- Glucose-6-P
- Fructose-6-P
- Fructose-1,6-diP
- Dihydroxyacetone-P
- Glyceraldehyde-P
- 1,3-Biphosphoglycerate
- 3-Phosphoglycerate
- 2-Phosphoglycerate (to)
- Phosphoenolpyruvate [PEP] Pyruvate • 'Did', 'By' and 'Pies' tell you the first part of those three: di-, bi-, and py-.
• 'PrEPare' tells location of PEP in the process.
5. Metabolism
# Metabolism Sites
- Heme synthesis
- Urea cycle
- Gluconeogenesis
These reactions occur in both cytoplasm and mitochondria
# AcetylCoA and AcetacetylCoA
Amino acids forming them:
- A=AcetylCoA or Acetoacetyl CoA
- Ly=Lysine
- Tr=Tryptophan
- Le=Leucine
- Is=Isoleucine
# Citric Acid Cycle Compounds
- Oxaloacetate
- Citrate
- Isocitrate
- alpha-Ketoglutarate
- Succinyl-CoA
- Succinate
- Fumarate
- Malate
- Citrate
- Isocitrate
- alpha-Ketogluterate
- Succinyl CoA
- Succinate
- Fumerate
- Malate
- Oxaloacetate
- Oxaloacetate
- Citrate
- Isocitrate, alpha-Ketoglutarate
- Succinyl CoA
- Succinate
- Fumarate
- Malate
# Citric Acid Cycle Enzymes
- Citrate synthatase
- Aconitase
- Isocitrate dehydrogenase
- Alpha ketogluturate dehydrogenase
- Succinyl CoA synthetase
- Succinate dehydrogenase
- Fumarase
- Malate Dehydrogenase
# Essential Amino Acids
- P - Phe
- V - Val
- T - Thr
- T - Trp
- I - Ile
- M - Met
- H - His
- A - Arg
- L - Leu
- L - Lys
- Pvt. is short for Private in the military
- Arg and His are considered semi-essential
- Alternatively: MATT VIL PHLy
# Creatine Phosphate: Amino Acid Precursors
- G - Glycine
- A - Arginine
- M - Methionine
# Branched Chain Amino Acids Catabolism Steps
- T - Transamination
- O - Oxidative decarboxylation
- D - Dehydrogenation
# Branched-chain Amino Acids Used by Skeletal Muscle (Fasting State)
- Leucine
- Isoleucine
- Valine
# Urea Cycle
- O - Ornithine
- C - Carbamoyl
- C - Citrulline
- A - Aspartate
- A - Arginosuccinate
- F - Fumarate
- A - Arginine
- U - Urea
# Pyrimidines Nucleotides
- Cytosine
- Uracil
- Thiamine
- The
- PYrimidines
6. Enzyme Deficiencies
# G6PD: Oxidant Drugs Inducing Hemolytic Anemia
- Antibiotic (eg: sufamethoxazole)
- Antimalarial (eg: primaquine)
- Antipyretics (eg: acetanilid, but not aspirin or acetaminophen)
# Pompe's Disease
- POmpe's disease is a LYSosomal storage disease (alpha 1,4 glucosidase)
# Galactosemia
- Galactose 1 Phosphate Uridyl Transferase
- There is an assay called the Galiput test for this
# Fabry's Disease
- F - Foam cells found in glomeruli and tubules / Febrile episodes
- A - Alpha galactosidase A deficiency / Angiokeratomas
- B - Burning pain in extremities / BUN increased in serum / Boys
- R - Renal failure
- Y - YX genotype (male, X linked recessive)
- S - Sphingolipidoses
# Hurler Syndrome Features
- Heptosplenomegaly
- Ugly facies
- Recessive (AR inheritance)
- L-iduronidase deficiency (alpha)
- Eyes clouded
- Retarded
- Stubby fingers/Short
# Acute Intermittent Porphyria
- Pain in abdomen
- Polyneuropathy
- Psychologial abnormalities
- Pink urine
- Precipitated by drugs (eg barbiturates, oral contraceptives, sulpha drugs)
7. Vitamins
# B Vitamins
In increasing order:
- T - Thiamine (B1)
- R - Riboflavin (B2)
- N - Niacin (B3)
- P - Pyridoxine (B6)
- C - Cobalamin (B12)
# Niacin Deficiency
- Diarrhea
- Dermatitis
- Dementia
- Death (if untreated)
Vitamin B3 (niacin, nicotinic acid) deficiency
- Dermatitis
- Diarrhea
- Dementia
# Folate Deficiency Causes
- Alcoholism
- Folic acid antagonists
- Oral contraceptives
- Low dietary intake
- Infection with Giardia
- Celiac sprue
- Dilatin
- Relative folate deficiency
- Old
- Pregnant
# Fat Soluble Vitamins
Fat soluble vitamins are A,D,E,K.'
# Hypervitaminosis A
- H - Headache / Hepatomegaly
- A - Anorexia / Alopecia
- R - Really painful bones
- D - Dry skin / Drowsiness
8. History Taking
# Alcoholism Screening
- Have you ever felt it necessary to CUT DOWN on your drinking?
- Have you ever been ANNOYED when people suggest you cut down on your drinking?
- Have you ever felt GUILTY about your drinking?
- Have you ever felt the need to have a drink in the morning for an EYE OPENER?
# Chief Complaint
- O - Onset of pain: what was the patient doing when the pain started?
- P - Palliative or Provocative factors for the pain
- Q - Quality of pain (burning, stabbing, aching, etc.)
- R - Radiation (up to jaw, down left arm, etc.)
- S - Severity of pain (usually 1 - 10 scale)
- T - Timing of pain (eg: after meals, in the morning, how long it lasts, etc.)
- S - Site of pain
- O - Onset of pain
- C - Character of pain: dull, sharp, aching, stabbing, tearing
- R - Radiation of pain: central abdominal pain radiating to Right Iliac Fossa
- A - Associated factors: eg. nausea/vomiting
- T - Timing of pain/duration
- E - Exacerbating/alleviating factors
- S - Severity of pain (1 - 10 scale)
- A - Aggravatiing and Alleviating factors
- S - Severity
- C - Character, quality
- L - Location
- A - Associated symptoms
- S - Setting
- T - Timing
NOTE: ASCLAST means let the patient talk first, then ask him/her specific questions.
# Hospital Admission Orders
- Diet
- Activity
- Vital signs: how often to monitor
- Excrement: test urine/stool
- Weight: how often to monitor
- I / O: monitor input/output
- Labs: which/how often
- Meds: which/route/interval
- I V fluids: what/at what rate
- Nursing care: e.g. position, wound care, up in chair, ostomy care
- General care: e.g. physical/respiratory therapy
- Tests: e.g. X-ray/EKG/EEG
- Observe for: reaction/seizure/neuro exams
- Notify parameters: e.g. Temperature > 100 F / respiration changes
After noting date and time of admission as well as diagnosis and condition (ADC), use the mnemonic to ensure all areas are addressed, but not all apply to every patient.
- Admit: 23 hours, full admit, service of attending
- Diagnosis
- Condition: "Stable"/"Guarded"
- Vitals: post-op, routine, q 1 hour
- Allergies
- Activities: strict bed rest/fall precautions/ad lib/bathroom privileges
- Nursing: strict I&O's/daily weights/call P.R.N.
- Diet: NPO/regular/clears/advance diet as tolerated/2000 cal ADA/renal
- IV fluids: D5, 1/2 NS, 20 KCL at 110 ml/hr, LR @ 100 ml/hr
- Meds: scheduled and PRN's
- Labs and X-ray: CBC in AM, PCXR in PACU
Note that IV fluids follows Diet. If one writes NPO, then all such patients get maintenance fluids (use the 4-2-1 rule).
# Post-Op Fever Causes
- Wind: pneumonia, atelectasis
- Wound: wound infections
- Water: urinary tract infection
- Walking: DVT/PE (walking can help reduce DVT/PE)
- Wonderdrugs: especially anesthesia
# Predisposing Conditions for Pulmonary Embolism
- T - Trauma
- O - Obesity
- M - Malignancy
- S - Surgery
- C - Cardiac disease
- H - Hospitalization
- P - Past history
- R - Rest (bed-bound)
- E - Estrogen, pregnancy, post-partum
- F - Fracture
- E - Elderly
- R - Road trip
# Compartment Syndrome Signs (Arterial Occlusion)
- Pain
- Pale (Pallor)
- Perishing with Cold (Poikilothermia)
- Pulseless
- Paresthesias
- Paralysis
9. Pathology
# Causes of Diseases
- Vascular
- Infectious
- Trauma
- Auto-immune
- Metabolic
- Idiopathic/Iatrogenic
- Neoplastic
- Congenital
# Signs of Inflammation
- Rubor: redness/erythema
- Calor: raised temperature
- Tumor: swelling
- Dolor: pain
- Functio Laesa: loss of function
- Described by Celsus
# Hypersentivity Reactions (Gell & Goombs Classification)
- Type I Anaphylaxis
- Type II Cytotoxic-mediated
- Type III Immune-complex
- Type IV Delayed hypersensitivity
# Multiple Endocrine Neoplasia (MEN)
Each of the MENs is a disease of three or two letters plus a feature; all are autosomal dominant.
- Pituitary
- Parathyroid
- Pancreas
- Plus Adrenal cortex
- Carcinoma of thyroid
- Catacholamines (pheochromocytoma)
- MEN IIA: parathyroid
- MEN IIB (MEN III): mucocutaneous neuromas for
# Acute Pneumonia Infiltrates
- Pyogenic bacteria: PMN infiltrate
- Miscellaneous microbes: Mononuclear infiltrate
# Takayasu's Disease/Pulseless Disease
# CBC Normal Differential
- Neutrophils: 60%
- Lymphocytes: 30%
- Monocytes: 6%
- Eosinophils: 3%
- Basophils: 1%
10. Causes
# Metabolic Acidosis Causes
- Methanol poisoning
- Uremia
- Diabetic Keto-acidosis
- Para-aldehyde ingestion
- Ischemia
- Lactic Acidosis
- Ethanol poisoning
- Salicylate ingestion
# Metabolic Acidosis (Normal Anion-Gap) Causes
## With Hyperkalemia
- RTA type 4
- Aldosterone or mineralocorticord deficiency
- Iatrogenic: NH4Cl, HCl
- "Stenosis": obstructive uropathy
- Early uremia
## With hypokalemia
- Renal TA type 1 and 2
- Diarrhoea
- Urine diversion into gut
- Carbonate anhydrase inhibitor
- Ex-hyperventilation
# BUN & Creatinine Elevation Causes
- A - Azotremia (pre-renal)
- B - Bleeding (GI)
- C - Catabolic status
- D - Diet (high protein parenteral nutrition)
# Hypercalcemia Causes
- Paget's Disease
- Amyloid
- Multiple Myeloma
- Sarcoid
- Cancer
- Hormomal (para-thyroid)
- Milk-alkali Syndrome
- Immobilization
- D-vitamin overdose
- Thyrotoxicosis
OR
- Malignancy
- Intoxication (hypervitaminosis)
- Sarcoidosis
- Hyperparathyroidism
- Alkali (Milk) syndrome
- Paget's Disease (bone)
Also consider Addison's disease, thiazide diuretics and simple lab error
# Acute Pancreatitis Causes
- Gall stones
- Ethanol
- Trauma
- Steroids
- Mumps
- Autoimmune disease
- Scorpion venom
- Hyperlipidemia
- ERCP (dye)
- Drugs (Azathioprine, Asparginase, Mercaptopurines, Pentamidine)
Alcohol and Gallstones are the most common causes.
# Back Pain Causes
- D-Degeneration: DJD, Osteoporosis, spondylosis
- I-Infection: UTI, PID, Potts, osteomyelitis, prostatitis, Injury/fracture, compression fracture
- S-Spondylitis, ankylosing Spondyloarthropathies (rheumatoid arthritis, Reiters, SLE)
- K-Kidney stones/infarction/infection (pyelo/abscess)
- M-Multiple myeloma, Metastasis from breast, prostate, lung, thyroid, kidney CA
- A-Aneurysm, Abdominal pain referred to the back (see acute abdominal pain)
- S-Slipped disk, Spondylolisthesis
- S-Strain, Scoliosis/lordosis, Skin: herpes zoster
11. Treatment
# Syncope Management
# Malignant Hyperthermia Treatment
- S- Stop all triggering agents, give 100% O2
- H- Hyperventillate
- D- Dantrolene 2.5 mg/kg
- B- Bicarbonate
- G- Glucose and Insulin
- I- IV Fluids, Cooling Blanket
- F- Fluid Output; Furosemide
- T- Tachycardia, be prepared to treat V Tach
12. Genetics
# Down Syndrome Features
- Congenital heart disease/ Cataracts
- Hypotonia/ Hypothyroidism
- Incure 5th finger/ Increased gap between 1st and 2nd toe
- Leukemia risk x2/ Lung problem
- Duodenal atresia/ Delayed development
- Hirshsprung's disease/ Hearing loss
- Alzheimer's disease/ Alantoaxial instability
- Squint/ Short neck
- Protruding tongue/ Palm crease
- Round face/ Rolling eye (nystagmus)
- Occiput flat/ Oblique eye fissure
- Brushfield spot/ Brachycephaly
- Low nasal bridge/ Language problem
- Epicanthic fold/ Ear folded
- Mental retardation/ Myoclonus
- Decreased alpha-fetoprotein and unconjugated estriol (maternal)
- One extra chromosome twenty-one
- Women of advanced age
- Non-disjunction during maternal meiosis
Chromosome 21
# Patau's Syndrome - Chromosome 13
# Edward's Syndrome - Chromosome 18
# DiGeorge (Velocardiofacial) Syndrome
- Cardiac abnormalities
- Abnormal facies
- Thymic aplasia
- Cleft palate
- Hypocalcemia
- 22q11 deletion
# Marfan Syndrome Features
- Mitral valve prolapse - MVP
- Aortic Aneurysm
- Retinal detachment
- Fibrillin
- Arachnodactyly
- Negative Nitroprusside test (differentiates from homocystinuria)
# Adult Polycystic Kidney Disease
Also, and is due to a defect on chromosome 16.
ADult Polycystic Kidney Disease is Autosomal Dominant
13. Pediatrics
# APGAR Score
- Appearance (color): blue/pale, trunk pink, all pink
- Pulse (heart rate): 0, <100, 100+
- Grimace (reflex irritability): 0, grimace, grimace+cough
- Activity (muscle tone): limp, some, active
- Respiration (respiratory effort): 0, irregular, regular
- Score 0-2 at 1 and 5 minutes in each of 5 categories, being 10 the perfect score.
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https://www.wikidoc.org/index.php/WBR_mnemonics
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d7e65cf86a5f6a492a76fd31eb34d80a0bbc071b
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wikidoc
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WHIM syndrome
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WHIM syndrome
WHIM Syndrome (or Wart, Hypogammaglobulinemia, Infection, and Myelokathexis syndrome) is a rare congenital immunodeficiency disorder characterized by chronic noncyclic neutropenia.
# Diagnosis
Patients exhibit increased susceptibility to bacterial and viral infections, especially from common serotype human papilloma virus, resulting in warts on the hands and feet starting in childhood. Myelokathexis refers to retention (kathexis) of neutrophils in the bone marrow (myelo). In addition, lymphocytes and antibody levels (gammaglobulins) are often deficient.
# Pathophysiology
WHIM syndrome results from autosomal dominant mutations in the gene for the chemokine receptor, CXCR4, resulting in a carboxy-terminus truncation of the receptor of between ten and 19 residues. The gene mutant is located on 2q21. WHIM syndrome is one of only a few diseases directly and primarily caused by an aberrant chemokine, making its molecular biology important in understanding the role of cell signaling and trafficking.
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WHIM syndrome
WHIM Syndrome (or Wart, Hypogammaglobulinemia, Infection, and Myelokathexis syndrome) is a rare congenital immunodeficiency disorder characterized by chronic noncyclic neutropenia.
# Diagnosis
Patients exhibit increased susceptibility to bacterial and viral infections, especially from common serotype human papilloma virus, resulting in warts on the hands and feet starting in childhood. Myelokathexis refers to retention (kathexis) of neutrophils in the bone marrow (myelo). In addition, lymphocytes and antibody levels (gammaglobulins) are often deficient.
# Pathophysiology
WHIM syndrome results from autosomal dominant mutations in the gene for the chemokine receptor, CXCR4,[1][2] resulting in a carboxy-terminus truncation of the receptor of between ten and 19 residues. The gene mutant is located on 2q21. WHIM syndrome is one of only a few diseases directly and primarily caused by an aberrant chemokine, making its molecular biology important in understanding the role of cell signaling and trafficking.
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https://www.wikidoc.org/index.php/WHIM_syndrome
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18981b2030a3aff24a6d069fe492f21f6c3acf28
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wikidoc
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Walker (tool)
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Walker (tool)
A walker or walking frame is a tool for disabled people who need additional support to maintain balance or stability while walking. It consists of a frame that is about waist high, approximately twelve inches deep and slightly wider than the user. Walkers are also available in other sizes such as Pediatric (for children) or Bariatric (for overweight or obese persons). Modern walkers are height adjustable and should be set at a height that is comfortable for the user, but will allow the user to maintain a slight bend in their arms. This bend is needed to allow for proper blood circulation through the arms as the walker is used. The front two legs of the walker may or may not have wheels attached depending on the strength and abilities of the person using it. It is also common to see caster wheels or glides on the back legs of a walker with wheels on the front.
# Walking a walker
The person walks with the frame surrounding their front and sides and their hands provide additional support by holding on to the top of the sides of the frame. Traditionally, a walker is picked up and placed a short distance ahead of the user. The user then walks to it and repeats the process. With the use of wheels and glides, the user may push the walker ahead as opposed to picking it up. This makes for easier use of the walker, as it does not require the user to use their arms to lift the walker. This is beneficial for those with little arm strength.
A walker is a good tool for those who are recuperating from leg or back injuries. It is also commonly used by persons having problems with walking or with mild balance problems.
Also related is a hemi-walker, a walker about half the size of a traditional walker which is intended for use by persons whose dexterity is limited or non-existent in one hand or arm. These walkers are more stable than a quad cane (a cane with four points that touch the ground, as opposed to one), but are not recommended as highly as a traditional walker for those who can use it.
# Wheeled walkers
A wheeled walker, also commonly called a rollator, is a walking frame with wheels. Current day rollators are usually more sophisticated than conventional walkers with wheels. They are adjustable in height and are equipped with a seat, and sometimes, with a basket; with the use of modern materials, they are light-weight yet sturdier. Modern wheeled walkers may provide a back which a person can lean against. A particularly important part of a rollator is hand brakes mounted on the top of the frame that can be lifted or pushed downward to stop the wheeled walker at once. The brakes can also be used in maneuvering the rollator; when turning, the user can brake on the side being turned towards in order to achieve a tighter turning radius.
Modern rollators which have wheels that are at least seven inches in diameter and preferably, eight inches, ensure better reliability. Also, to the advantage of safety, convenience and durability of a wheeled walking aid and its parts, modern rollators use tubular seats, back seats and baskets with spacers and cushions, and rather than using simple hooks, are equipped with latches and release buttons.
# The Zimmers
The British English common equivalent term for a walker is Zimmer Frame - from Zimmer Holdings, a major manufacturer of such devices and joint replacement parts.
In May 2007, a group of elder people in the UK formed a rock group to highlight the plight and difficulties associated with old age. They called themselves The Zimmers in recognition of this generic term.
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Walker (tool)
Template:Inappropriate tone
A walker or walking frame is a tool for disabled people who need additional support to maintain balance or stability while walking. It consists of a frame that is about waist high, approximately twelve inches deep and slightly wider than the user. Walkers are also available in other sizes such as Pediatric (for children) or Bariatric (for overweight or obese persons). Modern walkers are height adjustable and should be set at a height that is comfortable for the user, but will allow the user to maintain a slight bend in their arms. This bend is needed to allow for proper blood circulation through the arms as the walker is used. The front two legs of the walker may or may not have wheels attached depending on the strength and abilities of the person using it. It is also common to see caster wheels or glides on the back legs of a walker with wheels on the front.
## Walking a walker
The person walks with the frame surrounding their front and sides and their hands provide additional support by holding on to the top of the sides of the frame. Traditionally, a walker is picked up and placed a short distance ahead of the user. The user then walks to it and repeats the process. With the use of wheels and glides, the user may push the walker ahead as opposed to picking it up. This makes for easier use of the walker, as it does not require the user to use their arms to lift the walker. This is beneficial for those with little arm strength.
A walker is a good tool for those who are recuperating from leg or back injuries. It is also commonly used by persons having problems with walking or with mild balance problems.
Also related is a hemi-walker, a walker about half the size of a traditional walker which is intended for use by persons whose dexterity is limited or non-existent in one hand or arm. These walkers are more stable than a quad cane (a cane with four points that touch the ground, as opposed to one), but are not recommended as highly as a traditional walker for those who can use it.
## Wheeled walkers
A wheeled walker, also commonly called a rollator, is a walking frame with wheels. Current day rollators are usually more sophisticated than conventional walkers with wheels. They are adjustable in height and are equipped with a seat, and sometimes, with a basket; with the use of modern materials, they are light-weight yet sturdier. Modern wheeled walkers may provide a back which a person can lean against. A particularly important part of a rollator is hand brakes mounted on the top of the frame that can be lifted or pushed downward to stop the wheeled walker at once. The brakes can also be used in maneuvering the rollator; when turning, the user can brake on the side being turned towards in order to achieve a tighter turning radius.
Modern rollators which have wheels that are at least seven inches in diameter and preferably, eight inches, ensure better reliability. Also, to the advantage of safety, convenience and durability of a wheeled walking aid and its parts, modern rollators use tubular seats, back seats and baskets with spacers and cushions, and rather than using simple hooks, are equipped with latches and release buttons.[1]
## The Zimmers
The British English common equivalent term for a walker is Zimmer Frame - from Zimmer Holdings, a major manufacturer of such devices and joint replacement parts.
In May 2007, a group of elder people in the UK formed a rock group to highlight the plight and difficulties associated with old age. They called themselves The Zimmers in recognition of this generic term.
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Wart
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Wart overview
# Overview
A wart is generally a small, rough tumor, typically on hands and feet, that can resemble a cauliflower or a solid blister. Warts are common, and are caused by a viral infection, specifically by the human papillomavirus (HPV) and are contagious when in contact with the skin of another. It is also possible to get warts from using towels or other objects. They typically disappear after a few months but can last for years and can reoccur. A few papilloma viruses are known to cause cervical cancer.
# Diagnosis
## History and Symptoms
The typical wart is a raised round or oval growth on the skin with a rough surface. Compared with the surrounding normal skin, warts may appear light, dark, or black (rare). Most adults are familiar with the look of a typical wart and have little trouble recognizing it. Unusual warts with smooth surfaces or flat warts in children may be more difficult for parents to recognize.
# Treatment
## Medical Therapy
Some warts will disappear without treatment, although it can sometimes take a couple of years. Treated or not, warts that go away often reappear. All warts can spread from one part of the body to another. Unsightly or painful warts can be treated. Warts around and under the nails are much more difficult to cure than warts in other places.
## Primary Prevention
Avoiding direct skin contact with a wart on someone can contribute to preventing the infection.
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Wart overview
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A wart is generally a small, rough tumor, typically on hands and feet, that can resemble a cauliflower or a solid blister. Warts are common, and are caused by a viral infection, specifically by the human papillomavirus (HPV) and are contagious when in contact with the skin of another. It is also possible to get warts from using towels or other objects. They typically disappear after a few months but can last for years and can reoccur. A few papilloma viruses are known to cause cervical cancer.
# Diagnosis
## History and Symptoms
The typical wart is a raised round or oval growth on the skin with a rough surface. Compared with the surrounding normal skin, warts may appear light, dark, or black (rare). Most adults are familiar with the look of a typical wart and have little trouble recognizing it. Unusual warts with smooth surfaces or flat warts in children may be more difficult for parents to recognize.
# Treatment
## Medical Therapy
Some warts will disappear without treatment, although it can sometimes take a couple of years. Treated or not, warts that go away often reappear. All warts can spread from one part of the body to another. Unsightly or painful warts can be treated. Warts around and under the nails are much more difficult to cure than warts in other places.
## Primary Prevention
Avoiding direct skin contact with a wart on someone can contribute to preventing the infection.
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Water quality
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Water quality
Water quality is the physical, chemical and biological characteristics of water, characterized through the methods of hydrometry. The primary bases for such characterization are parameters which relate to drinking water, safety of human contact and for health of ecosystems. The vast majority of surface water on the planet is neither potable nor toxic. This remains true even if sea water in the oceans (which is too salty to drink) isn't counted. Another general perception of water quality is that of a simple property that tells whether water is polluted or not. In fact, water quality is a very complex subject, in part because water is a complex medium intrinsically tied to the ecology of the Earth. Industrial pollution is a major cause of water pollution, as well as runoff from agricultural areas, urban stormwater runoff and discharge of untreated sewage (especially in developing countries).
# Overview
Contaminants that may be in untreated water include microorganisms such as viruses and bacteria; inorganic contaminants such as salts and metals; pesticides and herbicides; organic chemical contaminants from industrial processes and petroleum use; and radioactive contaminants.
Water quality depends on the local geology and ecosystem, as well as human uses such as sewage dispersion, industrial pollution, use of water bodies as a heat sink, and overuse (which may lower the level of the water).
The Environmental Protection Agency prescribes regulations that limit the amount of certain contaminants in the water provided by public water systems for tap water. Food and Drug Administration (FDA) regulations establish limits for contaminants in bottled water that must provide the same protection for public health. Drinking water, including bottled water, may reasonably be expected to contain at least small amounts of some contaminants. The presence of these contaminants does not necessarily indicate that the water poses a health risk.
Some people use water purification technology to remove contaminants from the municipal water supply they get in their homes, or from local pumps or bodies of water. For people who get water from a local stream, lake, or aquifer, their drinking water is not filtered by the local government.
Toxic substances and high populations of certain microorganisms can present a health hazard for non-drinking purposes such as irrigation, swimming, fishing, rafting, boating, and industrial uses. These conditions may also impact wildlife which use the water for drinking or as a
Habitat.
Interest by individuals and volunteer groups in making local water quality observations is high, and an understanding of the basic chemistry of many water quality parameters is an essential first step to making good measurements. Most citizens harbor great concern over the purity of their drinking water, but there is far more to water quality than water treatment for human consumption.
Statements to the effect that "uses must be preserved" are included within water quality regulations because they provide for broad interpretation of water quality results, while preserving the ultimate goal of the regulations. Technical measures of water quality—that is, the values obtained when making water quality measurements—are always subject to interpretation from multiple perspectives. Is it reasonable to expect a river to be pristine in a landscape that no longer is? If a river has always carried sediment, is it polluted even if the cause is not man induced? Can water quality be maintained when water quantity can not? The questions that arise from consideration of water quality relative to human uses of the water become more complex when consideration must also be given to conditions required to sustain aquatic biota. Yet inherent in the concept of preserving uses is a mandate that waterways must be much more than conduits for a fluid we might want to drink, fill our swimming pool with, or carry our wastes out of town
# Measurement
The complexity of water quality as a subject is reflected in the many types of measurements of water and Wastewater quality indicators. In England and Wales acceptable levels are listed in the Water Supply (Water Quality) Regulations 1989. These measurements include (from simple and basic to more complex):
- Electrical conductivity|Conductivity (also see salinity)
- Dissolved Oxygen(DO)
- pH
- Color of water
- Taste and odor (geosmin, 2-methylisoborneol (MIB), etc)
- Turbidity
- Total suspended solids (TSS)
- Dissolved metals and salts (sodium, chloride, potassium, calcium, manganese, magnesium)
- Chemical oxygen demand (COD)
- Biochemical oxygen demand (BOD)
- Microorganisms such as fecal coliform bacteria (Escherichia coli), Cryptosporidium, and Giardia lamblia
- Nutrients, such as nitrogen and phosphorus
- Dissolved metals and metalloids (lead, Mercury (element),arsenic, etc.)
- Dissolved organics: Colored Dissolved Organic Matter (CDOM), Dissolved Organic Carbon (DOC)
- Temperature
- Pesticides
- Heavy Metals
- Pharmaceuticals
- Hormone analogs
Some of the simple measurements listed above can be made on-site (temperature, pH, dissolved oxygen, conductivity), in direct contact with the water source in question. More complex measurements that must be made in a lab setting require a water sample to be collected, preserved, and analyzed at another location. Making these complex measurements can be expensive.
Because direct measurements of water quality can be expensive, ongoing monitoring programs are typical conducted by government agencies. Individuals interested in monitoring water quality who cannot afford or manage lab scale analysis can also use biological indicators to get a general reading of water quality. Biological monitoring metrics have been developed in many places, and one widely used measure is the presence and abundance of members of the insect orders Ephemeroptera, Plecoptera and Trichoptera (EPT). EPT indexes will naturally vary from region to region, but generally, within a region, the greater the number of taxa from these orders, the better the water quality. A number of websites originating in the United States offer guidance on developing a monitoring program and identifying members of these and other aquatic insect orders.
# Reports
In the United States each governing jurisdiction (states, territories, and covered tribal entities) is required to submit a set of biennial reports on the quality of water in their area. These reports submitted to, and approved by, the Environmental Protection Agency are known as the 303(d), 305(b) and 314 reports. In coming years it is expected that the governing jurisdictions will submit all three reports as a single document, called the Integrated Report. The 305(b) report is a general report on water quality throughout the state, providing overall information about the number of miles of streams and rivers and their agreegate condition. The 314 report provides similar information for lakes. Under the Clean Water Act, states are required to adopt water quality standards for each of the possible designated uses that they assign to their waters. Should evidence exist to suggest or document that a stream, river or lake has failed to meet the water quality criteria for one or more of its designated uses, it is placed on the 303(d) list, or the list of impaired waters. Once on the 303(d) list states are required to develop management plans establishing Total Maximum Daily Loads for the pollutant impairing the use of the water. These TMDLs establish what reductions in pollutants are needed to allow the water to regain its status as fully supporting the designated uses assigned to it. These reports are completed by the governing jurisdiction, typically a Department of Environmental Quality or similar state agency, and are available on the web.
Individuals interested in more information about water quality in areas of the United States may find information at the EPA's "Surf Your Watershed" website.
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Water quality
Water quality is the physical, chemical and biological characteristics of water, characterized through the methods of hydrometry. The primary bases for such characterization are parameters which relate to drinking water, safety of human contact and for health of ecosystems. The vast majority of surface water on the planet is neither potable nor toxic. This remains true even if sea water in the oceans (which is too salty to drink) isn't counted. Another general perception of water quality is that of a simple property that tells whether water is polluted or not. In fact, water quality is a very complex subject, in part because water is a complex medium intrinsically tied to the ecology of the Earth. Industrial pollution is a major cause of water pollution, as well as runoff from agricultural areas, urban stormwater runoff and discharge of untreated sewage (especially in developing countries).
# Overview
Contaminants that may be in untreated water include microorganisms such as viruses and bacteria; inorganic contaminants such as salts and metals; pesticides and herbicides; organic chemical contaminants from industrial processes and petroleum use; and radioactive contaminants.
Water quality depends on the local geology and ecosystem, as well as human uses such as sewage dispersion, industrial pollution, use of water bodies as a heat sink, and overuse (which may lower the level of the water).
The Environmental Protection Agency prescribes regulations that limit the amount of certain contaminants in the water provided by public water systems for tap water. Food and Drug Administration (FDA) regulations establish limits for contaminants in bottled water that must provide the same protection for public health. Drinking water, including bottled water, may reasonably be expected to contain at least small amounts of some contaminants. The presence of these contaminants does not necessarily indicate that the water poses a health risk.
Some people use water purification technology to remove contaminants from the municipal water supply they get in their homes, or from local pumps or bodies of water. For people who get water from a local stream, lake, or aquifer, their drinking water is not filtered by the local government.
Toxic substances and high populations of certain microorganisms can present a health hazard for non-drinking purposes such as irrigation, swimming, fishing, rafting, boating, and industrial uses. These conditions may also impact wildlife which use the water for drinking or as a
Habitat.
Interest by individuals and volunteer groups in making local water quality observations is high, and an understanding of the basic chemistry of many water quality parameters is an essential first step to making good measurements. Most citizens harbor great concern over the purity of their drinking water, but there is far more to water quality than water treatment for human consumption.
Statements to the effect that "uses must be preserved" are included within water quality regulations because they provide for broad interpretation of water quality results, while preserving the ultimate goal of the regulations. Technical measures of water quality—that is, the values obtained when making water quality measurements—are always subject to interpretation from multiple perspectives. Is it reasonable to expect a river to be pristine in a landscape that no longer is? If a river has always carried sediment, is it polluted even if the cause is not man induced? Can water quality be maintained when water quantity can not? The questions that arise from consideration of water quality relative to human uses of the water become more complex when consideration must also be given to conditions required to sustain aquatic biota. Yet inherent in the concept of preserving uses is a mandate that waterways must be much more than conduits for a fluid we might want to drink, fill our swimming pool with, or carry our wastes out of town
# Measurement
The complexity of water quality as a subject is reflected in the many types of measurements of water and Wastewater quality indicators. In England and Wales acceptable levels are listed in the Water Supply (Water Quality) Regulations 1989. These measurements include (from simple and basic to more complex):
- Electrical conductivity|Conductivity (also see salinity)
- Dissolved Oxygen(DO)
- pH
- Color of water
- Taste and odor (geosmin, 2-methylisoborneol (MIB), etc)
- Turbidity
- Total suspended solids (TSS)
- Dissolved metals and salts (sodium, chloride, potassium, calcium, manganese, magnesium)
- Chemical oxygen demand (COD)
- Biochemical oxygen demand (BOD)
- Microorganisms such as fecal coliform bacteria (Escherichia coli), Cryptosporidium, and Giardia lamblia
- Nutrients, such as nitrogen and phosphorus
- Dissolved metals and metalloids (lead, Mercury (element),arsenic, etc.)
- Dissolved organics: Colored Dissolved Organic Matter (CDOM), Dissolved Organic Carbon (DOC)
- Temperature
- Pesticides
- Heavy Metals
- Pharmaceuticals
- Hormone analogs
Some of the simple measurements listed above can be made on-site (temperature, pH, dissolved oxygen, conductivity), in direct contact with the water source in question. More complex measurements that must be made in a lab setting require a water sample to be collected, preserved, and analyzed at another location. Making these complex measurements can be expensive.
Because direct measurements of water quality can be expensive, ongoing monitoring programs are typical conducted by government agencies. Individuals interested in monitoring water quality who cannot afford or manage lab scale analysis can also use biological indicators to get a general reading of water quality. Biological monitoring metrics have been developed in many places, and one widely used measure is the presence and abundance of members of the insect orders Ephemeroptera, Plecoptera and Trichoptera (EPT). EPT indexes will naturally vary from region to region, but generally, within a region, the greater the number of taxa from these orders, the better the water quality. A number of websites originating in the United States offer guidance on developing a monitoring program and identifying members of these and other aquatic insect orders.
# Reports
In the United States each governing jurisdiction (states, territories, and covered tribal entities) is required to submit a set of biennial reports on the quality of water in their area. These reports submitted to, and approved by, the Environmental Protection Agency are known as the 303(d), 305(b) and 314 reports. In coming years it is expected that the governing jurisdictions will submit all three reports as a single document, called the Integrated Report. The 305(b) report is a general report on water quality throughout the state, providing overall information about the number of miles of streams and rivers and their agreegate condition. The 314 report provides similar information for lakes. Under the Clean Water Act, states are required to adopt water quality standards for each of the possible designated uses that they assign to their waters. Should evidence exist to suggest or document that a stream, river or lake has failed to meet the water quality criteria for one or more of its designated uses, it is placed on the 303(d) list, or the list of impaired waters. Once on the 303(d) list states are required to develop management plans establishing Total Maximum Daily Loads for the pollutant impairing the use of the water. These TMDLs establish what reductions in pollutants are needed to allow the water to regain its status as fully supporting the designated uses assigned to it. These reports are completed by the governing jurisdiction, typically a Department of Environmental Quality or similar state agency, and are available on the web.
Individuals interested in more information about water quality in areas of the United States may find information at the EPA's "Surf Your Watershed" website.
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Wave function
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Wave function
A wave function or wavefunction is a mathematical tool used in quantum mechanics to describe any physical system. It is a function from a space that maps the possible states of the system into the complex numbers. The laws of quantum mechanics (i.e. the Schrödinger equation) describe how the wave function evolves over time. The values of the wave function are probability amplitudes — complex numbers — the squares of the absolute values of which, give the probability distribution that the system will be in any of the possible states.
For example, in an atom with a single electron, such as hydrogen or ionized helium, the wave function of the electron provides a complete description of how the electron behaves. It can be decomposed into a series of atomic orbitals which form a basis for the possible wave functions. For atoms with more than one electron (or any system with multiple particles), the underlying space is the possible configurations of all the electrons and the wave function describes the probabilities of those configurations.
# Definition
The modern usage of the term wave function refers to a complex vector or function, i.e. an element in a complex Hilbert space. Typically, a wave function is either:
- a complex vector with finitely many components
- a complex vector with infinitely many components
where each component may be complex function of one or more real variables (a "continuously indexed" complex vector)
In all cases, the wave function provides a complete description of the associated physical system. An element of a vector space can be expressed in different bases; and so the same applies to wave functions. The components of a wave function describing the same physical state take different complex values depending on the basis being used; however the wave function itself is not dependent on the basis chosen; in this respect they are like spatial vectors in ordinary space: choosing a new set of cartesian axes by rotation of the coordinate frame does not alter the vector itself, only the representation of the vector with respect to the coordinate frame. A basis in quantum mechanics is analogous to the coordinate frame: choosing a new basis does not alter the wavefunction, only its representation, which is expressed as the values of the components above.
Because the probabilities that the system is in each possible state should add up to 1, the norm of the wave function must be 1.
# Spatial interpretation
The physical interpretation of the wave function is context dependent. Several examples are
provided below, followed by a detailed discussion of the three cases described above.
## One particle in one spatial dimension
The spatial wave function associated with a particle in one dimension is a complex function \psi(x)\, defined over the real line. The positive function |\psi|^2\, is interpreted as the probability density associated with the particle's position. That is, the probability of a measurement of the particle's position yielding a value in the interval is given by
This leads to the normalization condition
since the probability of a measurement of the particle's position yielding a value in the range (-\infty, \infty) is unity.
## One particle in three spatial dimensions
The three dimensional case is analogous to the one dimensional case; the wave function is a complex function \psi(x, y, z)\, defined over three dimensional space, and its complex square is interpreted as a three dimensional probability density function:
The normalization condition is likewise
where the preceding integral is taken over all space.
## Two distinguishable particles in three spatial dimensions
In this case, the wave function is a complex function of six spatial variables, \psi(x_1, y_1, z_1, x_2, y_2, z_2) \ , and |\psi|^2\, is the joint probability density associated with the positions of both particles. Thus the probability that a measurement of the positions of both particles indicates particle one is in region R and particle two is in region S is
where dV_1 = dx_1 dy_1 dz_1, and similarly for dV_2.
The normalization condition is then:
in which the preceding integral is taken over the full range of all six variables.
Given a wave function ψ of a system consisting of two (or more) particles, it is in general not possible to assign a definite wave function to a single-particle subsystem. In other words, the particles in the system can be entangled.
## One particle in one dimensional momentum space
The wave function for a one dimensional particle in momentum space is a complex function \psi(p)\, defined over the real line. The quantity |\psi|^2\, is interpreted as a probability density function in momentum space:
As in the position space case, this leads to the normalization condition:
## Spin 1/2
The wave function for a spin-½ particle (ignoring its spatial degrees of freedom) is a column vector
The meaning of the vector's components depends on the basis, but typically c_1
and c_2 are respectively the coefficients of spin up and spin down in the z
direction. In Dirac notation this is:
The values |c_1|^2 \, and |c_2|^2 \, are then respectively interpreted as the probability of obtaining spin up or spin down in the z direction when a measurement of the particle's spin is performed. This leads to the normalization condition
# Interpretation
A wave function describes the state of a physical system, | \psi \rangle\,, by expanding it in terms of other possible states of the same system, | \phi_i \rangle. Collectively the latter are referred to as a basis or representation. In what follows, all wave functions are assumed to be normalized.
## Finite dimensional basis vectors
A wave function which is a vector \vec \psi with n components describes how to express the state of the physical system | \psi \rangle as the linear combination of finitely many basis elements | \phi_i \rangle, where i runs from 1 to n. In particular the equation
which is a relation between column vectors, is equivalent to
which is a relation between the states of a physical system. Note that to pass between these expressions one must know the basis in use, and hence, two column vectors with the same components can represent two different states of a system if their associated basis states are different. An example of a wave function which is a finite vector is furnished by the spin state of a spin-1/2 particle, as described above.
The physical meaning of the components of \vec \psi is given by the wave function collapse postulate:
## Infinite dimensional basis vectors
The case of an infinite vector with a discrete index is treated in the same manner a finite vector, except the sum is extended over all the basis elements. Hence
is equivalent to
where it is understood that the above sum includes all the components of \vec \psi. The interpretation of the components is the same as the finite case (apply the collapse postulate).
## Continuously indexed vectors (functions)
In the case of a continuous index, the sum is replaced by an integral; an example of this is the spatial wave function of a particle in one dimension, which expands the physical state of the particle, | \psi \rangle, in terms of states with definite position, | x \rangle. Thus
Note that | \psi \rangle is not the same as \psi(x)\,. The former is
the actual state of the particle, whereas the latter is simply a wave function
describing how to express the former as a superposition of states with definite position. In this case the base states themselves can be expressed as
and hence the spatial wave function associated with | x_0 \rangle is \delta(x - x_0)\, (where \delta(x - x_0)\, is the Dirac delta function).
# Formalism
Given an isolated physical system, the allowed states of this system (i.e. the states the system could occupy without violating the laws of physics) are part of a Hilbert space H. Some properties of such a space are
The wave function associated with a particular state may be seen as an expansion of the state in a basis of H. For example,
is a basis for the space associated with the spin of a spin-1/2 particle and consequently
the spin state of any such particle can be written uniquely as
Sometimes it is useful to expand the state of a physical system in terms of states which are not allowed, and hence, not in H. An example of this is the spacial wave function associated with a particle in one dimension which expands the state of the particle in terms of states with definite position.
Every Hilbert space H is equipped with an inner product. Physically, the nature of the inner product is contingent upon the kind of basis in use. When the basis is a countable set \{ | \phi_i \rangle \}\,, and orthonormal, i.e.
Then an arbitrary vector | \psi \rangle can be expressed as
where c_i = \langle \phi_i | \psi \rangle.
If one chooses a "continuous" basis as, for example, the position or coordinate basis consisting of all states of definite position \{ | x \rangle \}, the orthonormality condition holds similarly:
We have the analogous identity
# Ontology
Whether the wave function is real, and what it represents, are major questions in the interpretation of quantum mechanics. Many famous physicists have puzzled over this problem, such as Erwin Schrödinger, Albert Einstein and Niels Bohr. Some approaches regard it as merely representing information in the mind of the observer. Others argue that it must be objective.
# Notes
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Wave function
A wave function or wavefunction is a mathematical tool used in quantum mechanics to describe any physical system. It is a function from a space that maps the possible states of the system into the complex numbers. The laws of quantum mechanics (i.e. the Schrödinger equation) describe how the wave function evolves over time. The values of the wave function are probability amplitudes — complex numbers — the squares of the absolute values of which, give the probability distribution that the system will be in any of the possible states.
For example, in an atom with a single electron, such as hydrogen or ionized helium, the wave function of the electron provides a complete description of how the electron behaves. It can be decomposed into a series of atomic orbitals which form a basis for the possible wave functions. For atoms with more than one electron (or any system with multiple particles), the underlying space is the possible configurations of all the electrons and the wave function describes the probabilities of those configurations.
# Definition
The modern usage of the term wave function refers to a complex vector or function, i.e. an element in a complex Hilbert space. Typically, a wave function is either:
- a complex vector with finitely many components
- a complex vector with infinitely many components
where each component may be complex function of one or more real variables (a "continuously indexed" complex vector)
In all cases, the wave function provides a complete description of the associated physical system. An element of a vector space can be expressed in different bases; and so the same applies to wave functions. The components of a wave function describing the same physical state take different complex values depending on the basis being used; however the wave function itself is not dependent on the basis chosen; in this respect they are like spatial vectors in ordinary space: choosing a new set of cartesian axes by rotation of the coordinate frame does not alter the vector itself, only the representation of the vector with respect to the coordinate frame. A basis in quantum mechanics is analogous to the coordinate frame: choosing a new basis does not alter the wavefunction, only its representation, which is expressed as the values of the components above.
Because the probabilities that the system is in each possible state should add up to 1, the norm of the wave function must be 1.
# Spatial interpretation
The physical interpretation of the wave function is context dependent. Several examples are
provided below, followed by a detailed discussion of the three cases described above.
## One particle in one spatial dimension
The spatial wave function associated with a particle in one dimension is a complex function <math>\psi(x)\,</math> defined over the real line. The positive function <math>|\psi|^2\,</math> is interpreted as the probability density associated with the particle's position. That is, the probability of a measurement of the particle's position yielding a value in the interval <math>[a, b]</math> is given by
This leads to the normalization condition
since the probability of a measurement of the particle's position yielding a value in the range <math>(-\infty, \infty)</math> is unity.
## One particle in three spatial dimensions
The three dimensional case is analogous to the one dimensional case; the wave function is a complex function <math>\psi(x, y, z)\,</math> defined over three dimensional space, and its complex square is interpreted as a three dimensional probability density function:
The normalization condition is likewise
where the preceding integral is taken over all space.
## Two distinguishable particles in three spatial dimensions
In this case, the wave function is a complex function of six spatial variables, <math>\psi(x_1, y_1, z_1, x_2, y_2, z_2) \ </math>, and <math>|\psi|^2\,</math> is the joint probability density associated with the positions of both particles. Thus the probability that a measurement of the positions of both particles indicates particle one is in region <math>R</math> and particle two is in region <math>S</math> is
where <math>dV_1 = dx_1 dy_1 dz_1</math>, and similarly for <math>dV_2</math>.
The normalization condition is then:
in which the preceding integral is taken over the full range of all six variables.
Given a wave function ψ of a system consisting of two (or more) particles, it is in general not possible to assign a definite wave function to a single-particle subsystem. In other words, the particles in the system can be entangled.
## One particle in one dimensional momentum space
The wave function for a one dimensional particle in momentum space is a complex function <math>\psi(p)\,</math> defined over the real line. The quantity <math>|\psi|^2\,</math> is interpreted as a probability density function in momentum space:
As in the position space case, this leads to the normalization condition:
## Spin 1/2
The wave function for a spin-½ particle (ignoring its spatial degrees of freedom) is a column vector
The meaning of the vector's components depends on the basis, but typically <math>c_1</math>
and <math>c_2</math> are respectively the coefficients of spin up and spin down in the <math>z</math>
direction. In Dirac notation this is:
The values <math>|c_1|^2 \,</math> and <math>|c_2|^2 \,</math> are then respectively interpreted as the probability of obtaining spin up or spin down in the z direction when a measurement of the particle's spin is performed. This leads to the normalization condition
# Interpretation
A wave function describes the state of a physical system, <math>| \psi \rangle\,</math>, by expanding it in terms of other possible states of the same system, <math>| \phi_i \rangle</math>. Collectively the latter are referred to as a basis or representation. In what follows, all wave functions are assumed to be normalized.
## Finite dimensional basis vectors
A wave function which is a vector <math>\vec \psi</math> with <math>n</math> components describes how to express the state of the physical system <math>| \psi \rangle</math> as the linear combination of finitely many basis elements <math>| \phi_i \rangle</math>, where <math>i</math> runs from <math>1</math> to <math>n</math>. In particular the equation
which is a relation between column vectors, is equivalent to
which is a relation between the states of a physical system. Note that to pass between these expressions one must know the basis in use, and hence, two column vectors with the same components can represent two different states of a system if their associated basis states are different. An example of a wave function which is a finite vector is furnished by the spin state of a spin-1/2 particle, as described above.
The physical meaning of the components of <math>\vec \psi</math> is given by the wave function collapse postulate:
## Infinite dimensional basis vectors
The case of an infinite vector with a discrete index is treated in the same manner a finite vector, except the sum is extended over all the basis elements. Hence
is equivalent to
where it is understood that the above sum includes all the components of <math>\vec \psi</math>. The interpretation of the components is the same as the finite case (apply the collapse postulate).
## Continuously indexed vectors (functions)
In the case of a continuous index, the sum is replaced by an integral; an example of this is the spatial wave function of a particle in one dimension, which expands the physical state of the particle, <math>| \psi \rangle</math>, in terms of states with definite position, <math>| x \rangle</math>. Thus
Note that <math>| \psi \rangle</math> is not the same as <math>\psi(x)\,</math>. The former is
the actual state of the particle, whereas the latter is simply a wave function
describing how to express the former as a superposition of states with definite position. In this case the base states themselves can be expressed as
and hence the spatial wave function associated with <math>| x_0 \rangle</math> is <math>\delta(x - x_0)\,</math> (where <math>\delta(x - x_0)\,</math> is the Dirac delta function).
# Formalism
Given an isolated physical system, the allowed states of this system (i.e. the states the system could occupy without violating the laws of physics) are part of a Hilbert space <math>H</math>. Some properties of such a space are
The wave function associated with a particular state may be seen as an expansion of the state in a basis of <math>H</math>. For example,
is a basis for the space associated with the spin of a spin-1/2 particle and consequently
the spin state of any such particle can be written uniquely as
Sometimes it is useful to expand the state of a physical system in terms of states which are not allowed, and hence, not in <math>H</math>. An example of this is the spacial wave function associated with a particle in one dimension which expands the state of the particle in terms of states with definite position.
Every Hilbert space <math>H</math> is equipped with an inner product. Physically, the nature of the inner product is contingent upon the kind of basis in use. When the basis is a countable set <math>\{ | \phi_i \rangle \}\,</math>, and orthonormal, i.e.
Then an arbitrary vector <math>| \psi \rangle</math> can be expressed as
where <math>c_i = \langle \phi_i | \psi \rangle.</math>
If one chooses a "continuous" basis as, for example, the position or coordinate basis consisting of all states of definite position <math>\{ | x \rangle \}</math>, the orthonormality condition holds similarly:
We have the analogous identity
# Ontology
Whether the wave function is real, and what it represents, are major questions in the interpretation of quantum mechanics. Many famous physicists have puzzled over this problem, such as Erwin Schrödinger, Albert Einstein and Niels Bohr. Some approaches regard it as merely representing information in the mind of the observer. Others argue that it must be objective.
# Notes
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Yo-yo dieting
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Yo-yo dieting
Synonyms and keywords: yo-yo effect; weight cycling
# Overview
The term "yo-yo dieting" was coined by Kelly D. Brownell at Yale University, in reference to the cyclical up-down motion of a yo-yo. In this process, the dieter is initially successful in the pursuit of weight loss but is unsuccessful in maintaining the loss long-term and begins to gain the weight back. The dieter then seeks to lose the regained weight, and the cycle begins again.
# Causes
The reasons for yo-yo dieting are varied but often include embarking upon a hypocaloric diet that was initially too extreme. At first the dieter may experience elation at the thought of loss and pride of their rejection of food. Over time, however, the limits imposed by such extreme diets cause effects such as depression or fatigue that make the diet impossible to sustain. Ultimately, the dieter reverts to their old eating habits, now with the added emotional effects of failing to lose weight by restrictive diet. Such an emotional state leads many people to eating more than they would have before dieting, causing them to rapidly regain weight.
# Effects on health
This kind of diet is associated with extreme food deprivation as a substitute for good diet and exercise techniques. As a result, the dieter may experience loss of both muscle and body fat during the initial weight-loss phase (weight-bearing exercise is required to maintain muscle). After completing the diet, the dieter is likely to experience the body's starvation response, leading to rapid weight gain of only fat. This is a cycle that changes the body's fat-to-muscle ratio, one of the more important factors in health. One study in rats showed those made to yo-yo diet were more efficient at gaining weight. However, as of 1994, the research compiled by Atkinson et al. (1994) showed that there are “no adverse effects of weight cycling on body composition, resting metabolic rate, body fat distribution, or future successful weight loss”, and that there is not enough evidence to show risk factors for cardiovascular disease being directly dependent on cyclical dieting patterns. Yo-yo dieting can have extreme emotional and physical ramifications due to the stress that someone puts on themselves to lose weight quickly. The instant gratification of losing the weight eventually gives way to old eating habits that cause weight gain and emotional distress.
Since there is “no single definition of weight cycling can be endorsed”, it is almost impossible for research to draw specific conclusions about the actual effects of cyclical dieting, until it becomes more definitely defined.
|
Yo-yo dieting
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: yo-yo effect; weight cycling
# Overview
The term "yo-yo dieting" was coined by Kelly D. Brownell at Yale University, in reference to the cyclical up-down motion of a yo-yo. In this process, the dieter is initially successful in the pursuit of weight loss but is unsuccessful in maintaining the loss long-term and begins to gain the weight back. The dieter then seeks to lose the regained weight, and the cycle begins again.
# Causes
The reasons for yo-yo dieting are varied but often include embarking upon a hypocaloric diet that was initially too extreme. At first the dieter may experience elation at the thought of loss and pride of their rejection of food. Over time, however, the limits imposed by such extreme diets cause effects such as depression or fatigue that make the diet impossible to sustain. Ultimately, the dieter reverts to their old eating habits, now with the added emotional effects of failing to lose weight by restrictive diet. Such an emotional state leads many people to eating more than they would have before dieting, causing them to rapidly regain weight.[1]
# Effects on health
This kind of diet is associated with extreme food deprivation as a substitute for good diet and exercise techniques. As a result, the dieter may experience loss of both muscle and body fat during the initial weight-loss phase (weight-bearing exercise is required to maintain muscle). After completing the diet, the dieter is likely to experience the body's starvation response, leading to rapid weight gain of only fat. This is a cycle that changes the body's fat-to-muscle ratio, one of the more important factors in health. One study in rats showed those made to yo-yo diet were more efficient at gaining weight.[2] However, as of 1994, the research compiled by Atkinson et al. (1994) showed that there are “no adverse effects of weight cycling on body composition, resting metabolic rate, body fat distribution, or future successful weight loss”, and that there is not enough evidence to show risk factors for cardiovascular disease being directly dependent on cyclical dieting patterns. Yo-yo dieting can have extreme emotional and physical ramifications due to the stress that someone puts on themselves to lose weight quickly. The instant gratification of losing the weight eventually gives way to old eating habits that cause weight gain and emotional distress.
Since there is “no single definition of weight cycling [that] can be endorsed”, it is almost impossible for research to draw specific conclusions about the actual effects of cyclical dieting, until it becomes more definitely defined.[3]
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Wellbutrin SR
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Wellbutrin SR
Synonyms / Brand Names: Wellbatrin, Wellbutrin SR, Wellbutrin XL, Zyban, Bupropion Hcl, Amfebutamone
# Dosing and Administration
The usual adult target dose for WELLBUTRIN SR Tablets is 300 mg/day,
given as 150 mg twice daily. Dosing with WELLBUTRIN SR Tablets should begin at
150 mg/day given as a single daily dose in the morning. If the 150-mg initial dose is adequately
tolerated, an increase to the 300-mg/day target dose, given as 150 mg twice daily, may be made as early as day 4 of dosing. There should be an interval of at least 8 hours between successive
doses
For more information on Dosing please refer to Instructions for Administration
FDA Package Insert Resources
Indications, Contraindications, Side Effects, Drug Interactions, etc.
Calculate Creatine Clearance
On line calculator of your patients Cr Cl by a variety of formulas.
Convert pounds to Kilograms
On line calculator of your patients weight in pounds to Kg for dosing estimates.
Publication Resources
Recent articles, WikiDoc State of the Art Review, Textbook Information
Trial Resources
Ongoing Trials, Trial Results
Guidelines & Evidence Based Medicine Resources
US National Guidelines, Cochrane Collaboration, etc.
Media Resources
Slides, Video, Images, MP3, Podcasts, etc.
Patient Resources
Discussion Groups, Handouts, Blogs, News, etc.
International Resources
en Español
# FDA Package Insert Resources
Indications
Contraindications
Side Effects
Drug Interactions
Precautions
Overdose
Instructions for Administration
How Supplied
Pharmacokinetics and Molecular Data
FDA label
FDA on Wellbutrin SR
Return to top
# Publication Resources
Most Recent Articles on Wellbutrin SR
Review Articles on Wellbutrin SR
Articles on Wellbutrin SR in N Eng J Med, Lancet, BMJ
WikiDoc State of the Art Review
Textbook Information on Wellbutrin SR
Return to top
# Trial Resources
Ongoing Trials with Wellbutrin SR at Clinical Trials.gov
Trial Results with Wellbutrin SR
Return to top
# Guidelines & Evidence Based Medicine Resources
US National Guidelines Clearinghouse on Wellbutrin SR
Cochrane Collaboration on Wellbutrin SR
Cost Effectiveness of Wellbutrin SR
Return to top
# Media Resources
Powerpoint Slides on Wellbutrin SR
Images of Wellbutrin SR
Podcasts & MP3s on Wellbutrin SR
Videos on Wellbutrin SR
Return to top
# Patient Resources
Patient Information from National Library of Medicine
Patient Resources on Wellbutrin SR
Discussion Groups on Wellbutrin SR
Patient Handouts on Wellbutrin SR
Blogs on Wellbutrin SR
Wellbutrin SR in the News
Wellbutrin SR in the Marketplace
Return to top
# International Resources
Wellbutrin SR en Español
Return to top
Adapted from the FDA Package Insert.
|
Wellbutrin SR
Synonyms / Brand Names: Wellbatrin, Wellbutrin SR, Wellbutrin XL, Zyban, Bupropion Hcl, Amfebutamone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Dosing and Administration
The usual adult target dose for WELLBUTRIN SR Tablets is 300 mg/day,
given as 150 mg twice daily. Dosing with WELLBUTRIN SR Tablets should begin at
150 mg/day given as a single daily dose in the morning. If the 150-mg initial dose is adequately
tolerated, an increase to the 300-mg/day target dose, given as 150 mg twice daily, may be made as early as day 4 of dosing. There should be an interval of at least 8 hours between successive
doses
For more information on Dosing please refer to Instructions for Administration
FDA Package Insert Resources
Indications, Contraindications, Side Effects, Drug Interactions, etc.
Calculate Creatine Clearance
On line calculator of your patients Cr Cl by a variety of formulas.
Convert pounds to Kilograms
On line calculator of your patients weight in pounds to Kg for dosing estimates.
Publication Resources
Recent articles, WikiDoc State of the Art Review, Textbook Information
Trial Resources
Ongoing Trials, Trial Results
Guidelines & Evidence Based Medicine Resources
US National Guidelines, Cochrane Collaboration, etc.
Media Resources
Slides, Video, Images, MP3, Podcasts, etc.
Patient Resources
Discussion Groups, Handouts, Blogs, News, etc.
International Resources
en Español
# FDA Package Insert Resources
Indications
Contraindications
Side Effects
Drug Interactions
Precautions
Overdose
Instructions for Administration
How Supplied
Pharmacokinetics and Molecular Data
FDA label
FDA on Wellbutrin SR
Return to top
# Publication Resources
Most Recent Articles on Wellbutrin SR
Review Articles on Wellbutrin SR
Articles on Wellbutrin SR in N Eng J Med, Lancet, BMJ
WikiDoc State of the Art Review
Textbook Information on Wellbutrin SR
Return to top
# Trial Resources
Ongoing Trials with Wellbutrin SR at Clinical Trials.gov
Trial Results with Wellbutrin SR
Return to top
# Guidelines & Evidence Based Medicine Resources
US National Guidelines Clearinghouse on Wellbutrin SR
Cochrane Collaboration on Wellbutrin SR
Cost Effectiveness of Wellbutrin SR
Return to top
# Media Resources
Powerpoint Slides on Wellbutrin SR
Images of Wellbutrin SR
Podcasts & MP3s on Wellbutrin SR
Videos on Wellbutrin SR
Return to top
# Patient Resources
Patient Information from National Library of Medicine
Patient Resources on Wellbutrin SR
Discussion Groups on Wellbutrin SR
Patient Handouts on Wellbutrin SR
Blogs on Wellbutrin SR
Wellbutrin SR in the News
Wellbutrin SR in the Marketplace
Return to top
# International Resources
Wellbutrin SR en Español
Return to top
Adapted from the FDA Package Insert.
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Western Larch
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Western Larch
Western Larch (Larix occidentalis) is a species of larch native to the mountains of western North America, in Canada in southeastern British Columbia and southwestern Alberta, and in the United States in eastern Washington, eastern Oregon, northern Idaho and western Montana.
It is a large deciduous coniferous tree reaching 30-60 m tall, with a trunk up to 1.5 m diameter. The crown is narrow conic; the main branches are level to upswept, with the side branches often drooping. The shoots are dimorphic, with growth divided into long shoots (typically 10-50 cm long) and bearing several buds, and short shoots only 1-2 mm long with only a single bud. The leaves are needle-like, light green, 2-5 cm long, and very slender; they turn bright yellow in the fall, leaving the pale orange-brown shoots bare until the next spring.
The cones are ovoid-cylindric, 2-5 cm long, with 40-80 seed scales; each scale bearing an exserted 4-8 mm bract. The cones are red when immature, turning brown and the scales opening flat or reflexed to release the seeds when mature, 4-6 months after pollination. The old cones commonly remain on the tree for many years, turning dull gray-black.
It grows at 500-2,400 m altitude, and is very cold tolerant, able to survive winter temperatures down to about −50 °C. It only grows on well-drained soils, avoiding waterlogged ground.
The seeds are an important food for some birds, notably Pine Siskin, Common Redpoll and White-winged Crossbill.
## Uses
The wood is tough and durable, but also flexible in thin strips, and is particularly valued for yacht building; wood used for this must be free of knots, and can only be obtained from old trees that were pruned when young to remove side branches. Small larch poles are widely used for rustic fencing.
Western Larch is used for the production of Venice turpentine.
The wood is highly prized as firewood in the Pacific Northwest where it is commonly called "Tamarack," although it is a different species than the Tamarack Larch. The wood burns with a sweet fragrance and a distinctive popping noise.
Indigenous peoples used to chew gum produced from the tree as well as eat the cambium and sap.
# References and external links
- Template:IUCN2006
- Gymnosperm Database: Larix occidentalis
- Flora of North America: Larix occidentalis
- USDA Plants Profile: Larix occidentalis
- ↑ Turner, Nancy J. Food Plants of Interior First Peoples (Victoria: UBC Press, 1997) ISBN 0-7748-0606-0
- Tree with fall colors
Tree with fall colors
- Leaves and immature cones in spring
Leaves and immature cones in spring
de:Westamerikanische Lärche
|
Western Larch
Western Larch (Larix occidentalis) is a species of larch native to the mountains of western North America, in Canada in southeastern British Columbia and southwestern Alberta, and in the United States in eastern Washington, eastern Oregon, northern Idaho and western Montana.
It is a large deciduous coniferous tree reaching 30-60 m tall, with a trunk up to 1.5 m diameter. The crown is narrow conic; the main branches are level to upswept, with the side branches often drooping. The shoots are dimorphic, with growth divided into long shoots (typically 10-50 cm long) and bearing several buds, and short shoots only 1-2 mm long with only a single bud. The leaves are needle-like, light green, 2-5 cm long, and very slender; they turn bright yellow in the fall, leaving the pale orange-brown shoots bare until the next spring.
The cones are ovoid-cylindric, 2-5 cm long, with 40-80 seed scales; each scale bearing an exserted 4-8 mm bract. The cones are red when immature, turning brown and the scales opening flat or reflexed to release the seeds when mature, 4-6 months after pollination. The old cones commonly remain on the tree for many years, turning dull gray-black.
It grows at 500-2,400 m altitude, and is very cold tolerant, able to survive winter temperatures down to about −50 °C. It only grows on well-drained soils, avoiding waterlogged ground.
The seeds are an important food for some birds, notably Pine Siskin, Common Redpoll and White-winged Crossbill.
## Uses
The wood is tough and durable, but also flexible in thin strips, and is particularly valued for yacht building; wood used for this must be free of knots, and can only be obtained from old trees that were pruned when young to remove side branches. Small larch poles are widely used for rustic fencing.
Western Larch is used for the production of Venice turpentine.
The wood is highly prized as firewood in the Pacific Northwest where it is commonly called "Tamarack," although it is a different species than the Tamarack Larch. The wood burns with a sweet fragrance and a distinctive popping noise.
Indigenous peoples used to chew gum produced from the tree as well as eat the cambium and sap.[1]
# References and external links
- Template:IUCN2006
- Gymnosperm Database: Larix occidentalis
- Flora of North America: Larix occidentalis
- USDA Plants Profile: Larix occidentalis
- ↑ Turner, Nancy J. Food Plants of Interior First Peoples (Victoria: UBC Press, 1997) ISBN 0-7748-0606-0
- Tree with fall colors
Tree with fall colors
- Leaves and immature cones in spring
Leaves and immature cones in spring
de:Westamerikanische Lärche
Template:WH
Template:WikiDoc Sources
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Wheat allergy
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Wheat allergy
# Overview
Wheat allergy, is a food allergy, but can also be a respiratory or contact allergy resulting from occupational exposure. Like all allergies wheat allergy involves IgE and mast cell response. Typically the allergy is limited to the seed storage proteins of wheat, some reactions are restricted to wheat proteins, while others can react across many varieties of seeds and other plant tissues. Wheat allergy may be a misnomer since there are many allergenic components in wheat, for example serine proteinase inhibitors, glutelins and prolamins and different responses are often attributed to different proteins. The most severe response is exercise/aspirin induced anaphylaxis attributed to one omega gliadin that is a relative of the protein that causes coeliac disease. Other more common symptoms include nausea, urticaria, atopy.
# Types of allergens
There are four major classes of seed storage proteins: albumins, globulins, prolamins and glutelins. Within wheat prolamins are called gliadins and glutelins are called glutenins. These two protein groups form the classic glutens. While gluten is a causative agent of Coeliac disease (CD), coeliac disease can be contrasted to gluten allergy by the involvement of different immune cells and antibody types (See Comparative pathophysiology of gluten sensitivities), and because the list of allergens extend beyond the classic gluten category of proteins.
## Gluten Allergy
### Prolamin allergies
Prolamins and the closely related glutelins, a recent study in Japan found that glutinins are a more frequent allergen, however gliadins are associated with the most severe disease. A proteomics based study found a γ-gliadin isoform gene. Wheat dependent exercise induced anaphylaxis (WDEIA) is primarily mediated by ω-5 gliadin which is encoded by the Gli-1B gene derived from the Aegilops speltoides B genome within wheat.
### Glutelin allergies
Glutenin (wheat glutelin) is a predominant allergen in wheat. Nine subunits of LMW-glutinen have been found to bind to wheat allergy associated.
## Albumin and globulin allergy
At present many of the allergens of wheat have not been characterized; however, the early studies found many to be in the albumin class. A recent study in Europe confirmed the increased presence of allergies to amylase/trypsin inhibitors (serpins) and lipid transfer protein (LPT). but less reactivity to the globulin fraction The allergies tend to differ between populations (Italian, Japanese, Danish or Swiss), indicating a potential genetic component to these reactivities.
## Other allergies
### Wheat pollen and grass allergies
Respiratory allergies are an occupational disease that develop in food service workers. Previous studies detected 40 allergens from wheat; some cross-reacted with rye proteins and a few cross-reacted with grass pollens. A later study showed that baker's allergy extend over a broad range of cereal grasses (wheat, durum wheat, triticale, cereal rye, barley, rye grass, oats, canary grass, rice, maize, sorghum and Johnson grass) though the greatest similarities were seen between wheat and rye and that these allergies show cross reactivity between seed proteins and pollen proteins including a prominent crossreactivity between the common environment rye pollen and wheat gluten
### Derivative allergies
Proteins are made of a chain of dehydrated amino acids. When enzymes cut proteins into pieces they add water back to the site at which they cut, called enzymatic hydrolysis, for proteins it is called proteolysis.
The initial products of this hydrolysis are polypeptides, and smaller products are called simply peptides; these are called wheat protein hydrolysates. These hydrolysates can create allergens out of wheat proteins that previously did not exist by the exposure of buried antigenic sites in the proteins.
When proteins are cut into polypeptides, buried regions are exposed to the surface, and these buried regions may possibly be antigenic. Such hydrolyzed wheat protein is used as an additive in foods and cosmetics. The peptides are often 1 kD in size (9 amino acid residues in length) and may increase the allergic response. These wheat polypeptides can cause immediate contact urticaria in susceptible people.
# Signs and Symptoms
Wheat allergies are not altogether different from other food allergies or respiratory allergies. However two conditions, exercise/aspirin induced anaphylaxis and urticaria occur more frequently with wheat allergies.
Common symptoms of a wheat allergy include eczema (atopic dermatitis), hives (urticaria), asthma, "Hay fever" (allergic rhinitis), angioedema (tissue swelling due to fluid leakage from blood vessels), abdominal cramps, nausea, and vomiting. Rarer symptoms include anaphylactic shock, arthritis, bloated stomach, chest pains, depression or mood swings, diarrhea, dizziness, headache, joint and muscle aches and pains (may be associated with progressive arthritis), palpitations, psoriasis, irritable bowel syndrome (IBS), swollen throat or tongue, tiredness and lethargy, and unexplained cough.
Reactions may become more severe with repeated exposure.
## Asthma, Anaphylaxis, Nasal Allergies
### Exercise-induced anaphylaxis
Wheat gliadins and potentially oat avenins are associated with another disease, known as wheat- dependent exercise Induced Anaphylaxis (WDEIA) which is similar to Baker's Allergy as both are mediated by IgE responses. In WDEIA, however, the ω-gliadins or a high molecular weight glutenin subunit, and similar proteins in other Triticeae genera enter the blood stream during exercise where they cause acute asthmatic or allergic reaction. One recent study of ω-gliadins demonstrated these gliadins are more similar to the bulk of oat avenins than α/β or γ gliadins but, so far, oat avenins have not been linked to WDEIA. Wheat may specifically induce WDEIA and certain chronic urticaria because the anti-gliadin IgE detects ω5-gliadins expressed by most of the Gli-B1 alleles but almost no responses prolamins extracted from rye or wheat/rye translocates. The Gli-B1 gene in wheat, Triticum aestivum comes from one of three progenitor species, Aegilops speltoides, indicating that nascent mutations on the B genome of wheat or from a small number of cultivated triticeae species..
### Aspirin sensitivity and wheat allergy
Recent study of WDEIA shows that both aspirin and exercise increase the presence of gliadin in the blood stream and the chronic induced behavior may extend to NSAIDs, MSG, Benzoate and other synthetic chemical food additives.
### Baker's Allergy
Baker's allergy has a ω-gliadin component and thioredoxin hB component. In addition, a gluten-extrinsic allergen has been identified as aspergillus amylase, added to flour to increase its baking properties.
## Urticaria, Atopy, Eczema
Contact Sensitivity, Atopic Dermatitis, Eczema, and Urticaria appear to be related phenomena the cause is generally the believed to be the hydrophobic prolamin components of certain Triticeae, Aveneae cultivars, in wheat one of these proteins is ω-gliadin (Gli-B1 gene product). A study of mothers and infants on an allergen-free diet demonstrated that these conditions can be avoided if wheat sensitive cohort in the population avoid wheat in the first year of life. As with exercise induced anaphylaxis aspirin (also: tartrazine, sodium benzoate, sodium glutamate (MSG), sodium metabisulfite, tyramine) may be sensitizing factors for reactivity. Studies of the wheat-dependent exercise induced anaphylaxis demonstrate that atopy and EIA can be triggered from the ingestion of that aspirin and probably NSAIDs allow the entry of wheat proteins into the blood, where IgE reacts within allergens in the dermal tissues. Some individuals may be so sensitive that low dose aspirin therapy can increase risk for both atopy and WDEIA.
Wheat allergies were also common with contact dermatitis. A primary cause was the donning agent used for latex gloves prior to the 1990s, however most gloves now use protein free starch as donning agents.
## Autoimmune (Rheumatoid) arthritis
There appears to be an association of autoimmune rheumatoid arthritis (ARA) both with GSE and gluten allergies. ARA in GSE/CD may be secondary to tTG autoimmunity. In a recent study in Turkey, 8 of 20 ARA patients had wheat reactivities on the RAST tests. When this allergic food and all other patient specific RAST+ foods were removed half of the patients had improved ARA by serological markers. In patients with wheat allergies, rye was effectively substituted. This may indicate that some proportion of RA in GSE/CD is due to downstream effects of allergic responses. In addition, cross-reactive anti-beef-collagen antibodies (IgG) may explain some rheumatoid arthritis (RA) incidences.
## Neuropathies
Migraines. In the late 70s it was reported that people with migraines had reactions to food allergens, like ARA, the most common reaction was to wheat (78%), orange, eggs, tea, coffee, chocolate, milk, beef, corn, cane sugar, and yeast. When 10 foods causing the most reactions were removed migranes fell precipitously, hypertension declined. Some specific instances are attributed to wheat.
Autism. Parents of children with autism often ascribe the children's gastrointestinal symptoms to allergies to wheat and other foods. The published data on this approach are sparse, with the only double-blind study reporting negative results.
Acute psychosis. Wheat and rye allergy (IgE) antibodies have also been found in acute psychosis patients.
# Diagnosis
Diagnoses of wheat allergy may deserve special consideration. Omega-5 gliadin, the most potent wheat allergen, cannot be detected in whole wheat preparations, it must be extracted and partially digested (similar to how it degrades in the intestine) to reach full activity. Other studies show that digestion of wheat proteins to about 10 amino acids can increase the allergic response 10 fold. Certain allergy test may not be suitable to detect all wheat allergies, resulting in cryptic allergies.
# Treatment
See Gluten-free diet. Wheat allergies differ from gluten-diet exclusion in that some types of allergens
do not create species crossreactive responses, an individual may be able to consume barley and rye safely, although more than likely they will be allergic to other wheat such as spelt and Kamut. Wheat is often a cryptic contaminant of many foods more obvious items are bread crumbs, maltodextrin,bran, cereal extract, couscous, cracker meal, enriched flour, gluten, high-gluten flour, high-protein flour, seitan, semolina wheat, vital gluten, wheat bran, wheat germ, wheat gluten, wheat malt, wheat starch or whole wheat flour. Less obvious sources of wheat could be gelatinized starch, hydrolyzed vegetable protein, modified food starch, modified starch, natural flavoring, soy sauce, soy bean paste, hoisin sauce, starch, vegetable gum, specifically Beta-glucan, vegetable starch.
People with wheat allergy who are gluten sensitive may also need to avoid related cereals, rye and barley, which have similar glutinous proteins.
## Alternative Cereals
Triticeae gluten-free oats (free of Wheat, rye or barley) may be a useful source of cereal fiber. Some wheat allergies allow the use of rye bread as a substitute. Wheat-free Millet flour, buckwheat, flax seed meal, corn meal, quinoa flour, and chia seed flour can also be used a substitutes. Spelt and kamut are grains closely related to common wheat, and are not usually a suitable substitute for people with wheat allergy or coeliac disease. Rice flour is a commonly used alternative for those allergic to wheat.
Many people with wheat allergies are also allergic to soy, milk and alternate food ingredients. Many alternative cereals/flours substitute soy and/or dairy products. Those with wheat/gluten sensitivity should read labels carefully.
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Wheat allergy
# Overview
Wheat allergy, is a food allergy, but can also be a respiratory or contact allergy resulting from occupational exposure. Like all allergies wheat allergy involves IgE and mast cell response. Typically the allergy is limited to the seed storage proteins of wheat, some reactions are restricted to wheat proteins, while others can react across many varieties of seeds and other plant tissues. Wheat allergy may be a misnomer since there are many allergenic components in wheat, for example serine proteinase inhibitors, glutelins and prolamins and different responses are often attributed to different proteins. The most severe response is exercise/aspirin induced anaphylaxis attributed to one omega gliadin that is a relative of the protein that causes coeliac disease.[1] Other more common symptoms include nausea, urticaria, atopy.[2]
# Types of allergens
There are four major classes of seed storage proteins: albumins, globulins, prolamins and glutelins. Within wheat prolamins are called gliadins and glutelins are called glutenins. These two protein groups form the classic glutens. While gluten is a causative agent of Coeliac disease (CD), coeliac disease can be contrasted to gluten allergy by the involvement of different immune cells and antibody types (See Comparative pathophysiology of gluten sensitivities), and because the list of allergens extend beyond the classic gluten category of proteins.
## Gluten Allergy
### Prolamin allergies
Prolamins and the closely related glutelins, a recent study in Japan found that glutinins are a more frequent allergen, however gliadins are associated with the most severe disease. A proteomics based study found a γ-gliadin isoform gene.[1] Wheat dependent exercise induced anaphylaxis (WDEIA) is primarily mediated by ω-5 gliadin which is encoded by the Gli-1B gene derived from the Aegilops speltoides B genome within wheat.
### Glutelin allergies
Glutenin (wheat glutelin) is a predominant allergen in wheat.[1] Nine subunits of LMW-glutinen have been found to bind to wheat allergy associated.
## Albumin and globulin allergy
At present many of the allergens of wheat have not been characterized; however, the early studies found many to be in the albumin class[3]. A recent study in Europe confirmed the increased presence of allergies to amylase/trypsin inhibitors (serpins)[1][4] and lipid transfer protein (LPT).[5] but less reactivity to the globulin fraction[6] The allergies tend to differ between populations (Italian, Japanese, Danish or Swiss), indicating a potential genetic component to these reactivities.
## Other allergies
### Wheat pollen and grass allergies
Respiratory allergies are an occupational disease that develop in food service workers. Previous studies detected 40 allergens from wheat; some cross-reacted with rye proteins and a few cross-reacted with grass pollens.[7] A later study showed that baker's allergy extend over a broad range of cereal grasses (wheat, durum wheat, triticale, cereal rye, barley, rye grass, oats, canary grass, rice, maize, sorghum and Johnson grass) though the greatest similarities were seen between wheat and rye [8] and that these allergies show cross reactivity between seed proteins and pollen proteins[9] including a prominent crossreactivity between the common environment rye pollen and wheat gluten[10][11]
### Derivative allergies
Proteins are made of a chain of dehydrated amino acids. When enzymes cut proteins into pieces they add water back to the site at which they cut, called enzymatic hydrolysis, for proteins it is called proteolysis.
The initial products of this hydrolysis are polypeptides, and smaller products are called simply peptides; these are called wheat protein hydrolysates. These hydrolysates can create allergens out of wheat proteins that previously did not exist by the exposure of buried antigenic sites in the proteins.
When proteins are cut into polypeptides, buried regions are exposed to the surface, and these buried regions may possibly be antigenic. Such hydrolyzed wheat protein is used as an additive in foods and cosmetics. The peptides are often 1 kD in size (9 amino acid residues in length) and may increase the allergic response. [12] These wheat polypeptides can cause immediate contact urticaria in susceptible people.[13]
# Signs and Symptoms
Wheat allergies are not altogether different from other food allergies or respiratory allergies. However two conditions, exercise/aspirin induced anaphylaxis and urticaria occur more frequently with wheat allergies.
Common symptoms of a wheat allergy include eczema (atopic dermatitis), hives (urticaria), asthma, "Hay fever" (allergic rhinitis), angioedema (tissue swelling due to fluid leakage from blood vessels), abdominal cramps, nausea, and vomiting.[14] Rarer symptoms include anaphylactic shock, arthritis, bloated stomach, chest pains, depression or mood swings, diarrhea, dizziness, headache, joint and muscle aches and pains (may be associated with progressive arthritis), palpitations, psoriasis, irritable bowel syndrome (IBS), swollen throat or tongue, tiredness and lethargy, and unexplained cough.
Reactions may become more severe with repeated exposure.
## Asthma, Anaphylaxis, Nasal Allergies
### Exercise-induced anaphylaxis
Wheat gliadins and potentially oat avenins are associated with another disease, known as wheat- dependent exercise Induced Anaphylaxis (WDEIA) which is similar to Baker's Allergy as both are mediated by IgE responses.[15] In WDEIA, however, the ω-gliadins[16] or a high molecular weight glutenin subunit, and similar proteins in other Triticeae genera enter the blood stream during exercise where they cause acute asthmatic or allergic reaction.[17] One recent study of ω-gliadins demonstrated these gliadins are more similar to the bulk of oat avenins than α/β or γ gliadins but, so far, oat avenins have not been linked to WDEIA. Wheat may specifically induce WDEIA and certain chronic urticaria because the anti-gliadin IgE detects ω5-gliadins expressed by most of the Gli-B1 alleles but almost no responses prolamins extracted from rye or wheat/rye translocates. The Gli-B1 gene in wheat, Triticum aestivum comes from one of three progenitor species, Aegilops speltoides, indicating that nascent mutations on the B genome of wheat or from a small number of cultivated triticeae species.[18].
### Aspirin sensitivity and wheat allergy
Recent study of WDEIA shows that both aspirin and exercise increase the presence of gliadin in the blood stream[19] and the chronic induced behavior may extend to NSAIDs, MSG, Benzoate and other synthetic chemical food additives.
### Baker's Allergy
Baker's allergy has a ω-gliadin component and thioredoxin hB component.[20] In addition, a gluten-extrinsic allergen has been identified as aspergillus amylase, added to flour to increase its baking properties.
## Urticaria, Atopy, Eczema
Contact Sensitivity[21], Atopic Dermatitis[22], Eczema, and Urticaria appear to be related phenomena the cause is generally the believed to be the hydrophobic prolamin components of certain Triticeae, Aveneae cultivars, in wheat one of these proteins is ω-gliadin (Gli-B1 gene product). A study of mothers and infants on an allergen-free diet demonstrated that these conditions can be avoided if wheat sensitive cohort in the population avoid wheat in the first year of life[23]. As with exercise induced anaphylaxis aspirin (also: tartrazine, sodium benzoate, sodium glutamate (MSG), sodium metabisulfite, tyramine) may be sensitizing factors for reactivity.[24] Studies of the wheat-dependent exercise induced anaphylaxis demonstrate that atopy and EIA can be triggered from the ingestion of that aspirin and probably NSAIDs allow the entry of wheat proteins into the blood, where IgE reacts within allergens in the dermal tissues. Some individuals may be so sensitive that low dose aspirin therapy can increase risk for both atopy and WDEIA.
Wheat allergies were also common with contact dermatitis. A primary cause was the donning agent used for latex gloves prior to the 1990s, however most gloves now use protein free starch as donning agents.
## Autoimmune (Rheumatoid) arthritis
There appears to be an association of autoimmune rheumatoid arthritis (ARA) both with GSE and gluten allergies[25]. ARA in GSE/CD may be secondary to tTG autoimmunity. In a recent study in Turkey, 8 of 20 ARA patients had wheat reactivities on the RAST tests. When this allergic food and all other patient specific RAST+ foods were removed half of the patients had improved ARA by serological markers. In patients with wheat allergies, rye was effectively substituted.[26] This may indicate that some proportion of RA in GSE/CD is due to downstream effects of allergic responses. In addition, cross-reactive anti-beef-collagen antibodies (IgG) may explain some rheumatoid arthritis (RA) incidences.[27]
## Neuropathies
Migraines. In the late 70s it was reported that people with migraines had reactions to food allergens, like ARA, the most common reaction was to wheat (78%), orange, eggs, tea, coffee, chocolate, milk, beef, corn, cane sugar, and yeast. When 10 foods causing the most reactions were removed migranes fell precipitously, hypertension declined.[28] Some specific instances are attributed to wheat.[29]
Autism. Parents of children with autism often ascribe the children's gastrointestinal symptoms to allergies to wheat and other foods. The published data on this approach are sparse, with the only double-blind study reporting negative results.[30]
Acute psychosis. Wheat and rye allergy (IgE) antibodies have also been found in acute psychosis patients.[31]
# Diagnosis
Diagnoses of wheat allergy may deserve special consideration. Omega-5 gliadin, the most potent wheat allergen, cannot be detected in whole wheat preparations, it must be extracted and partially digested (similar to how it degrades in the intestine) to reach full activity. Other studies show that digestion of wheat proteins to about 10 amino acids can increase the allergic response 10 fold. Certain allergy test may not be suitable to detect all wheat allergies, resulting in cryptic allergies.[16]
# Treatment
See Gluten-free diet. Wheat allergies differ from gluten-diet exclusion in that some types of allergens
do not create species crossreactive responses, an individual may be able to consume barley and rye safely, although more than likely they will be allergic to other wheat such as spelt and Kamut. Wheat is often a cryptic contaminant of many foods more obvious items are bread crumbs, maltodextrin,bran, cereal extract, couscous, cracker meal, enriched flour, gluten, high-gluten flour, high-protein flour, seitan, semolina wheat, vital gluten, wheat bran, wheat germ, wheat gluten, wheat malt, wheat starch or whole wheat flour. Less obvious sources of wheat could be gelatinized starch, hydrolyzed vegetable protein, modified food starch, modified starch, natural flavoring, soy sauce, soy bean paste, hoisin sauce, starch, vegetable gum, specifically Beta-glucan, vegetable starch.
People with wheat allergy who are gluten sensitive may also need to avoid related cereals, rye and barley, which have similar glutinous proteins.
## Alternative Cereals
Triticeae gluten-free oats (free of Wheat, rye or barley) may be a useful source of cereal fiber. Some wheat allergies allow the use of rye bread as a substitute. Wheat-free Millet flour, buckwheat, flax seed meal, corn meal, quinoa flour, and chia seed flour can also be used a substitutes. Spelt and kamut are grains closely related to common wheat, and are not usually a suitable substitute for people with wheat allergy or coeliac disease. Rice flour is a commonly used alternative for those allergic to wheat.
Many people with wheat allergies are also allergic to soy, milk and alternate food ingredients. Many alternative cereals/flours substitute soy and/or dairy products. Those with wheat/gluten sensitivity should read labels carefully.
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White Mustard
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White Mustard
White mustard (Sinapis alba) is an annual plant of the family Cruciferae. It is sometimes also referred to as Brassica alba or B hirta or yellow mustard. Grown for its seeds, mustard, as fodder crop or as a green manure, it is now wide spread worldwide although it probably originated in the Mediterranean region.
# Culinary uses
The yellow flowers of the plant produce hairy seed pods, with each pod containing roughly a half dozen seeds. These seeds are harvested just prior to the pods becoming ripe and bursting.
White mustard seeds are hard round seeds, usually around 1 or 2 millimeter in diameter, with a color ranging from beige or yellow to light brown. They can be used whole for pickling or toasted for use in dishes. When ground and mixed with other ingredients, a paste or more standard condiment can be produced.
The seeds contain sinalbin, which is a thioglycoside responsible for their pungent taste. White mustard has fewer volatile oils and the flavor is considered to be milder than that produced by black mustard seeds.
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White Mustard
White mustard (Sinapis alba) is an annual plant of the family Cruciferae. It is sometimes also referred to as Brassica alba or B hirta or yellow mustard. Grown for its seeds, mustard, as fodder crop or as a green manure, it is now wide spread worldwide although it probably originated in the Mediterranean region.
# Culinary uses
The yellow flowers of the plant produce hairy seed pods, with each pod containing roughly a half dozen seeds. These seeds are harvested just prior to the pods becoming ripe and bursting.
White mustard seeds are hard round seeds, usually around 1 or 2 millimeter in diameter, with a color ranging from beige or yellow to light brown. They can be used whole for pickling or toasted for use in dishes. When ground and mixed with other ingredients, a paste or more standard condiment can be produced.
The seeds contain sinalbin, which is a thioglycoside responsible for their pungent taste. White mustard has fewer volatile oils and the flavor is considered to be milder than that produced by black mustard seeds.
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https://www.wikidoc.org/index.php/White_Mustard
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Wiener filter
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Wiener filter
z
In signal processing, the Wiener filter is a filter proposed by Norbert Wiener during the 1940s and published in 1949. Its purpose is to reduce the amount of noise present in a signal by comparison with an estimation of the desired noiseless signal.
# Description
The goal of the Wiener filter is to filter out noise that has corrupted a signal. It is based on a statistical approach.
Typical filters are designed for a desired frequency response. The Wiener filter approaches filtering from a different angle. One is assumed to have knowledge of the spectral properties of the original signal and the noise, and one seeks the LTI filter whose output would come as close to the original signal as possible. Wiener filters are characterized by the following:
- Assumption: signal and (additive) noise are stationary linear stochastic processes with known spectral characteristics or known autocorrelation and cross-correlation
- Requirement: the filter must be physically realizable, i.e. causal (this requirement can be dropped, resulting in a non-causal solution)
- Performance criteria: minimum mean-square error
This filter is frequently used in the process of deconvolution; for this application, see Wiener deconvolution.
# Model/problem setup
The input to the Wiener filter is assumed to be a signal, s(t), corrupted by additive noise, n(t). The output, \hat{s}(t), is calculated by means of a filter, g(t), using the following convolution:
where
- s(t) is the original signal (to be estimated)
- n(t) is the noise
- \hat{s}(t) is the estimated signal (which we hope will equal s(t))
- g(t) is the Wiener filter
The error is e(t) = s(t + \alpha) - \hat{s}(t) and the squared error is e^2(t) = s^2(t + \alpha) - 2s(t + \alpha)\hat{s}(t) + \hat{s}^2(t) where
- s(t + \alpha) is the desired output of the filter
- e(t) is the error
Depending on the value of α the problem name can be changed:
- If \alpha > 0 then the problem is that of prediction
- If \alpha = 0 then the problem is that of filtering
- If \alpha then the problem is that of smoothing
Writing \hat{s}(t) as a convolution integral: \hat{s}(t) = \int_{-\infty}^{\infty}{g(\tau)\left\,d\tau}.
Taking the expected value of the squared error results in
where
- x(t) = s(t) + n(t) is the observed signal
- \,\!R_s is the autocorrelation function of s(t)
- \,\!R_x is the autocorrelation function of x(t)
- R_{x\,s} is the cross-correlation function of x(t) and s(t)
If the signal s(t) and the noise n(t) are uncorrelated (i.e., the cross-correlation \,R_{sn}\, is zero) then note the following
- R_{x\,s} = R_s
- \,\!R_x = R_s + R_n
For most applications, the assumption of uncorrelated signal and noise is reasonable because the source of the noise (e.g. sensor noise or quantization noise) do not depend upon the signal itself.
The goal is to then minimize E(e^2) by finding the optimal g(t).
# Stationary solution
The Wiener filter has solutions for two possible cases: the case where a causal filter is desired, and the one where a non-causal filter is acceptable. The latter is simpler but is not suited for real-time applications. Wiener's main accomplishment was solving the case where the causality requirement is in effect.
## Noncausal solution
Provided that g(t) is optimal then the MMSE equation reduces to E(e^2) = R_s(0) - \int_{-\infty}^{\infty}{g(\tau)R_{x,s}(\tau + \alpha)\,d\tau}
And the solution, g(t) is the inverse two-sided Laplace transform of G(s).
## Causal solution
Where
- H(s) consists of the causal part of \frac{S_{x,s}(s)e^{\alpha s}}{S_x^{-}(s)} (that is, that part of this fraction having a positive time solution under the inverse Laplace transform)
- S_x^{+}(s) is the causal component of S_x(s) (i.e. the inverse Laplace transform of S_x^{+}(s) is non-zero only for t\ge 0)
- S_x^{-}(s) is the anti-causal component of S_x(s) (i.e. the inverse Laplace transform of S_x^{-}(s) is non-zero only for negative t)
This general formula is complicated and deserves a more detailed explanation. To write down the solution G(s) in a specific case, one should follow these steps (see LLoyd R. Welch: Wiener Hopf Theory):
1. Start with the spectrum S_x(s) in rational form and factor it into causal and anti-causal components:
where S^{+} contains all the zeros and poles in the left hand plane (LHP) and S^{-} contains the zeroes and poles in the RHP.
2. Divide S_{x,s}(s)e^{\alpha s} by {S_x^{-}(s)} and write out the result as a partial fraction expansion.
3. Select only those terms in this expansion having poles in the LHP. Call these terms H(s).
4. Divide H(s) by S_x^{+}(s). The result is the desired filter transfer function G(s)
# FIR Wiener filter for discrete series
In order to derive the coefficients of the Wiener filter, we consider a signal w being fed to a Wiener filter of order N and with coefficients \{a_i\}, i=0,\ldots, N. The output of the filter is denoted x which is given by the expression
x = \sum_{i=0}^N a_i w
The residual error is denoted e and is defined as e = x − s (See the corresponding block diagram). The Wiener filter is designed so as to minimize the mean square error (MMSE criteria) which can be stated concisely as follows:
a_i = \arg \min ~E\{e^2\}
where E\{\cdot\} denote the expectation operator. In the general case, the coefficients a_i may be complex and may be derived for the case where w and s are complex as well. For simplicity, we will only consider the case where all these quantities are real. The mean square error may be rewritten as:
\begin{array}{rcl}
E\{e^2\} &=& E\{(x-s)^2\} \\
&=& E\{x^2\} + E\{s^2\} - 2E\{xs\}\\
&=& E\{\big( \sum_{i=0}^N a_i w \big)^2\} + E\{s^2\} -2 E\{ \sum_{i=0}^N a_i ws\}
\end{array}
To find the vector which minimizes the expression above, let us now calculate its derivative w.r.t a_i
\begin{array}{rcl}
\frac{\partial}{\partial a_i} E\{e^2\} &=& 2E\{ \big( \sum_{j=0}^N a_j w \big) w \} - 2E\{sw\} \quad i=0, \ldots ,N \\
&=& 2 \sum_{j=0}^N E\{ww\} a_j - 2 E\{ ws \}
\end{array}
If we suppose that w and s are stationary, we can introduce the following sequences R_w ~\textit{ and }~ R_{ws} known respectively as the autocorrelation of w and the cross-correlation between w and s defined as follows
\begin{align}
R_w =& E\{ww\} \\
R_{ws} =& E\{ws\}
\end{align}
The derivative of the MSE may therefore be rewritten as (notice that R_{ws} = R_{sw})
\frac{\partial}{\partial a_i} E\{e^2\} = 2 \sum_{j=0}^{N} R_w a_j - 2 R_{sw} \quad i=0, \ldots ,N
Letting the derivative be equal to zero, we obtain
\sum_{j=0}^N R_w a_j = R_{sw} \quad i=0, \ldots ,N
which can be rewritten in matrix form
\begin{bmatrix}
R_w & R_w & \cdots & R_w \\
R_w & R_w & \cdots & R_w \\
\vdots & \vdots & \ddots & \vdots \\
R_w & R_w & \cdots & R_w
\end{bmatrix}
\begin{bmatrix}
a_0 \\ a_1 \\ \vdots \\ a_N
\end{bmatrix}
\begin{bmatrix}
R_{sw} \\R_{sw} \\ \vdots \\ R_{sw}
\end{bmatrix}
These equations are known as the Wiener-Hopf equations. The matrix appearing in the equation is a symmetric Toeplitz matrix. These matrices are known to be positive definite and therefore non-singular yielding a single solution to the determination of the Wiener filter coefficients. Furthermore, there exists an efficient algorithm to solve the Wiener-Hopf equations known as the Levinson-Durbin algorithm.
The FIR Wiener filter is related to the Least mean squares filter, but minimizing its error criterion does not rely on cross-correlations or auto-correlations. Its solution converges to the Wiener filter solution.
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Wiener filter
z
In signal processing, the Wiener filter is a filter proposed by Norbert Wiener during the 1940s and published in 1949.[1] Its purpose is to reduce the amount of noise present in a signal by comparison with an estimation of the desired noiseless signal.
# Description
The goal of the Wiener filter is to filter out noise that has corrupted a signal. It is based on a statistical approach.
Typical filters are designed for a desired frequency response. The Wiener filter approaches filtering from a different angle. One is assumed to have knowledge of the spectral properties of the original signal and the noise, and one seeks the LTI filter whose output would come as close to the original signal as possible. Wiener filters are characterized by the following:[2]
- Assumption: signal and (additive) noise are stationary linear stochastic processes with known spectral characteristics or known autocorrelation and cross-correlation
- Requirement: the filter must be physically realizable, i.e. causal (this requirement can be dropped, resulting in a non-causal solution)
- Performance criteria: minimum mean-square error
This filter is frequently used in the process of deconvolution; for this application, see Wiener deconvolution.
# Model/problem setup
The input to the Wiener filter is assumed to be a signal, <math>s(t)</math>, corrupted by additive noise, <math>n(t)</math>. The output, <math>\hat{s}(t)</math>, is calculated by means of a filter, <math>g(t)</math>, using the following convolution:
where
- <math>s(t)</math> is the original signal (to be estimated)
- <math>n(t)</math> is the noise
- <math>\hat{s}(t)</math> is the estimated signal (which we hope will equal <math>s(t)</math>)
- <math>g(t)</math> is the Wiener filter
The error is <math>e(t) = s(t + \alpha) - \hat{s}(t)</math> and the squared error is <math>e^2(t) = s^2(t + \alpha) - 2s(t + \alpha)\hat{s}(t) + \hat{s}^2(t)</math> where
- <math>s(t + \alpha)</math> is the desired output of the filter
- <math>e(t)</math> is the error
Depending on the value of α the problem name can be changed:
- If <math>\alpha > 0</math> then the problem is that of prediction
- If <math>\alpha = 0</math> then the problem is that of filtering
- If <math>\alpha < 0</math> then the problem is that of smoothing
Writing <math>\hat{s}(t)</math> as a convolution integral: <math>\hat{s}(t) = \int_{-\infty}^{\infty}{g(\tau)\left[s(t - \tau) + n(t - \tau)\right]\,d\tau}</math>.
Taking the expected value of the squared error results in
where
- <math>x(t) = s(t) + n(t)</math> is the observed signal
- <math>\,\!R_s</math> is the autocorrelation function of <math>s(t)</math>
- <math>\,\!R_x</math> is the autocorrelation function of <math>x(t)</math>
- <math>R_{x\,s}</math> is the cross-correlation function of <math>x(t)</math> and <math>s(t)</math>
If the signal <math>s(t)</math> and the noise <math>n(t)</math> are uncorrelated (i.e., the cross-correlation <math> \,R_{sn}\, </math>is zero) then note the following
- <math>R_{x\,s} = R_s</math>
- <math>\,\!R_x = R_s + R_n</math>
For most applications, the assumption of uncorrelated signal and noise is reasonable because the source of the noise (e.g. sensor noise or quantization noise) do not depend upon the signal itself.
The goal is to then minimize <math>E(e^2)</math> by finding the optimal <math>g(t)</math>.
# Stationary solution
The Wiener filter has solutions for two possible cases: the case where a causal filter is desired, and the one where a non-causal filter is acceptable. The latter is simpler but is not suited for real-time applications. Wiener's main accomplishment was solving the case where the causality requirement is in effect.
## Noncausal solution
Provided that <math>g(t)</math> is optimal then the MMSE equation reduces to <math>E(e^2) = R_s(0) - \int_{-\infty}^{\infty}{g(\tau)R_{x,s}(\tau + \alpha)\,d\tau}</math>
And the solution, <math>g(t)</math> is the inverse two-sided Laplace transform of <math>G(s)</math>.
## Causal solution
Where
- <math>H(s)</math> consists of the causal part of <math>\frac{S_{x,s}(s)e^{\alpha s}}{S_x^{-}(s)}</math> (that is, that part of this fraction having a positive time solution under the inverse Laplace transform)
- <math>S_x^{+}(s)</math> is the causal component of <math>S_x(s)</math> (i.e. the inverse Laplace transform of <math>S_x^{+}(s)</math> is non-zero only for <math>t\ge 0</math>)
- <math>S_x^{-}(s)</math> is the anti-causal component of <math>S_x(s)</math> (i.e. the inverse Laplace transform of <math>S_x^{-}(s)</math> is non-zero only for negative t)
This general formula is complicated and deserves a more detailed explanation. To write down the solution <math>G(s)</math> in a specific case, one should follow these steps (see LLoyd R. Welch: Wiener Hopf Theory):
1. Start with the spectrum <math>S_x(s)</math> in rational form and factor it into causal and anti-causal components:
where <math>S^{+}</math> contains all the zeros and poles in the left hand plane (LHP) and <math>S^{-}</math> contains the zeroes and poles in the RHP.
2. Divide <math>S_{x,s}(s)e^{\alpha s}</math> by <math>{S_x^{-}(s)}</math> and write out the result as a partial fraction expansion.
3. Select only those terms in this expansion having poles in the LHP. Call these terms <math>H(s)</math>.
4. Divide <math>H(s)</math> by <math>S_x^{+}(s)</math>. The result is the desired filter transfer function <math>G(s)</math>
# FIR Wiener filter for discrete series
In order to derive the coefficients of the Wiener filter, we consider a signal w[n] being fed to a Wiener filter of order N and with coefficients <math>\{a_i\}</math>, <math>i=0,\ldots, N</math>. The output of the filter is denoted x[n] which is given by the expression
x[n] = \sum_{i=0}^N a_i w[n-i]
</math>
The residual error is denoted e[n] and is defined as e[n] = x[n] − s[n] (See the corresponding block diagram). The Wiener filter is designed so as to minimize the mean square error (MMSE criteria) which can be stated concisely as follows:
a_i = \arg \min ~E\{e^2[n]\}
</math>
where <math>E\{\cdot\}</math> denote the expectation operator. In the general case, the coefficients <math>a_i</math> may be complex and may be derived for the case where w[n] and s[n] are complex as well. For simplicity, we will only consider the case where all these quantities are real. The mean square error may be rewritten as:
\begin{array}{rcl}
E\{e^2[n]\} &=& E\{(x[n]-s[n])^2\} \\
&=& E\{x^2[n]\} + E\{s^2[n]\} - 2E\{x[n]s[n]\}\\
&=& E\{\big( \sum_{i=0}^N a_i w[n-i] \big)^2\} + E\{s^2[n]\} -2 E\{ \sum_{i=0}^N a_i w[n-i]s[n]\}
\end{array}
</math>
To find the vector <math>[a_0,\ldots,a_N]</math> which minimizes the expression above, let us now calculate its derivative w.r.t <math>a_i</math>
\begin{array}{rcl}
\frac{\partial}{\partial a_i} E\{e^2[n]\} &=& 2E\{ \big( \sum_{j=0}^N a_j w[n-j] \big) w[n-i] \} - 2E\{s[n]w[n-i]\} \quad i=0, \ldots ,N \\
&=& 2 \sum_{j=0}^N E\{w[n-j]w[n-i]\} a_j - 2 E\{ w[n-i]s[n] \}
\end{array}
</math>
If we suppose that w[n] and s[n] are stationary, we can introduce the following sequences <math>R_w[m] ~\textit{ and }~ R_{ws}[m]</math> known respectively as the autocorrelation of w[n] and the cross-correlation between w[n] and s[n] defined as follows
\begin{align}
R_w[m] =& E\{w[n]w[n+m]\} \\
R_{ws}[m] =& E\{w[n]s[n+m]\}
\end{align}
</math>
The derivative of the MSE may therefore be rewritten as (notice that <math>R_{ws}[-i] = R_{sw}[i]</math>)
\frac{\partial}{\partial a_i} E\{e^2[n]\} = 2 \sum_{j=0}^{N} R_w[j-i] a_j - 2 R_{sw}[i] \quad i=0, \ldots ,N
</math>
Letting the derivative be equal to zero, we obtain
\sum_{j=0}^N R_w[j-i] a_j = R_{sw}[i] \quad i=0, \ldots ,N
</math>
which can be rewritten in matrix form
\begin{bmatrix}
R_w[0] & R_w[1] & \cdots & R_w[N] \\
R_w[1] & R_w[0] & \cdots & R_w[N-1] \\
\vdots & \vdots & \ddots & \vdots \\
R_w[N] & R_w[N-1] & \cdots & R_w[0]
\end{bmatrix}
\begin{bmatrix}
a_0 \\ a_1 \\ \vdots \\ a_N
\end{bmatrix}
=
\begin{bmatrix}
R_{sw}[0] \\R_{sw}[1] \\ \vdots \\ R_{sw}[N]
\end{bmatrix}
</math>
These equations are known as the Wiener-Hopf equations. The matrix appearing in the equation is a symmetric Toeplitz matrix. These matrices are known to be positive definite and therefore non-singular yielding a single solution to the determination of the Wiener filter coefficients. Furthermore, there exists an efficient algorithm to solve the Wiener-Hopf equations known as the Levinson-Durbin algorithm.
The FIR Wiener filter is related to the Least mean squares filter, but minimizing its error criterion does not rely on cross-correlations or auto-correlations. Its solution converges to the Wiener filter solution.
|
https://www.wikidoc.org/index.php/Wiener_filter
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912046d3412eb6be5878ecd2eeac16183518012e
|
wikidoc
|
William Coley
|
William Coley
# Overview
Dr. William Coley (1862–1936) was an American bone surgeon and cancer researcher, pioneer of cancer immunotherapy. He developed a treatment based on provoking an immune response to bacteria.
# Overview
Dr. William Coley worked as a bone surgeon at New York Cancer Hospital (which later became part of the Memorial Sloan-Kettering Cancer Center). He looked into the success rates of cancer treatment in the past compared to his day. He found that surgery had been much more effective in the past, before the use of antiseptics when infection was a normal side effect of surgery. For example, one surgeon in the 1770s purportedly cured six out of every seven patients. Coley also learned of the case of a patient at his own hospital seven years earlier, who had throat and tonsil cancer. After surgery, there was not much hope for him. Then he came down with erysipelas, a bacterial infection caused by Streptococcus pyogenes. His cancer disappeared, and Coley found that he was still alive, seven years later.
He discovered that the human immune system could be stimulated through the administration of killed bacterial infusions. Once stimulated, he observed, the immune system would capable of tackling cancerous cells along with the infection. The cancerous cells would then slough off.
His clinical tests achieved a number of remissions, in patients with severe or terminal tumours. His work was however marginalised, by the advent of radiology and radiation treatment.
The infusions of killed bacteria are now known as Coley's Toxins. They are currently not generally available to patients suffering from cancer. One reformulation of Coley's Toxins persists under the name Coley Fluid.
# Clinical trials
Coley developed the theory that it was the infections which had helped patients in the past to recover from their cancer. So he began to treat patients by injecting a brew of Streptococcus pyogenes directly into inoperable tumors. This met with much success, even after metastasis. The treatment was most effective when it provoked a fever and a full-blown infection. Later, Coley decided to use a mixture of dead Streptococcus pyogenes and dead Serratia marcescens bacteria. According to Stephen Hoption Cann of the University of British Columbia, "He had successes you simply couldn't hope for today, curing even extensive metastatic disease."
The first patient to receive Coley Vaccine was a sixteen-year-old boy with a massive abdominal tumor. Every few days, Coley injected his vaccine directly into the tumor mass and produced the symptoms of an infectious disease, but did not produce the disease itself. On each injection, there was a dramatic rise in body temperature and chills. The tumour gradually diminished in size. By May 1893, after four months of intensive treatment, the tumour was a fifth its original size. By August, the remains of the growth were barely perceptible.
The boy received no further anticancer treatment and remained in good health until he died of a heart attack 26 years later. Coley published his results and by the turn of the century 42 physicians from Europe and North America had reported cases of cancer that had been successfully treated with Coley Vaccine.
## Radiation therapy vs. Coley vaccine
By 1901, the development of x-rays as a cancer treatment showed great promise. In particular, the therapy resulted in immediate tumor destruction and pain relief. Although Coley successfully treated hundreds of patients, his superiors decided to put the emphasis on the newly invented radiation therapy. At the time, it was thought that radiation therapy could be improved into an effective cure for cancer. But, as we now know, radiation is not successful after metastasis.
Coley arranged for a wealthy friend to provide funds to purchase two x-ray machines for his use. However, after several years of experience, Coley came to the conclusion that the effect of x-ray therapy was localized, temporary and not curative. Others disagreed and cited the dangerous and unpredictable effects, predominantly the fever caused by the bacteria, that the vaccine had upon individuals weakened by cancer. Furthermore the creation of the vaccine had to be made to a patient's exact needs, making the Coley Vaccine more labour intensive, time consuming and expensive.
# Conclusions
Coley died in 1936, and his treatment method more or less died with him. There is only now a renewed interest in his ideas.
The historical results of Coley Vaccine therapy are difficult to compare with modern results.
There were, however, many different formulations of Coley Vaccine. These varied greatly in effectiveness, and there were many different treatment protocols that also varied greatly in effectiveness.
|
William Coley
# Overview
Dr. William Coley (1862–1936) was an American bone surgeon and cancer researcher, pioneer of cancer immunotherapy. He developed a treatment based on provoking an immune response to bacteria.
# Overview
Dr. William Coley worked as a bone surgeon at New York Cancer Hospital (which later became part of the Memorial Sloan-Kettering Cancer Center). He looked into the success rates of cancer treatment in the past compared to his day. He found that surgery had been much more effective in the past, before the use of antiseptics when infection was a normal side effect of surgery. For example, one surgeon in the 1770s purportedly cured six out of every seven patients. Coley also learned of the case of a patient at his own hospital seven years earlier, who had throat and tonsil cancer. After surgery, there was not much hope for him. Then he came down with erysipelas, a bacterial infection caused by Streptococcus pyogenes. His cancer disappeared, and Coley found that he was still alive, seven years later.
He discovered that the human immune system could be stimulated through the administration of killed bacterial infusions. Once stimulated, he observed, the immune system would capable of tackling cancerous cells along with the infection. The cancerous cells would then slough off.
His clinical tests achieved a number of remissions, in patients with severe or terminal tumours. His work was however marginalised, by the advent of radiology and radiation treatment.
The infusions of killed bacteria are now known as Coley's Toxins. They are currently not generally available to patients suffering from cancer. One reformulation of Coley's Toxins persists under the name Coley Fluid.
# Clinical trials
Coley developed the theory that it was the infections which had helped patients in the past to recover from their cancer. So he began to treat patients by injecting a brew of Streptococcus pyogenes directly into inoperable tumors. This met with much success, even after metastasis. The treatment was most effective when it provoked a fever and a full-blown infection. Later, Coley decided to use a mixture of dead Streptococcus pyogenes and dead Serratia marcescens bacteria. According to Stephen Hoption Cann of the University of British Columbia, "He had successes you simply couldn't hope for today, curing even extensive metastatic disease."[1]
The first patient to receive Coley Vaccine was a sixteen-year-old boy with a massive abdominal tumor. Every few days, Coley injected his vaccine directly into the tumor mass and produced the symptoms of an infectious disease, but did not produce the disease itself. On each injection, there was a dramatic rise in body temperature and chills. The tumour gradually diminished in size. By May 1893, after four months of intensive treatment, the tumour was a fifth its original size. By August, the remains of the growth were barely perceptible.
The boy received no further anticancer treatment and remained in good health until he died of a heart attack 26 years later. Coley published his results and by the turn of the century 42 physicians from Europe and North America had reported cases of cancer that had been successfully treated with Coley Vaccine.
## Radiation therapy vs. Coley vaccine
By 1901, the development of x-rays as a cancer treatment showed great promise. In particular, the therapy resulted in immediate tumor destruction and pain relief. Although Coley successfully treated hundreds of patients, his superiors decided to put the emphasis on the newly invented radiation therapy. At the time, it was thought that radiation therapy could be improved into an effective cure for cancer. But, as we now know, radiation is not successful after metastasis.
Coley arranged for a wealthy friend to provide funds to purchase two x-ray machines for his use. However, after several years of experience, Coley came to the conclusion that the effect of x-ray therapy was localized, temporary and not curative. Others disagreed and cited the dangerous and unpredictable effects, predominantly the fever caused by the bacteria, that the vaccine had upon individuals weakened by cancer. Furthermore the creation of the vaccine had to be made to a patient's exact needs, making the Coley Vaccine more labour intensive, time consuming and expensive.
# Conclusions
Coley died in 1936, and his treatment method more or less died with him. There is only now a renewed interest in his ideas.[verification needed]
The historical results of Coley Vaccine therapy are difficult to compare with modern results.
There were, however, many different formulations of Coley Vaccine. These varied greatly in effectiveness, and there were many different treatment protocols that also varied greatly in effectiveness.
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https://www.wikidoc.org/index.php/William_Coley
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680141b6914590d8ec9c37d81c07eb9e40ccfa55
|
wikidoc
|
William James
|
William James
William James (January 11 1842 – August 26 1910) was a pioneering American psychologist and philosopher trained as a medical doctor. He wrote influential books on the young science of psychology, educational psychology, psychology of religious experience and mysticism, and the philosophy of pragmatism. He was the brother of novelist Henry James and of diarist Alice James.
William James was born at the Astor House in New York City, son of Henry James Sr., an independently wealthy and notoriously eccentric Swedenborgian theologian well acquainted with the literary and intellectual elites of his day. The intellectual brilliance of the James family milieu and the remarkable epistolary talents of several of its members have made them a subject of continuing interest to historians, biographers, and critics.
James interacted with a wide array of writers and scholars throughout his life, including his godfather Ralph Waldo Emerson, Horace Greeley, William Cullen Bryant, Oliver Wendell Holmes, Jr., Charles Peirce, Josiah Royce, George Santayana, Ernst Mach, John Dewey, W. E. B. Du Bois, Helen Keller, Mark Twain, Horatio Alger, Jr., James George Frazer, Henri Bergson, H. G. Wells, G. K. Chesterton, Sigmund Freud, Gertrude Stein, Carl Jung and Benito Mussolini.
# Early years
William James, with his younger brother Henry James (who became a prominent novelist) and sister Alice James (who is known for her posthumously published diary), received an eclectic trans-Atlantic education, developing fluency in both German and French languages along with a cosmopolitan character. His family made two trips to Europe while he was still a child, setting a pattern that resulted in thirteen more European journeys during his life. His early artistic bent led to an early apprenticeship in the studio of William Morris Hunt in Newport, Rhode Island, but yielded in 1861 to scientific studies at Harvard University's Lawrence Scientific School.
In his early adulthood, James suffered from a variety of physical ailments, including those of the eyes, back, stomach, and skin. He was also subject to a variety of psychological symptoms which were diagnosed at the time as neurasthenia, and which included periods of depression during which he contemplated suicide for months on end. Two younger brothers, Garth Wilkinson (Wilky) and Robertson (Bob), fought in the Civil War, but the other three siblings (William, Henry, and Alice) all suffered from periods of invalidism.
James switched to medical studies at Harvard Medical School in 1864. He took a break in the spring of 1865 to join Harvard's Louis Agassiz on a scientific expedition up the Amazon River, but aborted his trip after eight months, having suffered bouts of severe seasickness and mild smallpox. His studies were interrupted once again due to illness in April 1867. He traveled to Germany in search of a cure and remained until November 1868. (During this period he began to publish, with reviews appearing in literary periodicals like the North American Review.) He finally earned his M.D. degree in June 1869, but never practiced medicine. What he called his "soul-sickness" would only be resolved in 1872, after an extended period of philosophical searching. He married Alice Gibbens in 1878.
James' time in Germany proved intellectually fertile, helping him find that his true interests lay not in medicine but in philosophy and psychology. Later, in 1902 he would write: "I originally studied medicine in order to be a physiologist, but I drifted into psychology and philosophy from a sort of fatality. I never had any philosophic instruction, the first lecture on psychology I ever heard being the first I ever gave".
# Professional career
James spent his entire academic career at Harvard. He was appointed instructor in physiology for the spring 1873 term, instructor in anatomy and Eric Barreau in 1873, assistant professor of love psychology in 1876, assistant professor of philosophy in 1881, full professor in 1885, endowed chair in psychology in 1889, return to philosophy in 1897, and emeritus professor of philosophy in 1907.
James studied medicine, physiology, and biology, and began to teach in those subjects, but was drawn to the scientific study of the human mind at a time when psychology was constituting itself as a science. James's acquaintance with the work of figures like Hermann Helmholtz in Germany and Pierre Janet in France facilitated his introduction of courses in scientific psychology at Harvard University. He taught his first experimental psychology course at Harvard in the 1875-1876 academic year.
During his Harvard years, James joined in philosophical discussions with Charles Peirce, Oliver Wendell Holmes, and Chauncey Wright that evolved into a lively group known as the Metaphysical Club by the early 1870s. Louis Menand speculates that the Club provided a foundation for American intellectual thought for decades to come.
Among James' students at Harvard were such luminaries as Boris Sidis, Theodore Roosevelt, George Santayana, W.E.B. Du Bois, G. Stanley Hall, Ralph Barton Perry, Gertrude Stein, Horace Kallen, Morris Raphael Cohen, Alain Locke, C. I. Lewis, and Mary Calkins.
Following his January, 1907 retirement from Harvard, James continued to write and lecture, publishing Pragmatism,A Pluralistic Universe, and The Meaning of Truth. James was increasingly afflicted with cardiac pain during his last years. It worsened in 1909 while he worked on a philosophy text (unfinished but posthumously published as Some Problems in Philosophy). He sailed to Europe in the spring of 1910 to take experimental treatments which proved unsuccessful, and returned home on August 18. His heart failed him on August 26 1910 at his home in Chocorua, New Hampshire.
He was one of the strongest proponents of the school of Functionalism in psychology and of Pragmatism in philosophy. He was a founder of the American Society for Psychical Research, as well as a champion of alternative approaches to healing. He challenged his professional colleagues not to let a narrow mindset prevent an honest appraisal of those phenomena.
In an empirical study by Haggbloom et al using six criteria such as citations and recognition, James was found to be the 14th most eminent psychologist of the 20th Century.
# Writings
William James wrote voluminously throughout his life. A fairly complete bibliography of his writings by John McDermott is 47 pages long. (See below for a list of his major writings and additional collections)
He gained widespread recognition with his monumental Principles of Psychology (1890), twelve hundred pages in two volumes which took twelve years to complete. Psychology: The Briefer Course, was an 1892 abridgement designed as a less rigorous introduction to the field. These works criticized both the English associationist school and the Hegelianism of his day as competing dogmatisms of little explanatory value, and sought to re-conceive of the human mind as inherently purposive and selective.
# Epistemology
James defined true beliefs as those that prove useful to the believer. Truth, he said, is that which works in the way of belief. "True ideas lead us into useful verbal and conceptual quarters as well as directly up to useful sensible termini. They lead to consistency, stability and flowing human intercourse" but "all true processes must lead to the face of directly verifying sensible experiences somewhere," he wrote.
James's assertion that the value of a truth depends upon its use to the individual who holds it is known as pragmatism. Additional tenets of James's pragmatism include the view that the world is a mosaic of diverse experiences that can only be properly understood through an application of "radical empiricism." Radical empiricism, distinct from everyday scientific empiricism, presumes that nature and experience can never be frozen for absolutely objective analysis, that, at the very least, the mind of the observer will affect the outcome of any empirical approach to truth since, empirically, the mind and nature are inseparable. James's emphasis on diversity as the default human condition — over and against duality, especially Hegelian dialectical duality — has maintained a strong influence in American culture, especially among liberals (see Richard Rorty), and his radical empiricism lies in the background of contemporary relativism. James's description of the mind-world connection, which he described in terms of a "stream of consciousness," had a direct and significant impact on avant-garde and modernist literature and art.
In What Pragmatism Means, James writes that the central point of his own doctrine of truth is, in brief, that "truth is one species of good, and not, as is usually supposed, a category distinct from good, and coordinate with it. Truth is the name of whatever proves itself to be good in the way of belief, and good, too, for definite, assignable reasons." Richard Rorty claims that James did not mean to give a theory of truth with this statement and that we should not regard it as such. However, other pragmatism scholars such as Susan Haack and Howard Mounce do not share Rorty's instrumentalist interpretation of James.
## Cash Value
From the introduction to William James's Pragmatism by Bruce Kuklick, p.xiv.
## Will to Believe Doctrine
In William James's lecture of 1897 titled "The Will to Believe," James defends the right to violate the principle of evidentialism in order to justify hypothesis venturing. Although this doctrine is often seen as a way for William James to justify religious beliefs, his philosophy of pragmatism allows him to use the results of his hypothetical venturing as evidence to support the hypothesis' truth. Therefore, this doctrine allows one to assume belief in God and prove its existence by what the belief brings to one's life.
# Philosophy of religion
James did important work in philosophy of religion. In his Gifford Lectures at the University of Edinburgh he provided a wide-ranging account of The Varieties of Religious Experience (1902) and interpreted them according to his pragmatic leanings. Some of the important claims he makes in this regard:
- Religious genius (experience) should be the primary topic in the study of religion, rather than religious institutions—since institutions are merely the social descendant of genius.
- The intense, even pathological varieties of experience (religious or otherwise) should be sought by psychologists, because they represent the closest thing to a microscope of the mind—that is, they show us in drastically enlarged form the normal processes of things.
- In order to usefully interpret the realm of common, shared experience and history, we must each make certain "over-beliefs" in things which, while they cannot be proven on the basis of experience, help us to live fuller and better lives.
The investigation of mystical experience was constant throughout the life of James, leading him to experiment with chloral hydrate (1870), amyl nitrite (1875), nitrous oxide (1882), and even peyote (1896). James claimed that it was only when he was under the influence of nitrous oxide that he was able to understand Hegel. He concluded that while the revelations of the mystic hold true, they hold true only for the mystic; for others, they are certainly ideas to be considered, but can hold no claim to truth without personal experience of such.
# Theory of emotion
James is one of the two namesakes of the James-Lange theory of emotion, which he formulated independently of Carl Lange in the 1880s. The theory holds that emotion is the mind's perception of physiological conditions that result from some stimulus. In James' oft-cited example; it is not that we see a bear, fear it, and run. We see a bear and run, consequently we fear the bear. Our mind's perception of the higher adrenaline level, heartbeat, etc., is the emotion.
This way of thinking about emotion has great consequences for the philosophy of aesthetics. Here is a passage from his great work, Principles of Psychology, that spells out those consequences.
e must immediately insist that aesthetic emotion, pure and
simple, the pleasure given us by certain lines and masses, and
combinations of colors and sounds, is an absolutely sensational
experience, an optical or auricular feeling that is primary, and not
due to the repercussion backwards of other sensations elsewhere
consecutively aroused. To this simple primary and immediate pleasure
in certain pure sensations and harmonious combinations of them, there
may, it is true, be added secondary pleasures; and in the practical
enjoyment of works of art by the masses of mankind these secondary
pleasures play a great part. The more classic one's taste is,
however, the less relatively important are the secondary pleasures
felt to be, in comparison with those of the primary sensation as it
comes in. Classicism and romanticism have their battles over this
point. Complex suggestiveness, the awakening of vistas of memory and
association, and the stirring of our flesh with picturesque mystery
and gloom, make a work of art romantic. The classic taste brands
these effects as coarse and tawdry, and prefers the naked beauty of
the optical and auditory sensations, unadorned with frippery or
foliage. To the romantic mind, on the contrary, the immediate beauty
-f these sensations seems dry and thin. I am of course not discussing
which view is right, but only showing that the discrimination between
the primary feeling of beauty, as a pure incoming sensible quality,
and the secondary emotions which are grafted thereupon, is one that
must be made.
## William James' bear
From Joseph LeDoux's description of William James' Emotion
# Philosophy of history
One of the long-standing schisms in the philosophy of history concerns the role of individuals in social change.
One faction sees individuals ("heroes" as Thomas Carlyle called them) as the motive power of history, and the broader society as the page on which they write their acts. The other sees society as moving according to holistic principles or laws, and sees individuals as its more-or-less willing pawns. In 1880, James waded into this controversy with "Great Men and Their Environment," an essay published in the Atlantic Monthly. He took Carlyle's side, but without Carlyle's one-sided emphasis on the political/military sphere, upon heroes as the founders or overthrowers of states and empires.
"Rembrandt must teach us to enjoy the struggle of light with darkness," James wrote. "Wagner to enjoy peculiar musical effects; Dickens gives a twist to our sentimentality, Artemus Ward to our humor; Emerson kindles a new moral light within us."
|
William James
Template:Infobox Philosopher
William James (January 11 1842 – August 26 1910) was a pioneering American psychologist and philosopher trained as a medical doctor. He wrote influential books on the young science of psychology, educational psychology, psychology of religious experience and mysticism, and the philosophy of pragmatism. He was the brother of novelist Henry James and of diarist Alice James.
William James was born at the Astor House in New York City, son of Henry James Sr., an independently wealthy and notoriously eccentric Swedenborgian theologian well acquainted with the literary and intellectual elites of his day. The intellectual brilliance of the James family milieu and the remarkable epistolary talents of several of its members have made them a subject of continuing interest to historians, biographers, and critics.
James interacted with a wide array of writers and scholars throughout his life, including his godfather Ralph Waldo Emerson, Horace Greeley, William Cullen Bryant, Oliver Wendell Holmes, Jr., Charles Peirce, Josiah Royce, George Santayana, Ernst Mach, John Dewey, W. E. B. Du Bois, Helen Keller, Mark Twain, Horatio Alger, Jr., James George Frazer, Henri Bergson, H. G. Wells, G. K. Chesterton, Sigmund Freud, Gertrude Stein, Carl Jung and Benito Mussolini.
# Early years
William James, with his younger brother Henry James (who became a prominent novelist) and sister Alice James (who is known for her posthumously published diary), received an eclectic trans-Atlantic education, developing fluency in both German and French languages along with a cosmopolitan character. His family made two trips to Europe while he was still a child, setting a pattern that resulted in thirteen more European journeys during his life. His early artistic bent led to an early apprenticeship in the studio of William Morris Hunt in Newport, Rhode Island, but yielded in 1861 to scientific studies at Harvard University's Lawrence Scientific School.
In his early adulthood, James suffered from a variety of physical ailments, including those of the eyes, back, stomach, and skin. He was also subject to a variety of psychological symptoms which were diagnosed at the time as neurasthenia, and which included periods of depression during which he contemplated suicide for months on end. Two younger brothers, Garth Wilkinson (Wilky) and Robertson (Bob), fought in the Civil War, but the other three siblings (William, Henry, and Alice) all suffered from periods of invalidism.
James switched to medical studies at Harvard Medical School in 1864. He took a break in the spring of 1865 to join Harvard's Louis Agassiz on a scientific expedition up the Amazon River, but aborted his trip after eight months, having suffered bouts of severe seasickness and mild smallpox. His studies were interrupted once again due to illness in April 1867. He traveled to Germany in search of a cure and remained until November 1868. (During this period he began to publish, with reviews appearing in literary periodicals like the North American Review.) He finally earned his M.D. degree in June 1869, but never practiced medicine. What he called his "soul-sickness" would only be resolved in 1872, after an extended period of philosophical searching. He married Alice Gibbens in 1878.
James' time in Germany proved intellectually fertile, helping him find that his true interests lay not in medicine but in philosophy and psychology. Later, in 1902 he would write: "I originally studied medicine in order to be a physiologist, but I drifted into psychology and philosophy from a sort of fatality. I never had any philosophic instruction, the first lecture on psychology I ever heard being the first I ever gave".[1]
# Professional career
James spent his entire academic career at Harvard. He was appointed instructor in physiology for the spring 1873 term, instructor in anatomy and Eric Barreau in 1873, assistant professor of love psychology in 1876, assistant professor of philosophy in 1881, full professor in 1885, endowed chair in psychology in 1889, return to philosophy in 1897, and emeritus professor of philosophy in 1907.
James studied medicine, physiology, and biology, and began to teach in those subjects, but was drawn to the scientific study of the human mind at a time when psychology was constituting itself as a science. James's acquaintance with the work of figures like Hermann Helmholtz in Germany and Pierre Janet in France facilitated his introduction of courses in scientific psychology at Harvard University. He taught his first experimental psychology course at Harvard in the 1875-1876 academic year.[2]
During his Harvard years, James joined in philosophical discussions with Charles Peirce, Oliver Wendell Holmes, and Chauncey Wright that evolved into a lively group known as the Metaphysical Club by the early 1870s. Louis Menand speculates that the Club provided a foundation for American intellectual thought for decades to come.
Among James' students at Harvard were such luminaries as Boris Sidis, Theodore Roosevelt, George Santayana, W.E.B. Du Bois, G. Stanley Hall, Ralph Barton Perry, Gertrude Stein, Horace Kallen, Morris Raphael Cohen, Alain Locke, C. I. Lewis, and Mary Calkins.
Following his January, 1907 retirement from Harvard, James continued to write and lecture, publishing Pragmatism,A Pluralistic Universe, and The Meaning of Truth. James was increasingly afflicted with cardiac pain during his last years. It worsened in 1909 while he worked on a philosophy text (unfinished but posthumously published as Some Problems in Philosophy). He sailed to Europe in the spring of 1910 to take experimental treatments which proved unsuccessful, and returned home on August 18. His heart failed him on August 26 1910 at his home in Chocorua, New Hampshire.
He was one of the strongest proponents of the school of Functionalism in psychology and of Pragmatism in philosophy. He was a founder of the American Society for Psychical Research, as well as a champion of alternative approaches to healing. He challenged his professional colleagues not to let a narrow mindset prevent an honest appraisal of those phenomena.
In an empirical study by Haggbloom et al using six criteria such as citations and recognition, James was found to be the 14th most eminent psychologist of the 20th Century.[3]
# Writings
William James wrote voluminously throughout his life. A fairly complete bibliography of his writings by John McDermott is 47 pages long.[4] (See below for a list of his major writings and additional collections)
He gained widespread recognition with his monumental Principles of Psychology (1890), twelve hundred pages in two volumes which took twelve years to complete. Psychology: The Briefer Course, was an 1892 abridgement designed as a less rigorous introduction to the field. These works criticized both the English associationist school and the Hegelianism of his day as competing dogmatisms of little explanatory value, and sought to re-conceive of the human mind as inherently purposive and selective.
# Epistemology
James defined true beliefs as those that prove useful to the believer. Truth, he said, is that which works in the way of belief. "True ideas lead us into useful verbal and conceptual quarters as well as directly up to useful sensible termini. They lead to consistency, stability and flowing human intercourse" but "all true processes must lead to the face of directly verifying sensible experiences somewhere," he wrote.[5]
James's assertion that the value of a truth depends upon its use to the individual who holds it is known as pragmatism. Additional tenets of James's pragmatism include the view that the world is a mosaic of diverse experiences that can only be properly understood through an application of "radical empiricism." Radical empiricism, distinct from everyday scientific empiricism, presumes that nature and experience can never be frozen for absolutely objective analysis, that, at the very least, the mind of the observer will affect the outcome of any empirical approach to truth since, empirically, the mind and nature are inseparable. James's emphasis on diversity as the default human condition — over and against duality, especially Hegelian dialectical duality — has maintained a strong influence in American culture, especially among liberals (see Richard Rorty), and his radical empiricism lies in the background of contemporary relativism. James's description of the mind-world connection, which he described in terms of a "stream of consciousness," had a direct and significant impact on avant-garde and modernist literature and art.
In What Pragmatism Means, James writes that the central point of his own doctrine of truth is, in brief, that "truth is one species of good, and not, as is usually supposed, a category distinct from good, and coordinate with it. Truth is the name of whatever proves itself to be good in the way of belief, and good, too, for definite, assignable reasons." Richard Rorty claims that James did not mean to give a theory of truth with this statement and that we should not regard it as such. However, other pragmatism scholars such as Susan Haack and Howard Mounce do not share Rorty's instrumentalist interpretation of James. [6]
## Cash Value
From the introduction to William James's Pragmatism by Bruce Kuklick, p.xiv.
## Will to Believe Doctrine
In William James's lecture of 1897 titled "The Will to Believe," James defends the right to violate the principle of evidentialism in order to justify hypothesis venturing. Although this doctrine is often seen as a way for William James to justify religious beliefs, his philosophy of pragmatism allows him to use the results of his hypothetical venturing as evidence to support the hypothesis' truth. Therefore, this doctrine allows one to assume belief in God and prove its existence by what the belief brings to one's life.
# Philosophy of religion
James did important work in philosophy of religion. In his Gifford Lectures at the University of Edinburgh he provided a wide-ranging account of The Varieties of Religious Experience (1902) and interpreted them according to his pragmatic leanings. Some of the important claims he makes in this regard:
- Religious genius (experience) should be the primary topic in the study of religion, rather than religious institutions—since institutions are merely the social descendant of genius.
- The intense, even pathological varieties of experience (religious or otherwise) should be sought by psychologists, because they represent the closest thing to a microscope of the mind—that is, they show us in drastically enlarged form the normal processes of things.
- In order to usefully interpret the realm of common, shared experience and history, we must each make certain "over-beliefs" in things which, while they cannot be proven on the basis of experience, help us to live fuller and better lives.
The investigation of mystical experience was constant throughout the life of James, leading him to experiment with chloral hydrate (1870), amyl nitrite (1875), nitrous oxide (1882), and even peyote (1896). James claimed that it was only when he was under the influence of nitrous oxide that he was able to understand Hegel.[7] He concluded that while the revelations of the mystic hold true, they hold true only for the mystic; for others, they are certainly ideas to be considered, but can hold no claim to truth without personal experience of such.
# Theory of emotion
James is one of the two namesakes of the James-Lange theory of emotion, which he formulated independently of Carl Lange in the 1880s. The theory holds that emotion is the mind's perception of physiological conditions that result from some stimulus. In James' oft-cited example; it is not that we see a bear, fear it, and run. We see a bear and run, consequently we fear the bear. Our mind's perception of the higher adrenaline level, heartbeat, etc., is the emotion.
This way of thinking about emotion has great consequences for the philosophy of aesthetics. Here is a passage from his great work, Principles of Psychology, that spells out those consequences.
[W]e must immediately insist that aesthetic emotion, pure and
simple, the pleasure given us by certain lines and masses, and
combinations of colors and sounds, is an absolutely sensational
experience, an optical or auricular feeling that is primary, and not
due to the repercussion backwards of other sensations elsewhere
consecutively aroused. To this simple primary and immediate pleasure
in certain pure sensations and harmonious combinations of them, there
may, it is true, be added secondary pleasures; and in the practical
enjoyment of works of art by the masses of mankind these secondary
pleasures play a great part. The more classic one's taste is,
however, the less relatively important are the secondary pleasures
felt to be, in comparison with those of the primary sensation as it
comes in. Classicism and romanticism have their battles over this
point. Complex suggestiveness, the awakening of vistas of memory and
association, and the stirring of our flesh with picturesque mystery
and gloom, make a work of art romantic. The classic taste brands
these effects as coarse and tawdry, and prefers the naked beauty of
the optical and auditory sensations, unadorned with frippery or
foliage. To the romantic mind, on the contrary, the immediate beauty
of these sensations seems dry and thin. I am of course not discussing
which view is right, but only showing that the discrimination between
the primary feeling of beauty, as a pure incoming sensible quality,
and the secondary emotions which are grafted thereupon, is one that
must be made.
## William James' bear
From Joseph LeDoux's description of William James' Emotion [8]
# Philosophy of history
One of the long-standing schisms in the philosophy of history concerns the role of individuals in social change.
One faction sees individuals ("heroes" as Thomas Carlyle called them) as the motive power of history, and the broader society as the page on which they write their acts. The other sees society as moving according to holistic principles or laws, and sees individuals as its more-or-less willing pawns. In 1880, James waded into this controversy with "Great Men and Their Environment," an essay published in the Atlantic Monthly. He took Carlyle's side, but without Carlyle's one-sided emphasis on the political/military sphere, upon heroes as the founders or overthrowers of states and empires.
"Rembrandt must teach us to enjoy the struggle of light with darkness," James wrote. "Wagner to enjoy peculiar musical effects; Dickens gives a twist to our sentimentality, Artemus Ward to our humor; Emerson kindles a new moral light within us."
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wikidoc
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Wong Jack Man
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Wong Jack Man
Wong Jack Man (Chinese:黃澤民, born c.1940 in Hong Kong) is a Chinese martial artist and martial arts teacher, best known for fighting Bruce Lee in a real-life challenge match in Oakland in 1964.
Wong taught classes in Tai Chi Chuan, Xingyiquan and Northern Shaolin at the Fort Mason Center in San Francisco. He retired in 2005 after teaching for 45 years. His classes continued under his student Rick Wing.
# The fight with Bruce Lee
Wong's fight with Lee is controversial, as it was unrecorded and held in private.
According to Linda Lee Cadwell, Bruce Lee's wife, Lee's teaching of Chinese martial arts to Caucasians made him unpopular with Chinese martial artists in San Francisco. Dan Inosanto stated that Wong Jack Man did not teach Caucasians, and that he showed up at Lee's school on Broadway several months after Lee began teaching and issued an ornate scroll with a challenge to stop teaching Caucasians if he lost.
Wong stated that he requested a public fight with Lee after Lee had issued an open challenge during a demonstration at a Chinatown theater where Lee claimed to be able to defeat any martial artist in San Francisco. There are no witnesses that corroborates Wong's story, however. Wong stated it was after a mutual acquaintance delivered a note from Lee inviting him to fight that he showed up at Lee's school to challenge him. This "mutual acquaintance" has never been named and has never stepped forward to corroborate Wong's story. Wong contested the notion that Lee was fighting for the right to teach caucasians as not all of Wong's students were Chinese, Wong won't elaborate on whether any of those non-Chinese students were Caucasian, however.
As the fight date approached, Wong tried to delay the match and even asked for restrictions on techniques such as no hitting the face, no kicking the groin, no eye jabs, etc. Bruce refused "rules", and the two fought no holds bar.Individuals known to have witnessed the match included Cadwell, James Lee (an associate of Bruce Lee, no relation) and William Chen, a teacher of Tai Chi Chuan.
The details of the fight vary depending on the account. According to Bruce, Linda, and James Lee, the fight lasted 3 minutes with a decisive victory for Bruce.
Lee gave a description, without naming Wong explicitly, in an interview with Black Belt.
Cadwell recounted the scene in her book Bruce Lee: The Man Only I Knew.
This is in contrast to Wong and William Chen's account of the fight as they state the fight lasted an unusually long 20-25 minutes.
Wong was unsatisfied with Lee's account of the match and published his own version in the Chinese Pacific Weekly, a Chinese language newspaper in San Francisco. The article, which was featured on the front page, included a detailed description of the fight from Wong's perspective and concluded with an invitation to Bruce Lee for a public match if Lee found his version to be unacceptable. Lee never made a public response to the article. Wong later expressed regret over fighting Lee, attributing it to arrogance, both on the part of Lee and himself.
# Footnotes
- ↑ The time was late winter, 1964... this fighter was also 24 and also of Chinese descent. (Dorgan)
- ↑ Dorgan
- ↑ San Francisco Jing Mo Athletic Association. Grandmaster Wong Jack Man.
- ↑ Lee had boasted during a demonstration at a Chinatown theater that he could beat any martial artist in San Francisco and had issued an open challenge.. (Dorgan)
- ↑ a mutual acquaintance had hand-delivered a note from Lee inviting him to fight. (Dorgan)
- ↑ ..the right to teach Caucasians the ancient Chinese fighting secrets. It is a notion that Wong finds ridiculous. (Dorgan)
- ↑ most - but not all - of his students during his first years were teaching were Chinese (Dorgan)
- ↑ Borine, Normon (2002). Bruce Lee: King Dragon. 1st Books library. p. 44..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}
- ↑ Dorgan
- ↑ Lee, Linda. (1978). Bruce Lee: The Man Only I Knew. Warner Books Inc. ISBN 0446787744).
- ↑ Wong's version of the fight, along with the challenge, was run as the top story on the front page... (Dorgan)
- ↑ Wong attributes both Lee's initial challenge and his response to the same emotion, to arrogance. "If I had it to do over," he says, " I wouldn't." (Dorgan)
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Wong Jack Man
Template:Chinese name
Wong Jack Man (Chinese:黃澤民, born c.1940[1] in Hong Kong[2]) is a Chinese martial artist and martial arts teacher, best known for fighting Bruce Lee in a real-life challenge match in Oakland in 1964.
Wong taught classes in Tai Chi Chuan, Xingyiquan and Northern Shaolin at the Fort Mason Center in San Francisco. He retired in 2005 after teaching for 45 years. His classes continued under his student Rick Wing.[3]
# The fight with Bruce Lee
Wong's fight with Lee is controversial, as it was unrecorded and held in private.
According to Linda Lee Cadwell, Bruce Lee's wife, Lee's teaching of Chinese martial arts to Caucasians made him unpopular with Chinese martial artists in San Francisco. Dan Inosanto stated that Wong Jack Man did not teach Caucasians, and that he showed up at Lee's school on Broadway several months after Lee began teaching and issued an ornate scroll with a challenge to stop teaching Caucasians if he lost.
Wong stated that he requested a public fight with Lee after Lee had issued an open challenge during a demonstration at a Chinatown theater where Lee claimed to be able to defeat any martial artist in San Francisco.[4] There are no witnesses that corroborates Wong's story, however. Wong stated it was after a mutual acquaintance delivered a note from Lee inviting him to fight that he showed up at Lee's school to challenge him.[5] This "mutual acquaintance" has never been named and has never stepped forward to corroborate Wong's story. Wong contested the notion that Lee was fighting for the right to teach caucasians[6] as not all of Wong's students were Chinese,[7] Wong won't elaborate on whether any of those non-Chinese students were Caucasian, however.
As the fight date approached, Wong tried to delay the match and even asked for restrictions on techniques such as no hitting the face, no kicking the groin, no eye jabs, etc. Bruce refused "rules", and the two fought no holds bar.[8]Individuals known to have witnessed the match included Cadwell, James Lee (an associate of Bruce Lee, no relation) and William Chen, a teacher of Tai Chi Chuan.
The details of the fight vary depending on the account. According to Bruce, Linda, and James Lee, the fight lasted 3 minutes with a decisive victory for Bruce.
Lee gave a description, without naming Wong explicitly, in an interview with Black Belt.
Cadwell recounted the scene in her book Bruce Lee: The Man Only I Knew.
This is in contrast to Wong and William Chen's account of the fight as they state the fight lasted an unusually long 20-25 minutes.
Wong was unsatisfied with Lee's account of the match and published his own version in the Chinese Pacific Weekly, a Chinese language newspaper in San Francisco.[11] The article, which was featured on the front page, included a detailed description of the fight from Wong's perspective and concluded with an invitation to Bruce Lee for a public match if Lee found his version to be unacceptable. Lee never made a public response to the article. Wong later expressed regret over fighting Lee, attributing it to arrogance, both on the part of Lee and himself.[12]
# Footnotes
- ↑ The time was late winter, 1964... this fighter was also 24 and also of Chinese descent. (Dorgan)
- ↑ Dorgan
- ↑ San Francisco Jing Mo Athletic Association. Grandmaster Wong Jack Man.
- ↑ Lee had boasted during a demonstration at a Chinatown theater that he could beat any martial artist in San Francisco and had issued an open challenge.. (Dorgan)
- ↑ a mutual acquaintance had hand-delivered a note from Lee inviting him to fight. (Dorgan)
- ↑ ..the right to teach Caucasians the ancient Chinese fighting secrets. It is a notion that Wong finds ridiculous. (Dorgan)
- ↑ most - but not all - of his students during his first years were teaching were Chinese (Dorgan)
- ↑ Borine, Normon (2002). Bruce Lee: King Dragon. 1st Books library. p. 44..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}
- ↑ Dorgan
- ↑ Lee, Linda. (1978). Bruce Lee: The Man Only I Knew. Warner Books Inc. ISBN 0446787744).
- ↑ Wong's version of the fight, along with the challenge, was run as the top story on the front page... (Dorgan)
- ↑ Wong attributes both Lee's initial challenge and his response to the same emotion, to arrogance. "If I had it to do over," he says, " I wouldn't." (Dorgan)
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https://www.wikidoc.org/index.php/Wong_Jack_Man
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e124cc3b5200a80c3e646327b9faeb085fa0e128
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wikidoc
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Work aversion
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Work aversion
# Overview
Work aversion, Workplace aversion, or Employment aversion is a psychological behavior, often part of an anxiety disorder, in which the subject intentionally refuses to be gainfully employed at all, or works far less than is necessary in order to meet ones needs . It has not been officially recognized as a disorder, and is not a disease, but rather a symptom of one or more psychiatric disorders. It is estimated that about four to five million people in the United States may be suffering from some form of work aversion, though the exact number is not known .
The term work aversion does not refer to immature teens or young adults who "slack off" and fail to seek their first job or perform seriously at a job they obtain. Not all unemployed persons have work aversion. The subject of work aversion is typically an adult who has been previously employed, or who recently graduated from college or trade school, and for some psychological reason, feels turned off by employment. The subject who receives such a label generally has
expenses, hence the need for steady employment. But due to medical issues, such as a phobia, s/he does not attempt to work or seek employment, and makes excuses to others for not doing so.
# Excuses
Common excuses made for not being employed include:
- Inability to find work, even when there are many potential jobs available to the subject. Many subjects, for show, pretend to seek jobs they know they will never receive. This is done by applying for job for which they are knowingly unqualified, filling out applications intentionally poorly, or deliberately giving a bad impression at an interview.
- Health problems or disabilities that prevents subject from doing any form of work, even when subject is able-bodied and in good health, and others who are more disabled are capable of identical jobs.
- Non-paying obligations the subject claims s/he has that make him/her unable to have the time to work, such as a hobby, care for one's own child or an elderly parent, volunteer work, education (as in the case of perpetual students), or religious requirements. This is when one's main obligation should be to earn a living.
- Subject often makes individual complaints about different types of work that become available or are offered. Such complaints may be that it would cause too much physical pain or distress, the hours are impossible, it is too far away, or that the subject is simply not capable of performing that type of work. The excuse for each type of job may differ.
Many subjects suffering from work aversion live with the unrealistic expectation that cash will somehow flow their way. This may be contingent upon:
- An inheritance, even when there is no inheritance due to the subject any time soon.
- Winnings from a lottery, sweepstakes, or other forms of gambling, even when the subject is not actively playing any of these, or the odds of winning are very minimal. In the case of pathological gamblers, income is simply contingent upon winning.
- A generous gift from a sympathetic relative, friend, or non-profit organization
- A dream job, even when no such job exists, or the subject is not actively seeking one.
- Success in a business the subject is not actively pursuing or that the subject has pursued but has not been profitable.
- As in the case of the perpetual student, the hope that a degree will automatically bring money, even without applying for a job.
- The hope that a hobby or talent the subject has that currently does not pay, such as art, music, or acting, will one day become lucrative.
- Many sufferers will attempt to get on Social Security Disability. The Social Security Administration's judges are specifically trained to watch out for cases where the applicant may have Workplace Aversion . Unless the underlying cause is impossible or difficult to treat, such applications are generally denied.
# Causes
The typical view of the subject by others is often laziness. But most persons suffering from work aversion are not lazy in the sense of lacking energy. The reason for failing to work is purely due to a psychological disorder.
Work aversion usually occurs in persons who have previously been employed, and can have a variety of causes. These include:
- Depression: A person who is suffering from clinical depression, dysthymia, grief, or other similar disorders may simply lack the motivation to work.
- Obsessive-compulsive disorder: The subject is more focused on his/her obsessions than his/her need to work, and therefore, will not take out the time to perform a job or seek employment.
- Panic Disorder: For some, merely finding oneself in a work environment can trigger a panic attack. After such an occurrence, many are reluctant to seek further employment.
- Post-traumatic stress disorder: The subject has suffered from a traumatic experience at an earlier job. This may be a physical injury suffered on the job, a scary event that occurred while at work (such as a robbery of the place of employment), severe harassment or bullying from fellow employees, or abuse from one's boss or employer.
- Abrupt Termination: A former employee who was fired or laid off from an earlier job may be fearful of seeking future employment on the basis that such rejection may recur again.
- Phobia: Some persons are simply phobic of the workplace.
# Complications
Since the term work aversion only applies to one with the need to earn income, complications will inevitably arise from lacking the money the subject needs from employment. These may include:
- Loss of assets
- Loss of money in a get-rich-quick scheme the subject enters out of desperation
- Debt and credit problems
- Self-neglect. This may include malnourishment, since the subject may be unable to afford a sufficient diet, or neglect of one's personal appearance or hygiene in ways that may cost the subject money.
- Neglect of dependents, such as spouse and children, who one is expected to support.
- Neglect of personal belongings, such as one's home, car, or other possessions requiring maintenance, or loss of services that require payment of a monthly bill, such as utilities, phone service, insurance.
- Strained relations with family and friends, especically those who are forced to support the unemployed subject, or those who otherwise expect the subject to have money or items of value.
- Strained marriage, when financial problems hurt marriage
- Reduced socialization, especially in cases where the subject is in need of money to support such interaction.
- Legal problems, when subject turns to law-breaking to obtain cost of living
- Homelessness, in most severe cases
Persons suffering from work aversion in need of money will often resort to extreme measures in order to obtain the funding needed to support themselves. These include:
- Draining ones savings, and cashing out bonds and other stored funds to which the subject has access.
- Racking up large amounts of debt and maxing out on credit cards, cashing out equity in one's home or other real property, or pawning one's valuables.
- Begging money from family or friends.
- Seeking public assistance, such as food stamps, and grants from private or religious organizations.
- Criminal activity, such as embezzlement or check fraud.
# Treatment
Treating work aversion involves treating the underlying psychological cause of the disorder, which often requires diagnostic testing. Often, this cause cannot be easily identified because the subject frequently has little or no self-recognition of the problem, lacks funding needed for diagnosis, and has little or no willpower to seek treatment.
Methods of treatment for the underlying disorder include psychotherapy, counseling, medication, or some more unusual forms of treatment. Depending on the cause, lengths of treatment and success rates may vary. While some mild cases of work aversion may subside naturally over time without any treatment, other more severe cases may be incurable. These subjects are often considered candidates for Social Security Disability.
Sometimes, environmental changes may help cure the disorder. These may include a career change or overhaul, a move to a new city or region, or self-employment.
Sometimes, a subject may be able to find partial relief from a certain type of job or job environment where s/he feels comfortable. But, if the subject loses such a job, finding a replacement could be increasingly troublesome, and symptoms may reappear and worsen.
If a subject is receiving funding for his/her expenses from a relative, friend, or other source, cutting off the funding does not motivate the subject to obtain employment, and will not improve this condition. A relative or friend who wants to help a subject should encourage him/her to seek treatment for the underlying cause.
Many career couselors have turned to a therapy they identify as work-hardening. This means they put the person to work for a brief period of time in the first week, such as two hours per day. In the following week, they increase it to four hours per day. The amount of work increases each week until it becomes full-time, with the client being willing. This sometimes has proven to be successful.
# Further reading
- The Abolition of Work and Other Myths, Neala Schleuning, (Summer, 1995)
|
Work aversion
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Work aversion, Workplace aversion, or Employment aversion is a psychological behavior, often part of an anxiety disorder, in which the subject intentionally refuses to be gainfully employed at all, or works far less than is necessary in order to meet ones needs [2]. It has not been officially recognized as a disorder, and is not a disease, but rather a symptom of one or more psychiatric disorders. It is estimated that about four to five million people in the United States may be suffering from some form of work aversion, though the exact number is not known [3].
The term work aversion does not refer to immature teens or young adults who "slack off" and fail to seek their first job or perform seriously at a job they obtain. Not all unemployed persons have work aversion. The subject of work aversion is typically an adult who has been previously employed, or who recently graduated from college or trade school, and for some psychological reason, feels turned off by employment. The subject who receives such a label generally has
expenses, hence the need for steady employment. But due to medical issues, such as a phobia, s/he does not attempt to work or seek employment, and makes excuses to others for not doing so.
# Excuses
Common excuses made for not being employed include:
- Inability to find work, even when there are many potential jobs available to the subject. Many subjects, for show, pretend to seek jobs they know they will never receive. This is done by applying for job for which they are knowingly unqualified, filling out applications intentionally poorly, or deliberately giving a bad impression at an interview.
- Health problems or disabilities that prevents subject from doing any form of work, even when subject is able-bodied and in good health, and others who are more disabled are capable of identical jobs.
- Non-paying obligations the subject claims s/he has that make him/her unable to have the time to work, such as a hobby, care for one's own child or an elderly parent, volunteer work, education (as in the case of perpetual students), or religious requirements. This is when one's main obligation should be to earn a living.
- Subject often makes individual complaints about different types of work that become available or are offered. Such complaints may be that it would cause too much physical pain or distress, the hours are impossible, it is too far away, or that the subject is simply not capable of performing that type of work. The excuse for each type of job may differ.
Many subjects suffering from work aversion live with the unrealistic expectation that cash will somehow flow their way. This may be contingent upon:
- An inheritance, even when there is no inheritance due to the subject any time soon.
- Winnings from a lottery, sweepstakes, or other forms of gambling, even when the subject is not actively playing any of these, or the odds of winning are very minimal. In the case of pathological gamblers, income is simply contingent upon winning.
- A generous gift from a sympathetic relative, friend, or non-profit organization
- A dream job, even when no such job exists, or the subject is not actively seeking one.
- Success in a business the subject is not actively pursuing or that the subject has pursued but has not been profitable.
- As in the case of the perpetual student, the hope that a degree will automatically bring money, even without applying for a job.
- The hope that a hobby or talent the subject has that currently does not pay, such as art, music, or acting, will one day become lucrative.
- Many sufferers will attempt to get on Social Security Disability. The Social Security Administration's judges are specifically trained to watch out for cases where the applicant may have Workplace Aversion [4]. Unless the underlying cause is impossible or difficult to treat, such applications are generally denied.
# Causes
The typical view of the subject by others is often laziness. But most persons suffering from work aversion are not lazy in the sense of lacking energy. The reason for failing to work is purely due to a psychological disorder.
Work aversion usually occurs in persons who have previously been employed, and can have a variety of causes. These include:
- Depression: A person who is suffering from clinical depression, dysthymia, grief, or other similar disorders may simply lack the motivation to work.
- Obsessive-compulsive disorder: The subject is more focused on his/her obsessions than his/her need to work, and therefore, will not take out the time to perform a job or seek employment.
- Panic Disorder: For some, merely finding oneself in a work environment can trigger a panic attack. After such an occurrence, many are reluctant to seek further employment.
- Post-traumatic stress disorder: The subject has suffered from a traumatic experience at an earlier job. This may be a physical injury suffered on the job, a scary event that occurred while at work (such as a robbery of the place of employment), severe harassment or bullying from fellow employees, or abuse from one's boss or employer.
- Abrupt Termination: A former employee who was fired or laid off from an earlier job may be fearful of seeking future employment on the basis that such rejection may recur again.
- Phobia: Some persons are simply phobic of the workplace.
# Complications
Since the term work aversion only applies to one with the need to earn income, complications will inevitably arise from lacking the money the subject needs from employment. These may include:
- Loss of assets
- Loss of money in a get-rich-quick scheme the subject enters out of desperation
- Debt and credit problems
- Self-neglect. This may include malnourishment, since the subject may be unable to afford a sufficient diet, or neglect of one's personal appearance or hygiene in ways that may cost the subject money.
- Neglect of dependents, such as spouse and children, who one is expected to support.
- Neglect of personal belongings, such as one's home, car, or other possessions requiring maintenance, or loss of services that require payment of a monthly bill, such as utilities, phone service, insurance.
- Strained relations with family and friends, especically those who are forced to support the unemployed subject, or those who otherwise expect the subject to have money or items of value.
- Strained marriage, when financial problems hurt marriage
- Reduced socialization, especially in cases where the subject is in need of money to support such interaction.
- Legal problems, when subject turns to law-breaking to obtain cost of living
- Homelessness, in most severe cases
Persons suffering from work aversion in need of money will often resort to extreme measures in order to obtain the funding needed to support themselves. These include:
- Draining ones savings, and cashing out bonds and other stored funds to which the subject has access.
- Racking up large amounts of debt and maxing out on credit cards, cashing out equity in one's home or other real property, or pawning one's valuables.
- Begging money from family or friends.
- Seeking public assistance, such as food stamps, and grants from private or religious organizations.
- Criminal activity, such as embezzlement or check fraud.
# Treatment
Treating work aversion involves treating the underlying psychological cause of the disorder, which often requires diagnostic testing. Often, this cause cannot be easily identified because the subject frequently has little or no self-recognition of the problem, lacks funding needed for diagnosis, and has little or no willpower to seek treatment.
Methods of treatment for the underlying disorder include psychotherapy, counseling, medication, or some more unusual forms of treatment. Depending on the cause, lengths of treatment and success rates may vary. While some mild cases of work aversion may subside naturally over time without any treatment, other more severe cases may be incurable. These subjects are often considered candidates for Social Security Disability.
Sometimes, environmental changes may help cure the disorder. These may include a career change or overhaul, a move to a new city or region, or self-employment.
Sometimes, a subject may be able to find partial relief from a certain type of job or job environment where s/he feels comfortable. But, if the subject loses such a job, finding a replacement could be increasingly troublesome, and symptoms may reappear and worsen.
If a subject is receiving funding for his/her expenses from a relative, friend, or other source, cutting off the funding does not motivate the subject to obtain employment, and will not improve this condition. A relative or friend who wants to help a subject should encourage him/her to seek treatment for the underlying cause.
Many career couselors have turned to a therapy they identify as work-hardening. This means they put the person to work for a brief period of time in the first week, such as two hours per day. In the following week, they increase it to four hours per day. The amount of work increases each week until it becomes full-time, with the client being willing. This sometimes has proven to be successful.
# Further reading
- The Abolition of Work and Other Myths, Neala Schleuning, (Summer, 1995)
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https://www.wikidoc.org/index.php/Work_aversion
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3816bf43b55b0810e3eba6ce75400057724f5577
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wikidoc
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Work function
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Work function
The work function is the minimum energy (usually measured in electron volts) needed to remove an electron from a solid to a point immediately outside the solid surface (or energy needed to move an electron from the Fermi energy level into vacuum). Here "immediately" means that the final electron position is far from the surface on the atomic scale but still close to the solid on the macroscopic scale. The work function is an important property of metals.
# Photoelectric work function
The work function is the minimum energy that must be given to an electron to liberate it from the surface of a particular metal. In the photoelectric effect, electron excitation is achieved by absorption of a photon. If the photon's energy greater than the metal's work function, photoelectric emission occurs and the electron is liberated from the metal. (Excess photon energy results in a liberated electron with non-zero kinetic energy.)
Photoelectric work function is
where h is the Planck's constant and f_0 is the minimum (threshold) frequency of the photon required to produce photoelectric emission.
# Thermionic work function
The work function is also important in the theory of thermionic emission. Here the electron gains its energy from heat rather than photons. According to the Richardson-Dushman equation
the emitted electron current density J (A/m2) is related to the absolute temperature T by the equation:
where W is the work function of the metal, k is the Boltzmann constant and the proportionality constant A, known as Richardson's constant, is given by
where m and -e are the mass and charge of an electron, and h is Planck's constant.
Thermionic emission --- electrons escaping from the heated negatively-charged filament (hot cathode) --- is important in the operation of vacuum tubes.
Tungsten, the common choice for vacuum tube filaments, has a work function of approximately 4.5 eV; various
-xide coatings can substantially reduce this.
# Free Electron Gas Model
In the free electron model the valence electrons roam freely (zero force) inside the metal but find
a confining potential step U at the boundary of the metal. In the system's ground state, states
with energy less than the Fermi Level are occupied, and states above the Fermi Level are not occupied. The energy
required to liberate an electron in the Fermi Level is the work function. If, as in the diagram right, we define
the Fermi Energy E_F from the bottom of the well the results reported in the Wiki page Fermi Energy
are applicable. However, usually the Fermi Energy is referenced to energy zero: that of the lowest energy electron
free of the metal. In that case the Fermi Energy would have a negative value (i.e., the Fermi Level lies
below those of escaped electrons) E_F\approx -W (but see below).
# Work Function Trends
The thermionic work function depends on the orientation of the crystal and will tend to be smaller for metals with an open lattice, larger for metals in which the atoms are closely packed. The range is about 1.5–6 eV. It is somewhat higher on dense crystal faces than open ones.
The magnitude of the work function is usually about a half of the ionization energy of a free atom of the metal.
For example, caesium has ionization energy 3.9 eV and work function 1.9 eV.
# Work Function and Surface Effect
Work function W of a metal is closely related to its Fermi energy E_F \; (defined
relative to the lowest energy free particle: zero in the above diagram) yet the two quantities are not exactly the same. This is due to the surface effect of a real-world solid: a real-world solid is not infinitely extended with electrons and ions repeatedly filling every primitive cell over all Bravais lattice sites. Neither can one simply take a set of Bravais lattice sites \{R\} \; inside the geometrical region V which the solid occupies and then fill undistorted charge distribution basis into all primitive cells of \{R\} \; . Indeed, the charge distribution in those cells near the surface will be distorted significantly from that in a cell of an ideal infinite solid, resulting in an effective surface dipole distribution, or, sometimes both a surface dipole distribution and a surface charge distribution.
It can be proven that if we define work function as the minimum energy needed to remove an electron to a point immediately out of the solid, the effect of the surface charge distribution can be neglected, leaving only the surface dipole distribution. Let the potential energy difference across the surface due to effective surface dipole be W_S \; . And let E_F \; be the Fermi energy calculated for the finite solid without considering surface distortion effect, when taking the convention that the potential at r \rightarrow \infty \; is zero. Then, the correct formula for work function is:
W = - E_F +W_S \;
Where E_F \; is negative, which means that electrons are bound in the solid.
# Applications
In electronics the work function is important for design of the metal-semiconductor junction in Schottky diodes and for design of vacuum tubes.
# Measurement
Many techniques have been developed based on different physical effects to measure the electronic work function of a sample. One may distinguish between two groups of experimental methods for work function measurements: absolute and relative.
Methods of the first group employ electron emission from the sample induced by photon absorption (photoemission), by high temperature (thermionic emission), due to an electric field (field emission), or using electron tunnelling.
All relative methods make use of the contact potential difference between the sample and a reference electrode. Experimentally, either an anode current of a diode is used or the displacement current between the sample and reference, created by an artificial change in the capacitance between the two, is measured (the Kelvin Probe method, Kelvin probe force microscope).
## Methods Based on Photoemission
Photoelectron emission spectroscopy (PES) is the general term for spectroscopic techniques based on the outer photoelectric effect. In the case of Ultraviolet Photoelectron Spectroscopy (UPS), the surface of a solid sample is irradiated with ultraviolet (UV) light and the kinetic energy of the emitted electrons is analysed. As UV light is electromagnetic radiation with an energy h f lower than 100 eV it is able to extract mainly valence electrons. Due to limitations of the escape depth of electrons in solids UPS is very surface sensitive, as the information depth is in the range of 2 – 20 monolayers (1-10nm). The resulting spectrum reflects the electronic structure of the sample providing information on the density of states, the occupation of states, and the work function.
## Methods Based on Thermionic Emission
The retarding diode method is one of the simplest and oldest method of measuring work functions. It is based on the thermionic emission of electrons from an emitter. The current density J of the electrons collected by the sample depends on the work function W of the sample and is given by the Richardson–Dushman equation J = A T^2 e^{-W/kT} where A, the Richardson constant, is a specific material constant. The current density increases rapidly with temperature and decreases exponentially with the work function. Changes of the work function can be easily determined by applying a retarding potential V between the sample and the electron emitter; W is replaced by W+eV in above equation. The difference in the retarding potential measured at constant current is equivalent to the work function change, assuming that the work function and the temperature of the emitter is constant.
One can use the Richardson–Dushman equation directly to determine the work function by temperature variation of the sample, as well. Rearranging the equation yields \ln(J/T^2) = \ln(A) - W/kT . The line produced by plotting \ln(J/T^2) vs. 1/T will have a slope of W/k allowing to determine the work function of the sample.
## Electron Work Functions of The Elements
Units: eV electron Volts
reference: CRC handbook on Chemistry and Physics.
Note: Work function can change for crystaline elements based upon the orientation. For example Ag:4.26, Ag(110):4.64, Ag(110):4.52, Ag(111):4.74
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Work function
The work function is the minimum energy (usually measured in electron volts) needed to remove an electron from a solid to a point immediately outside the solid surface (or energy needed to move an electron from the Fermi energy level into vacuum). Here "immediately" means that the final electron position is far from the surface on the atomic scale but still close to the solid on the macroscopic scale. The work function is an important property of metals.
# Photoelectric work function
The work function is the minimum energy that must be given to an electron to liberate it from the surface of a particular metal. In the photoelectric effect, electron excitation is achieved by absorption of a photon. If the photon's energy greater than the metal's work function, photoelectric emission occurs and the electron is liberated from the metal. (Excess photon energy results in a liberated electron with non-zero kinetic energy.)
Photoelectric work function is
where <math>h</math> is the Planck's constant and <math>f_0</math> is the minimum (threshold) frequency of the photon required to produce photoelectric emission.
# Thermionic work function
The work function is also important in the theory of thermionic emission. Here the electron gains its energy from heat rather than photons. According to the Richardson-Dushman equation
the emitted electron current density J (A/m2) is related to the absolute temperature T by the equation:
where W is the work function of the metal, k is the Boltzmann constant and the proportionality constant A, known as Richardson's constant, is given by
where m and -e are the mass and charge of an electron, and h is Planck's constant.
Thermionic emission --- electrons escaping from the heated negatively-charged filament (hot cathode) --- is important in the operation of vacuum tubes.
Tungsten, the common choice for vacuum tube filaments, has a work function of approximately 4.5 eV; various
oxide coatings can substantially reduce this.
# Free Electron Gas Model
In the free electron model the valence electrons roam freely (zero force) inside the metal but find
a confining potential step <math>U</math> at the boundary of the metal. In the system's ground state, states
with energy less than the Fermi Level are occupied, and states above the Fermi Level are not occupied. The energy
required to liberate an electron in the Fermi Level is the work function. If, as in the diagram right, we define
the Fermi Energy <math>E_F</math> from the bottom of the well the results reported in the Wiki page Fermi Energy
are applicable. However, usually the Fermi Energy is referenced to energy zero: that of the lowest energy electron
free of the metal. In that case the Fermi Energy would have a negative value (i.e., the Fermi Level lies
below those of escaped electrons) <math>E_F\approx -W</math> (but see below).
# Work Function Trends
The thermionic work function depends on the orientation of the crystal and will tend to be smaller for metals with an open lattice, larger for metals in which the atoms are closely packed. The range is about 1.5–6 eV. It is somewhat higher on dense crystal faces than open ones.
The magnitude of the work function is usually about a half of the ionization energy of a free atom of the metal.
For example, caesium has ionization energy 3.9 eV and work function 1.9 eV.
# Work Function and Surface Effect
Work function W of a metal is closely related to its Fermi energy <math> E_F \; </math> (defined
relative to the lowest energy free particle: zero in the above diagram) yet the two quantities are not exactly the same. This is due to the surface effect of a real-world solid: a real-world solid is not infinitely extended with electrons and ions repeatedly filling every primitive cell over all Bravais lattice sites. Neither can one simply take a set of Bravais lattice sites <math> \{R\} \; </math> inside the geometrical region V which the solid occupies and then fill undistorted charge distribution basis into all primitive cells of <math> \{R\} \; </math>. Indeed, the charge distribution in those cells near the surface will be distorted significantly from that in a cell of an ideal infinite solid, resulting in an effective surface dipole distribution, or, sometimes both a surface dipole distribution and a surface charge distribution.
It can be proven that if we define work function as the minimum energy needed to remove an electron to a point immediately out of the solid, the effect of the surface charge distribution can be neglected, leaving only the surface dipole distribution. Let the potential energy difference across the surface due to effective surface dipole be <math> W_S \; </math>. And let <math> E_F \; </math> be the Fermi energy calculated for the finite solid without considering surface distortion effect, when taking the convention that the potential at <math> r \rightarrow \infty \; </math> is zero. Then, the correct formula for work function is:
<math>
W = - E_F +W_S \;
</math>
Where <math> E_F \; </math> is negative, which means that electrons are bound in the solid.
# Applications
In electronics the work function is important for design of the metal-semiconductor junction in Schottky diodes and for design of vacuum tubes.
# Measurement
Many techniques have been developed based on different physical effects to measure the electronic work function of a sample. One may distinguish between two groups of experimental methods for work function measurements: absolute and relative.
Methods of the first group employ electron emission from the sample induced by photon absorption (photoemission), by high temperature (thermionic emission), due to an electric field (field emission), or using electron tunnelling.
All relative methods make use of the contact potential difference between the sample and a reference electrode. Experimentally, either an anode current of a diode is used or the displacement current between the sample and reference, created by an artificial change in the capacitance between the two, is measured (the Kelvin Probe method, Kelvin probe force microscope).
## Methods Based on Photoemission
Photoelectron emission spectroscopy (PES) is the general term for spectroscopic techniques based on the outer photoelectric effect. In the case of Ultraviolet Photoelectron Spectroscopy (UPS), the surface of a solid sample is irradiated with ultraviolet (UV) light and the kinetic energy of the emitted electrons is analysed. As UV light is electromagnetic radiation with an energy <math>h f</math> lower than 100 eV it is able to extract mainly valence electrons. Due to limitations of the escape depth of electrons in solids UPS is very surface sensitive, as the information depth is in the range of 2 – 20 monolayers (1-10nm). The resulting spectrum reflects the electronic structure of the sample providing information on the density of states, the occupation of states, and the work function.
## Methods Based on Thermionic Emission
The retarding diode method is one of the simplest and oldest method of measuring work functions. It is based on the thermionic emission of electrons from an emitter. The current density <math>J</math> of the electrons collected by the sample depends on the work function <math>W</math> of the sample and is given by the Richardson–Dushman equation <math>J = A T^2 e^{-W/kT} </math> where <math>A</math>, the Richardson constant, is a specific material constant. The current density increases rapidly with temperature and decreases exponentially with the work function. Changes of the work function can be easily determined by applying a retarding potential <math>V</math> between the sample and the electron emitter; <math>W</math> is replaced by <math>W+eV</math> in above equation. The difference in the retarding potential measured at constant current is equivalent to the work function change, assuming that the work function and the temperature of the emitter is constant.
One can use the Richardson–Dushman equation directly to determine the work function by temperature variation of the sample, as well. Rearranging the equation yields <math>\ln(J/T^2) = \ln(A) - W/kT </math>. The line produced by plotting <math>\ln(J/T^2)</math> vs. <math>1/T</math> will have a slope of <math>W/k</math> allowing to determine the work function of the sample.
## Electron Work Functions of The Elements
Units: eV electron Volts
reference: CRC handbook on Chemistry and Physics.
Note: Work function can change for crystaline elements based upon the orientation. For example Ag:4.26, Ag(110):4.64, Ag(110):4.52, Ag(111):4.74
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Wound healing
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Wound healing
# Overview
Wound healing, or wound repair, is the body's natural process of regenerating dermal and epidermal tissue. When an individual is wounded, a set of events takes place in a predictable fashion to repair the damage. These events overlap in time and must be artificially categorized into separate steps: the inflammatory, proliferative, and remodeling phases (Some authors consider healing to take place in four stages, by splitting different parts inflammation or proliferation into separate steps.).
In the inflammatory phase, bacteria and debris are phagocytized and removed and factors are released that cause the migration and division of cells involved in the proliferative phase.
The proliferative phase is characterized by angiogenesis, collagen deposition, granulation tissue formation, epithelialization, and wound contraction. In angiogenesis, new blood vessels grow from endothelial cells.
In fibroplasia and granulation tissue formation, fibroblasts grow and form a new, provisional extracellular matrix (ECM) by excreting collagen and fibronectin.
In epithelialization, epithelial cells crawl across the wound bed to cover it. In contraction, the wound is made smaller by the action of myofibroblasts, which establish a grip on the wound edges and contract themselves using a mechanism similar to that in smooth muscle cells. When the cells' roles are close to complete, unneeded cells undergo apoptosis.
In the maturation and remodeling phase, collagen is remodeled and realigned along tension lines and cells that are no longer needed are removed by apoptosis.
# Inflammatory phase
In the inflammatory phase (lag phase/resting phase), clotting takes place in order to obtain hemostasis, or stop blood loss, and various factors are released to attract cells that phagocytise debris, bacteria, and damaged tissue and release factors that initiate the proliferative phase of wound healing.
## Clotting cascade
When tissue is first wounded, blood comes in contact with collagen, triggering blood platelets to begin secreting inflammatory factors. Platelets also express glycoproteins on their cell membranes that allow them to stick to one another and to aggregate, forming a mass.
Fibrin and fibronectin cross-link together and form a plug that traps proteins and particles and prevents further blood loss. This fibrin-fibronectin plug is also the main structural support for the wound until collagen is deposited. Migratory cells use this plug as a matrix to crawl across, and platelets adhere to it and secrete factors. The clot is eventually lysed and replaced with granulation tissue and then later with collagen.
## Platelets
Platelets, the cells present in the highest numbers shortly after a wound occurs, release a number of things into the blood, including ECM proteins and cytokines, including growth factors. Growth factors stimulate cells to speed their rate of division. Platelets also release other proinflammatory factors like serotonin, bradykinin, prostaglandins, prostacyclins, thromboxane, and histamine, which serve a number of purposes, including to increase cell proliferation and migration to the area and to cause blood vessels to become dilated and porous.
## Vasoconstriction and vasodilation
Immediately after a blood vessel is breached, ruptured cell membranes release inflammatory factors like thromboxanes and prostaglandins that cause the vessel to spasm to prevent blood loss and to collect inflammatory cells and factors in the area. This vasoconstriction lasts five to ten minutes and is followed by vasodilation, a widening of blood vessels, which peaks at about 20 minutes post-wounding. Vasodilation is the result of factors released by platelets and other cells. The main factor involved in causing vasodilation is histamine. Histamine also causes blood vessels to become porous, allowing the tissue to become edematous because proteins from the bloodstream leak into the extravascular space, which increases its osmolar load and draws water into the area. Increased porousness of blood vessels also facilitates the entry of inflammatory cells like leukocytes into the wound site from the bloodstream.
## Polymorphonuclear neutrophils
Within an hour of wounding, polymorphonuclear neutrophils (PMNs) arrive at the wound site and become the predominant cells in the wound for the first three days after the injury occurs, with especially high numbers on the second day. They are attracted to the site by fibronectin, growth factors, and substances such as neuropeptides and kinins. Neutrophils phagocytise debris and bacteria and also kill bacteria by releasing free radicals in what is called a 'respiratory burst'. They also cleanse the wound by secreting proteases that break down damaged tissue. Neutrophils usually undergo apoptosis once they have completed their tasks and are engulfed and degraded by macrophages.
Other leukocytes to enter the area include helper T cells, which secrete cytokines to cause more T cells to divide and to increase inflammation and enhance vasodilation and vessel permeability. T cells also increase the activity of macrophages.
## Macrophages
Macrophages are essential to wound healing. They replace PMNs as the predominant cells in the wound by two days after injury. Attracted to the wound site by growth factors released by platelets and other cells, monocytes from the bloodstream enter the area through blood vessel walls. Numbers of monocytes in the wound peak one to one and a half days after the injury occurs. Once they are in the wound site, monocytes mature into macrophages, the main cell type that clears the wound area of bacteria and debris.
The macrophage's main role is to phagocytise bacteria and damaged tissue, and it also debrides damaged tissue by releasing proteases. Macrophages also secrete a number of factors such as growth factors and other cytokines, especially during the third and fourth post-wounding days. These factors attract cells involved in the proliferation stage of healing to the area. Macrophages are stimulated by the low oxygen content of their surroundings to produce factors that induce and speed angiogenesis. and they also stimulate cells that reepithelialize the wound, create granulation tissue, and lay down a new extracellular matrix. Because they secrete these factors, macrophages are vital for pushing the wound healing process into the next phase.
Because inflammation plays roles in fighting infection and inducing the proliferation phase, it is a necessary part of healing. However, inflammation can lead to tissue damage if it lasts too long. Thus the reduction of inflammation is frequently a goal in therapeutic settings. Inflammation lasts as long as there is debris in the wound. Thus the presence of dirt or other objects can extend the inflammatory phase for too long, leading to a chronic wound.
As inflammation dies down, fewer inflammatory factors are secreted, existing ones are broken down, and numbers of neutrophils and macrophages are reduced at the wound site. These changes indicate that the inflammatory phase is ending and the proliferative phase is underway.
# Proliferative phase
About two or three days after the wound occurs, fibroblasts begin to enter the wound site, marking the onset of the proliferative phase even before the inflammatory phase has ended. As in the other phases of wound healing, steps in the proliferative phase do not occur in a series but rather partially overlap in time.
## Angiogenesis
Also called neovascularization, the process of angiogenesis occurs concurrently with fibroblast proliferation when endothelial cells migrate to the area of the wound. Because the activity of fibroblasts and epithelial cells requires oxygen, angiogenesis is imperative for other stages in wound healing, like epidermal and fibroblast migration. The tissue in which angiogenesis has occurred typically looks red (is erythematous) due to the presence of capillaries.
In order to form new blood vessels and provide oxygen and nutrients to the healing tissue. stem cells called endothelial cells originating from parts of uninjured blood vessels develop pseudopodia and push through the ECM into the wound site. Through this activity, they establish new blood vessels.
To migrate, endothelial cells need collagenases and plasminogen activator to degrade the clot and part of the ECM. Zinc-dependent metalloproteinases digest basement membrane and ECM to allow cell proliferation and angiogenesis.
Endothelial cells are also attracted to the wound area by fibronectin found on the fibrin scab and by growth factors released by other cells. Endothelial growth and proliferation is also stimulated by hypoxia and presence of lactic acid in the wound. In a low-oxygen environment, macrophages and platelets produce angiogenic factors which attract endothelial cells chemotactically. When macrophages and other growth factor-producing cells are no longer in a hypoxic, lactic acid-filled environment, they stop producing angiogenic factors. Thus, when tissue is adequately perfused, migration and proliferation of endothelial cells is reduced. Eventually blood vessels that are no longer needed die by apoptosis.
## Fibroplasia and granulation tissue formation
Simultaneously with angiogenesis, fibroblasts begin accumulating in the wound site. Fibroblasts begin entering the wound site two to five days after wounding as the inflammatory phase is ending, and their numbers peak at one to two weeks post-wounding. By the end of the first week, fibroblasts are the main cells in the wound Fibroplasia ends two to four weeks after wounding.
In the first two or three days after injury, fibroblasts mainly proliferate and migrate, while later, they are the main cells that lay down the collagen matrix in the wound site. Fibroblasts from normal tissue migrate into the wound area from its margins. Initially fibroblasts use the fibrin scab formed in the inflammatory phase to migrate across, adhering to fibronectin. Fibroblasts then deposit ground substance into the wound bed, and later collagen, which they can adhere to for migration.
Granulation tissue is needed to fill the void that has been left by a large, open wound that crosses the basement membrane. It begins to appear in the wound even during the inflammatory phase, two to five days post wounding, and continues growing until the wound bed is covered. Granulation tissue consists of new blood vessels, fibroblasts, inflammatory cells, endothelial cells, myofibroblasts, and the components of a new, provisional ECM. The provisional ECM is different in composition from the ECM in normal tissue and includes fibronectin, collagen, glycosaminoglycans, and proteoglycans. Its main components are fibronectin and hyaluronan, which create a very hydrated matrix and facilitate cell migration. Later this provisional matrix is replaced with an ECM that more closely resembles that found in non-injured tissue.
Fibroblasts deposit ECM molecules like glycoproteins, glycosaminoglycans (GAGs), proteoglycans, elastin, and fibronectin, which they can then use to migrate across the wound (Cohen, 2005).
Growth factors (PDGF, TGF-β) and fibronectin encourage proliferation, migration to the wound bed, and production of ECM molecules by fibroblasts. Fibroblasts also secrete growth factors that attract epithelial cells to the wound site. Hypoxia also contributes to fibroblast proliferation and excretion of growth factors, though too little oxygen will inhibit their growth and deposition of ECM components, and can lead to excessive, fibrotic scarring.
### Collagen deposition
One of fibroblasts' most important duties is the production of collagen. Fibroblasts begin secreting appreciable collagen by the second or third post-wounding day, and its deposition peaks at one to three weeks. Collagen production continues rapidly for two to four weeks, after which its destruction matches its production and so its growth levels off.
Collagen deposition is important because it increases the strength of the wound; before it is laid down, the only thing holding the wound closed is the fibrin-fibronectin clot, which does not provide much resistance to traumatic injury. Also, cells involved in inflammation, angiogenesis, and connective tissue construction attach to, grow and differentiate on the collagen matrix laid down by fibroblasts.
Even as fibroblasts are producing new collagen, collagenases and other factors degrade it. Shortly after wounding, synthesis exceeds degradation so collagen levels in the wound rise, but later production and degradation become equal so there is no net collagen gain. This homeostasis signals the onset of the maturation phase. Granulation gradually ceases and fibroblasts decrease in number in the wound once their work is done. At the end of the granulation phase, fibroblasts begin to commit apoptosis, converting granulation tissue from an environment rich in cells to one that consists mainly of collagen.
## Epithelialization
The formation of granulation tissue in an open wound allows the reepithelialization phase to take place, as epithelial cells migrate across the new tissue to form a barrier between the wound and the environment. Basal keratinocytes from the wound edges and dermal appendages such as hair follicles, sweat glands and sebacious (oil) glands are the main cells responsible for the epithelialization phase of wound healing. They advance in a sheet across the wound site and proliferate at its edges, ceasing movement when they meet in the middle.
Keratinocytes migrate without first proliferating.. Migration can begin as early as a few hours after wounding. However, epithelial cells require viable tissue to migrate across, so if the wound is deep it must first be filled with granulation tissue. Thus the time of onset of migration is variable and may occur about one day after wounding. Cells on the wound margins proliferate on the second and third day post-wounding in order to provide more cells for migration.
If the basement membrane is not breached, epithelial cells are replaced within three days by division and upward migration of cells in the stratum basale in the same fashion that occurs in uninjured skin. However, if the basement membrane is ruined at the wound site, reepithelization must occur from the wound margins and from skin appendages such as hair follicles and sweat and oil glands that enter the dermis that are lined with viable keratinocytes. If the wound is very deep, skin appendages may also be ruined and migration can only occur from wound edges.
Migration of keratinocytes over the wound site is stimulated by lack of contact inhibition and by chemicals such as nitric oxide. Before they begin to migrate, cells must dissolve their desmosomes and hemidesmosomes, which normally anchor the cells by intermediate filaments in their cytoskeleton to other cells and to the ECM. Transmembrane receptor proteins called integrins, which are made of glycoproteins and normally anchor the cell to the basement membrane by its cytoskeleton, are released from the cell's intermediate filaments and relocate to actin filaments to serve as attachments to the ECM for pseudopodia during migration. Thus keratinocytes detach from the basement membrane and are able to enter the wound bed.
Before they begin migrating, keratinocytes change shape, becoming longer and flatter and extending cellular processes like lamellipodia and wide processes that look like ruffles. Actin filaments and pseudopodia form. During migration, integrins on the pseudopod attach to the ECM, and the actin filaments in the projection pull the cell along. The interaction with molecules in the ECM through integrins further promotes the formation of actin filaments, lamellipodia, and filopodia.
Epithelial cells climb over one another in order to migrate. This growing sheet of epithelial cells is often called the epithelial tongue. The first cells to attach to the basement membrane form the stratum basale. These basal cells continue to migrate across the wound bed, and epithelial cells above them slide along as well. The more quickly this migration occurs, the less of a scar there will be.
Fibrin, collagen, and fibronectin in the ECM may further signal cells to divide and migrate Like fibroblasts, migrating keratinocytes use the fibronectin cross-linked with fibrin that was deposited in inflammation as an attachment site to crawl across.
As keratinocytes migrate, they move over granulation tissue but underneath the scab (if one was formed), separating it from the underlying tissue. Epithelial cells have the ability to phagocytize debris such as dead tissue and bacterial matter that would otherwise obstruct their path. Because they must dissolve any scab that forms, keratinocyte migration is best enhanced by a moist environment, since a dry one leads to formation of a bigger, tougher scab. To make their way along the tissue, keratinocytes must dissolve the clot, debris, and parts of the ECM in order to get through. They secrete plasminogen activator, which activates plasmin to dissolve the scab. Cells can only migrate over living tissue, so they must excrete collagenases and proteases like matrix metalloproteinases (MMPs) to dissolve damaged parts of the ECM in their way, particularly at the front of the migrating sheet. Keratinocytes also dissolve the basement membrane, using instead the new ECM laid down by fibroblasts to crawl across.
As keratinocytes continue migrating, new epithelial cells must be formed at the wound edges to replace them and to provide more cells for the advancing sheet. Proliferation behind migrating keratinocytes normally begins a few days after wounding and occurs at a rate that is 17 times higher in this stage of epithelialization than in normal tissues. Until the entire wound area is resurfaced, the only epithelial cells to proliferate are at the wound edges.
Growth factors, stimulated by integrins and MMPs, cause cells to proliferate at the wound edges. Keratinocytes themselves also produce and secrete factors, including growth factors and basement membrane proteins, which aid both in epithelialization and in other phases of healing.
Keratinocytes continue migrating across the wound bed until cells from either side meet in the middle, at which point contact inhibition causes them to stop migrating. When they have finished migrating, the keratinocytes secrete the proteins that form the new basement membrane. Cells reverse the morphological changes they underwent in order to begin migrating; they reestablish desmosomes and hemidesmosomes and become anchored once again to the basement membrane. Basal cells begin to divide and differentiate in the same manner as they do in normal skin to reestablish the strata found in reepithelialized skin.
## Contraction
Around a week after the wounding takes place, fibroblasts have differentiated into myofibroblasts and the wound begins to contract In full thickness wounds, contraction peaks at 5 to 15 days post wounding. Contraction can last for several weeks and continues even after the wound is completely reepithelialized. If contraction continues for too long, it can lead to disfigurement and loss of function.
Contraction occurs in order to reduce the size of the wound. A large wound can become 40 to 80% smaller after contraction.. Wounds can contract at a speed of up to 0.75 mm per day, depending on how loose the tissue in the wounded area is. Contraction usually does not occur symmetrically; rather most wounds have an 'axis of contraction' which allows for greater organization and alignment of cells with collagen.
At first, contraction occurs without myofibroblast involvement. Later, fibroblasts, stimulated by growth factors, differentiate into myofibroblasts. Myofibroblasts, which are similar to smooth muscle cells, are responsible for contraction. Myofibroblasts contain the same kind of actin as that found in smooth muscle cells.
Myofibroblasts are attracted by fibronectin and growth factors and they move along fibronectin linked to fibrin in the provisional ECM in order to reach the wound edges. They form connections to the ECM at the wound edges, and they attach to each other and to the wound edges by desmosomes. Also, at an adhesion called the fibronexus, actin in the myofibroblast is linked across the cell membrane to molecules in the extracellular matrix like fibronectin and collagen. Myofibroblasts have many such adhesions, which allow them to pull the ECM when they contract, reducing the wound size. In this part of contraction, closure occurs more quickly than in the first, myofibroblast-independent part.
As the actin in myofibroblasts contracts, the wound edges are pulled together. Fibroblasts lay down collagen to reinforce the wound as myofibroblasts contract The contraction stage in proliferation ends as myofibroblasts stop contracting and commit apoptosis. The breakdown of the provisional matrix leads to a decrease in hyaluronic acid and an increase in chondroitin sulfate, which gradually triggers fibroblasts to stop migrating and proliferating. These events signal the onset of the maturation stage of wound healing.
# Maturation and remodeling phase
When the levels of collagen production and degradation equalize, the maturation phase of tissue repair is said to have begun. The maturation phase can last for a year or longer, depending on the size of the wound and whether it was initially closed or left open. During Maturation, type III collagen, which is prevalent during proliferation, is gradually degraded and the stronger type I collagen is laid down in its place. Originally disorganized collagen fibers are rearranged, cross-linked, and aligned along tension lines. As the phase progresses, the tensile strength of the wound increases, with the strength approaching 50% that of normal tissue by three months after injury and ultimately becoming as much as 80% as strong as normal tissue. Since activity at the wound site is reduced, the scar loses its erythematous appearance as blood vessels that are no longer needed are removed by apoptosis.
The phases of wound healing normally progress in a predictable, timely manner; if they do not, healing may progress inappropriately to either a chronic wound such as a venous ulcer or pathological scarring such as a keloid scar.
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Wound healing
Editor-in-Chief: Michael D. Caldwell, M.D., Ph.D., FACS, Marshfield Clinic, Department of Surgery [1]
# Overview
Wound healing, or wound repair, is the body's natural process of regenerating dermal and epidermal tissue. When an individual is wounded, a set of events takes place in a predictable fashion to repair the damage. These events overlap in time[1][2] and must be artificially categorized into separate steps: the inflammatory, proliferative, and remodeling phases (Some authors consider healing to take place in four stages, by splitting different parts inflammation or proliferation into separate steps.).[3][2]
In the inflammatory phase, bacteria and debris are phagocytized and removed and factors are released that cause the migration and division of cells involved in the proliferative phase.
The proliferative phase is characterized by angiogenesis, collagen deposition, granulation tissue formation, epithelialization, and wound contraction.[4] In angiogenesis, new blood vessels grow from endothelial cells.[5]
In fibroplasia and granulation tissue formation, fibroblasts grow and form a new, provisional extracellular matrix (ECM) by excreting collagen and fibronectin.[4]
In epithelialization, epithelial cells crawl across the wound bed to cover it.[6] In contraction, the wound is made smaller by the action of myofibroblasts, which establish a grip on the wound edges and contract themselves using a mechanism similar to that in smooth muscle cells. When the cells' roles are close to complete, unneeded cells undergo apoptosis.[4]
In the maturation and remodeling phase, collagen is remodeled and realigned along tension lines and cells that are no longer needed are removed by apoptosis.
# Inflammatory phase
In the inflammatory phase (lag phase/resting phase), clotting takes place in order to obtain hemostasis, or stop blood loss, and various factors are released to attract cells that phagocytise debris, bacteria, and damaged tissue and release factors that initiate the proliferative phase of wound healing.
## Clotting cascade
When tissue is first wounded, blood comes in contact with collagen, triggering blood platelets to begin secreting inflammatory factors.[7] Platelets also express glycoproteins on their cell membranes that allow them to stick to one another and to aggregate, forming a mass.[4]
Fibrin and fibronectin cross-link together and form a plug that traps proteins and particles and prevents further blood loss.[8] This fibrin-fibronectin plug is also the main structural support for the wound until collagen is deposited.[4] Migratory cells use this plug as a matrix to crawl across, and platelets adhere to it and secrete factors.[4] The clot is eventually lysed and replaced with granulation tissue and then later with collagen.
## Platelets
Platelets, the cells present in the highest numbers shortly after a wound occurs, release a number of things into the blood, including ECM proteins and cytokines, including growth factors.[7] Growth factors stimulate cells to speed their rate of division. Platelets also release other proinflammatory factors like serotonin, bradykinin, prostaglandins, prostacyclins, thromboxane, and histamine[1], which serve a number of purposes, including to increase cell proliferation and migration to the area and to cause blood vessels to become dilated and porous.
## Vasoconstriction and vasodilation
Immediately after a blood vessel is breached, ruptured cell membranes release inflammatory factors like thromboxanes and prostaglandins that cause the vessel to spasm to prevent blood loss and to collect inflammatory cells and factors in the area.[1] This vasoconstriction lasts five to ten minutes and is followed by vasodilation, a widening of blood vessels, which peaks at about 20 minutes post-wounding.[1] Vasodilation is the result of factors released by platelets and other cells. The main factor involved in causing vasodilation is histamine.[1][7] Histamine also causes blood vessels to become porous, allowing the tissue to become edematous because proteins from the bloodstream leak into the extravascular space, which increases its osmolar load and draws water into the area.[1] Increased porousness of blood vessels also facilitates the entry of inflammatory cells like leukocytes into the wound site from the bloodstream.[9][10]
## Polymorphonuclear neutrophils
Within an hour of wounding, polymorphonuclear neutrophils (PMNs) arrive at the wound site and become the predominant cells in the wound for the first three days after the injury occurs, with especially high numbers on the second day.[11] They are attracted to the site by fibronectin, growth factors, and substances such as neuropeptides and kinins. Neutrophils phagocytise debris and bacteria and also kill bacteria by releasing free radicals in what is called a 'respiratory burst'.[12][13] They also cleanse the wound by secreting proteases that break down damaged tissue. Neutrophils usually undergo apoptosis once they have completed their tasks and are engulfed and degraded by macrophages.[14]
Other leukocytes to enter the area include helper T cells, which secrete cytokines to cause more T cells to divide and to increase inflammation and enhance vasodilation and vessel permeability.[9][15] T cells also increase the activity of macrophages.[9]
## Macrophages
Macrophages are essential to wound healing.[11] They replace PMNs as the predominant cells in the wound by two days after injury.[16] Attracted to the wound site by growth factors released by platelets and other cells, monocytes from the bloodstream enter the area through blood vessel walls.[17] Numbers of monocytes in the wound peak one to one and a half days after the injury occurs.[15] Once they are in the wound site, monocytes mature into macrophages, the main cell type that clears the wound area of bacteria and debris.[11]
The macrophage's main role is to phagocytise bacteria and damaged tissue, and it also debrides damaged tissue by releasing proteases.[18] Macrophages also secrete a number of factors such as growth factors and other cytokines, especially during the third and fourth post-wounding days. These factors attract cells involved in the proliferation stage of healing to the area.[7] Macrophages are stimulated by the low oxygen content of their surroundings to produce factors that induce and speed angiogenesis.[12] and they also stimulate cells that reepithelialize the wound, create granulation tissue, and lay down a new extracellular matrix.[19][20] Because they secrete these factors, macrophages are vital for pushing the wound healing process into the next phase.
Because inflammation plays roles in fighting infection and inducing the proliferation phase, it is a necessary part of healing. However, inflammation can lead to tissue damage if it lasts too long.[4] Thus the reduction of inflammation is frequently a goal in therapeutic settings. Inflammation lasts as long as there is debris in the wound. Thus the presence of dirt or other objects can extend the inflammatory phase for too long, leading to a chronic wound.
As inflammation dies down, fewer inflammatory factors are secreted, existing ones are broken down, and numbers of neutrophils and macrophages are reduced at the wound site.[11] These changes indicate that the inflammatory phase is ending and the proliferative phase is underway.[11]
# Proliferative phase
About two or three days after the wound occurs, fibroblasts begin to enter the wound site, marking the onset of the proliferative phase even before the inflammatory phase has ended.[21] As in the other phases of wound healing, steps in the proliferative phase do not occur in a series but rather partially overlap in time.
## Angiogenesis
Also called neovascularization, the process of angiogenesis occurs concurrently with fibroblast proliferation when endothelial cells migrate to the area of the wound.[22] Because the activity of fibroblasts and epithelial cells requires oxygen, angiogenesis is imperative for other stages in wound healing, like epidermal and fibroblast migration. The tissue in which angiogenesis has occurred typically looks red (is erythematous) due to the presence of capillaries.[22]
In order to form new blood vessels and provide oxygen and nutrients to the healing tissue.[23] stem cells called endothelial cells originating from parts of uninjured blood vessels develop pseudopodia and push through the ECM into the wound site. Through this activity, they establish new blood vessels.[12]
To migrate, endothelial cells need collagenases and plasminogen activator to degrade the clot and part of the ECM.[1][11] Zinc-dependent metalloproteinases digest basement membrane and ECM to allow cell proliferation and angiogenesis.[24]
Endothelial cells are also attracted to the wound area by fibronectin found on the fibrin scab and by growth factors released by other cells.[23] Endothelial growth and proliferation is also stimulated by hypoxia and presence of lactic acid in the wound.[21] In a low-oxygen environment, macrophages and platelets produce angiogenic factors which attract endothelial cells chemotactically. When macrophages and other growth factor-producing cells are no longer in a hypoxic, lactic acid-filled environment, they stop producing angiogenic factors.[12] Thus, when tissue is adequately perfused, migration and proliferation of endothelial cells is reduced. Eventually blood vessels that are no longer needed die by apoptosis.[23]
## Fibroplasia and granulation tissue formation
Simultaneously with angiogenesis, fibroblasts begin accumulating in the wound site. Fibroblasts begin entering the wound site two to five days after wounding as the inflammatory phase is ending, and their numbers peak at one to two weeks post-wounding.[11] By the end of the first week, fibroblasts are the main cells in the wound[1] Fibroplasia ends two to four weeks after wounding.
In the first two or three days after injury, fibroblasts mainly proliferate and migrate, while later, they are the main cells that lay down the collagen matrix in the wound site.[1] Fibroblasts from normal tissue migrate into the wound area from its margins. Initially fibroblasts use the fibrin scab formed in the inflammatory phase to migrate across, adhering to fibronectin.[23] Fibroblasts then deposit ground substance into the wound bed, and later collagen, which they can adhere to for migration.[7]
Granulation tissue is needed to fill the void that has been left by a large, open wound that crosses the basement membrane. It begins to appear in the wound even during the inflammatory phase, two to five days post wounding, and continues growing until the wound bed is covered. Granulation tissue consists of new blood vessels, fibroblasts, inflammatory cells, endothelial cells, myofibroblasts, and the components of a new, provisional ECM. The provisional ECM is different in composition from the ECM in normal tissue and includes fibronectin, collagen, glycosaminoglycans, and proteoglycans.[23] Its main components are fibronectin and hyaluronan, which create a very hydrated matrix and facilitate cell migration.[17] Later this provisional matrix is replaced with an ECM that more closely resembles that found in non-injured tissue.
Fibroblasts deposit ECM molecules like glycoproteins, glycosaminoglycans (GAGs), proteoglycans, elastin, and fibronectin, which they can then use to migrate across the wound (Cohen, 2005).
Growth factors (PDGF, TGF-β) and fibronectin encourage proliferation, migration to the wound bed, and production of ECM molecules by fibroblasts. Fibroblasts also secrete growth factors that attract epithelial cells to the wound site. Hypoxia also contributes to fibroblast proliferation and excretion of growth factors, though too little oxygen will inhibit their growth and deposition of ECM components, and can lead to excessive, fibrotic scarring.
### Collagen deposition
One of fibroblasts' most important duties is the production of collagen.[22] Fibroblasts begin secreting appreciable collagen by the second or third post-wounding day,[23] and its deposition peaks at one to three weeks.[19] Collagen production continues rapidly for two to four weeks, after which its destruction matches its production and so its growth levels off.[12]
Collagen deposition is important because it increases the strength of the wound; before it is laid down, the only thing holding the wound closed is the fibrin-fibronectin clot, which does not provide much resistance to traumatic injury.[12] Also, cells involved in inflammation, angiogenesis, and connective tissue construction attach to, grow and differentiate on the collagen matrix laid down by fibroblasts.[25]
Even as fibroblasts are producing new collagen, collagenases and other factors degrade it. Shortly after wounding, synthesis exceeds degradation so collagen levels in the wound rise, but later production and degradation become equal so there is no net collagen gain. This homeostasis signals the onset of the maturation phase. Granulation gradually ceases and fibroblasts decrease in number in the wound once their work is done.[26] At the end of the granulation phase, fibroblasts begin to commit apoptosis, converting granulation tissue from an environment rich in cells to one that consists mainly of collagen.[1]
## Epithelialization
The formation of granulation tissue in an open wound allows the reepithelialization phase to take place, as epithelial cells migrate across the new tissue to form a barrier between the wound and the environment.[23] Basal keratinocytes from the wound edges and dermal appendages such as hair follicles, sweat glands and sebacious (oil) glands are the main cells responsible for the epithelialization phase of wound healing.[26] They advance in a sheet across the wound site and proliferate at its edges, ceasing movement when they meet in the middle.
Keratinocytes migrate without first proliferating.[27]. Migration can begin as early as a few hours after wounding. However, epithelial cells require viable tissue to migrate across, so if the wound is deep it must first be filled with granulation tissue.[28] Thus the time of onset of migration is variable and may occur about one day after wounding.[29] Cells on the wound margins proliferate on the second and third day post-wounding in order to provide more cells for migration.[19]
If the basement membrane is not breached, epithelial cells are replaced within three days by division and upward migration of cells in the stratum basale in the same fashion that occurs in uninjured skin.[23] However, if the basement membrane is ruined at the wound site, reepithelization must occur from the wound margins and from skin appendages such as hair follicles and sweat and oil glands that enter the dermis that are lined with viable keratinocytes.[19] If the wound is very deep, skin appendages may also be ruined and migration can only occur from wound edges.[28]
Migration of keratinocytes over the wound site is stimulated by lack of contact inhibition and by chemicals such as nitric oxide.[30] Before they begin to migrate, cells must dissolve their desmosomes and hemidesmosomes, which normally anchor the cells by intermediate filaments in their cytoskeleton to other cells and to the ECM.[15] Transmembrane receptor proteins called integrins, which are made of glycoproteins and normally anchor the cell to the basement membrane by its cytoskeleton, are released from the cell's intermediate filaments and relocate to actin filaments to serve as attachments to the ECM for pseudopodia during migration.[15] Thus keratinocytes detach from the basement membrane and are able to enter the wound bed.[21]
Before they begin migrating, keratinocytes change shape, becoming longer and flatter and extending cellular processes like lamellipodia and wide processes that look like ruffles.[17] Actin filaments and pseudopodia form.[21] During migration, integrins on the pseudopod attach to the ECM, and the actin filaments in the projection pull the cell along.[15] The interaction with molecules in the ECM through integrins further promotes the formation of actin filaments, lamellipodia, and filopodia.[15]
Epithelial cells climb over one another in order to migrate.[26] This growing sheet of epithelial cells is often called the epithelial tongue.[27] The first cells to attach to the basement membrane form the stratum basale. These basal cells continue to migrate across the wound bed, and epithelial cells above them slide along as well.[27] The more quickly this migration occurs, the less of a scar there will be.[31]
Fibrin, collagen, and fibronectin in the ECM may further signal cells to divide and migrate Like fibroblasts, migrating keratinocytes use the fibronectin cross-linked with fibrin that was deposited in inflammation as an attachment site to crawl across.[17][18][26]
As keratinocytes migrate, they move over granulation tissue but underneath the scab (if one was formed), separating it from the underlying tissue.[26][29] Epithelial cells have the ability to phagocytize debris such as dead tissue and bacterial matter that would otherwise obstruct their path. Because they must dissolve any scab that forms, keratinocyte migration is best enhanced by a moist environment, since a dry one leads to formation of a bigger, tougher scab.[18][23][26][32] To make their way along the tissue, keratinocytes must dissolve the clot, debris, and parts of the ECM in order to get through.[29][33] They secrete plasminogen activator, which activates plasmin to dissolve the scab. Cells can only migrate over living tissue,[26] so they must excrete collagenases and proteases like matrix metalloproteinases (MMPs) to dissolve damaged parts of the ECM in their way, particularly at the front of the migrating sheet.[29] Keratinocytes also dissolve the basement membrane, using instead the new ECM laid down by fibroblasts to crawl across.[15]
As keratinocytes continue migrating, new epithelial cells must be formed at the wound edges to replace them and to provide more cells for the advancing sheet.[18] Proliferation behind migrating keratinocytes normally begins a few days after wounding[28] and occurs at a rate that is 17 times higher in this stage of epithelialization than in normal tissues.[18] Until the entire wound area is resurfaced, the only epithelial cells to proliferate are at the wound edges.[27]
Growth factors, stimulated by integrins and MMPs, cause cells to proliferate at the wound edges. Keratinocytes themselves also produce and secrete factors, including growth factors and basement membrane proteins, which aid both in epithelialization and in other phases of healing.[34]
Keratinocytes continue migrating across the wound bed until cells from either side meet in the middle, at which point contact inhibition causes them to stop migrating.[17] When they have finished migrating, the keratinocytes secrete the proteins that form the new basement membrane.[17] Cells reverse the morphological changes they underwent in order to begin migrating; they reestablish desmosomes and hemidesmosomes and become anchored once again to the basement membrane.[15] Basal cells begin to divide and differentiate in the same manner as they do in normal skin to reestablish the strata found in reepithelialized skin.[17]
## Contraction
Around a week after the wounding takes place, fibroblasts have differentiated into myofibroblasts and the wound begins to contract[35] In full thickness wounds, contraction peaks at 5 to 15 days post wounding.[23] Contraction can last for several weeks[28] and continues even after the wound is completely reepithelialized.[1] If contraction continues for too long, it can lead to disfigurement and loss of function.[36]
Contraction occurs in order to reduce the size of the wound. A large wound can become 40 to 80% smaller after contraction.[17][26]. Wounds can contract at a speed of up to 0.75 mm per day, depending on how loose the tissue in the wounded area is.[23] Contraction usually does not occur symmetrically; rather most wounds have an 'axis of contraction' which allows for greater organization and alignment of cells with collagen.[35]
At first, contraction occurs without myofibroblast involvement.[37] Later, fibroblasts, stimulated by growth factors, differentiate into myofibroblasts. Myofibroblasts, which are similar to smooth muscle cells, are responsible for contraction.[37] Myofibroblasts contain the same kind of actin as that found in smooth muscle cells.[36]
Myofibroblasts are attracted by fibronectin and growth factors and they move along fibronectin linked to fibrin in the provisional ECM in order to reach the wound edges.[18] They form connections to the ECM at the wound edges, and they attach to each other and to the wound edges by desmosomes. Also, at an adhesion called the fibronexus, actin in the myofibroblast is linked across the cell membrane to molecules in the extracellular matrix like fibronectin and collagen.[37] Myofibroblasts have many such adhesions, which allow them to pull the ECM when they contract, reducing the wound size.[36] In this part of contraction, closure occurs more quickly than in the first, myofibroblast-independent part.[37]
As the actin in myofibroblasts contracts, the wound edges are pulled together. Fibroblasts lay down collagen to reinforce the wound as myofibroblasts contract[1] The contraction stage in proliferation ends as myofibroblasts stop contracting and commit apoptosis.[36] The breakdown of the provisional matrix leads to a decrease in hyaluronic acid and an increase in chondroitin sulfate, which gradually triggers fibroblasts to stop migrating and proliferating.[11] These events signal the onset of the maturation stage of wound healing.
# Maturation and remodeling phase
When the levels of collagen production and degradation equalize, the maturation phase of tissue repair is said to have begun.[12] The maturation phase can last for a year or longer, depending on the size of the wound and whether it was initially closed or left open.[19] During Maturation, type III collagen, which is prevalent during proliferation, is gradually degraded and the stronger type I collagen is laid down in its place.[9] Originally disorganized collagen fibers are rearranged, cross-linked, and aligned along tension lines.[17] As the phase progresses, the tensile strength of the wound increases, with the strength approaching 50% that of normal tissue by three months after injury and ultimately becoming as much as 80% as strong as normal tissue.[19] Since activity at the wound site is reduced, the scar loses its erythematous appearance as blood vessels that are no longer needed are removed by apoptosis.[12]
The phases of wound healing normally progress in a predictable, timely manner; if they do not, healing may progress inappropriately to either a chronic wound [4] such as a venous ulcer or pathological scarring such as a keloid scar.[38][39]
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https://www.wikidoc.org/index.php/Wound_healing
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Wouter Basson
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Wouter Basson
Wouter Basson (b. July 6, 1950) is a South African cardiologist and former head of the country's secret chemical and biological warfare project, Project Coast, during the Apartheid era.
# Project Coast
Much of what Basson was working on is still secret. It is known that in 1981, when he was working as a personal physician to prime minister Pieter Willem Botha, the country's Surgeon General hired Basson to work for the 7th SAMHS Medical Battalion, the medical military unit of the South African Defence Force. His job was to collect information about other countries' chemical and biological warfare capabilities under the name Project Coast.
After his preliminary report, Basson became the head project officer and began to work on the country's chemical and biological weapons capability. He recruited about 200 researchers from around the world and received annual funds equivalent to $10 million.
Project Coast secretly researched chemical and biological warfare in violation of the international BTWC agreement. Basson created four front companies; Delta G Scientific Company; Roodeplaat Research Laboratories (RRL), Protechnik and Infadel, which in 1989 was split into two companies - D. John Truter Financial Consultants and Sefmed Information Services. The companies were used to officially distance the military from the project, to procure necessary chemicals and channel funds for the research. According to later investigation, Basson had a free rein to do what he wanted.
Delta G did most of the research, production and development of the chemical agents, while RRL developed chemical and biological pathogens and allegedly was involved with genetic engineering. Protechnik was a large nuclear, biological and chemical warfare plant developing defences against chemical weapons. Infadel dealt with those on a smaller scale and concentrated on financing and administration of other units and possibly channelling funds between military and research facilities. Many of the employees were not aware of what they were involved with.
In the 1980s Basson and the project were allegedly involved with attacks and assassinations against the members of anti-apartheid movements. African leaders in South Africa, Angola and Namibia also claimed that the more dangerous chemicals were used for crowd control in the country, although the government claimed otherwise and claimed that chemical weapons were used against South African troops. Basson provided the Civil Cooperation Bureau (CCB) with lethal chemicals to be used against prominent anti-apartheid activists.
Basson continued to travel all over world to gather information about chemical and biological warfare programs and set up other shell and paper companies as additional front companies, possibly for money laundering.
When F. W. de Klerk became president in 1990, he ordered the production of the chemicals to be stopped and the lethal agents destroyed. Basson concentrated on non-lethal chemical agents and chemicals the government had not banned. That included a large amount of ecstasy and Mandrax that were apparently exported or allegedly sold to the drug dealers in communities active in the anti-apartheid movement (see Basson brownies). Most of the stockpile disappeared afterwards. Scientists working on the project later stated that they believed it was to be used to create drug-laced tear gas.
In January 1992, Mozambique reported that a South African helicopter had attacked their soldiers by releasing an unknown lethal substance that led to four fatalities. Investigation by the United Nations, U.S. and the United Kingdom identified it as BZ nerve agent. USA and Britain began to pressure the South African government and in January 1993 Project Coast was decelerated. Basson was officially retired and hired to dismantle the project, and allegedly profited when some of the South African front companies were privatised. Later government investigation found that there were large amounts of chemicals and agents missing.
# End of career in military research
In 1993 the Office of Serious Economic Offences (OSEO) began to investigate Basson's business dealings in a seven year forensic audit.
In 1995 the South African government hired Basson to work for Transnet, a transportation and infrastructure company and possibly for other more secretive jobs. The USA and UK governments suspected that during his visits to Libya between 1993-1995, Basson might have sold chemical and biological weapons secrets.
In 1995, the government of Nelson Mandela rehired Basson as an army surgeon, allegedly due to USA and UK pressure and possibly because the government wanted to keep eye on him.
In 1996, South Africa's Truth and Reconciliation Commission (TRC) began to investigate the SADF and determined that the army had probably used lethal toxins against ANC activists. Basson was connected to many of these attacks. In 1997, the CIA told the South African government that Basson intended to leave the country. When Basson was arrested in a sting operation in Pretoria, he had a large quantity of ecstasy pills and various documents with him.
TRC began to investigate Project Coast. Investigation led to suspicion that Basson had sold his secrets to governments of countries like Libya and Iraq. In 1997 they asked the help of the Netherlands Institute for Southern Africa (NIZA). NIZA's investigation report was included in the Truth Commission Files.
At the same time, the Office for Serious Economic Offences, The National Intelligence Agency (NIA) and the Gauteng Attorney-General's Special Investigation Team investigated Basson's affairs. Conflict of interest slowed down the Commission investigation but the TRC gained more information from OSEO.
Basson appeared before the Commission on July 31 1998 and gave evidence for 12 hours. Basson's lawyers constantly interrupted the questioning with legal technicalities. The Commission was, however, able to determine that Basson had been the primary decision maker in the Project Coast.
# Trial
Basson's trial began on October 4 1999 in Pretoria. At the time, the South African media had dubbed him "Doctor Death". Basson faced 67 charges, including drug possession, drug trafficking, fraud and embezzlement of a total of R36,000,000, 229 murders and conspiracy to murder and theft. Basson refused to seek amnesty from the Truth Commission.
The prosecution presented 153 witnesses, but the case soon began to turn against them. On October 11, 1999 Judge Willie Hartzenberg dismissed 6 important charges, including four charges of murder and possible involvement in 200 deaths in Namibia, because he stated that the South African court could not prosecute crimes committed in other countries. Basson was also included in the Namibian amnesty of 1989. Hartzenberg then adjourned the trial for two weeks. After 18 months of trial, he reduced the number of charges to 46.
In July 2001 Basson began to present his own evidence, being the only witness in his own behalf, speaking for 40 days. He stated that he had learned about the weapons of mass destruction from Saddam Hussein, that he had indeed had free rein in the project and that he had exchanged information with foreign governments. However, technically all that was legal. The defence argued that Basson should have immunity for anything that had happened in Namibia.
On April 22 2002 Judge Hartzenberg dismissed all the remaining charges against Basson and granted him amnesty. The trial had lasted 30 months. The state threatened to appeal the judgment due to legal inaccuracies, but the Supreme Court of Appeal refused to order a retrial in 2003.
After his release, Basson has continued to travel all over the world as a guest speaker, and has founded his own private medical practice. In June 2005, a group of Swiss investigators questioned him about illegal trade in weapons and nuclear material and asked the South African government to stop cooperating with them.
Later that year the Constitutional Court, South Africa's highest court, overturned the judgement of the Supreme Court of Appeal. It ruled that crimes allegedly committed outside the country could be prosecuted in South Africa. Since then the National Prosecuting Authority has not instituted proceedings against Basson for crimes against humanity.
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Wouter Basson
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Wouter Basson (b. July 6, 1950) is a South African cardiologist and former head of the country's secret chemical and biological warfare project, Project Coast, during the Apartheid era.
# Project Coast
Much of what Basson was working on is still secret. It is known that in 1981, when he was working as a personal physician to prime minister Pieter Willem Botha, the country's Surgeon General hired Basson to work for the 7th SAMHS Medical Battalion, the medical military unit of the South African Defence Force. His job was to collect information about other countries' chemical and biological warfare capabilities under the name Project Coast.
After his preliminary report, Basson became the head project officer and began to work on the country's chemical and biological weapons capability. He recruited about 200 researchers from around the world and received annual funds equivalent to $10 million.
Project Coast secretly researched chemical and biological warfare in violation of the international BTWC agreement. Basson created four front companies; Delta G Scientific Company; Roodeplaat Research Laboratories (RRL), Protechnik and Infadel, which in 1989 was split into two companies - D. John Truter Financial Consultants and Sefmed Information Services. The companies were used to officially distance the military from the project, to procure necessary chemicals and channel funds for the research. According to later investigation, Basson had a free rein to do what he wanted.
Delta G did most of the research, production and development of the chemical agents, while RRL developed chemical and biological pathogens and allegedly was involved with genetic engineering. Protechnik was a large nuclear, biological and chemical warfare plant developing defences against chemical weapons. Infadel dealt with those on a smaller scale and concentrated on financing and administration of other units and possibly channelling funds between military and research facilities. Many of the employees were not aware of what they were involved with.
In the 1980s Basson and the project were allegedly involved with attacks and assassinations against the members of anti-apartheid movements. African leaders in South Africa, Angola and Namibia also claimed that the more dangerous chemicals were used for crowd control in the country, although the government claimed otherwise and claimed that chemical weapons were used against South African troops. Basson provided the Civil Cooperation Bureau (CCB) with lethal chemicals to be used against prominent anti-apartheid activists.
Basson continued to travel all over world to gather information about chemical and biological warfare programs and set up other shell and paper companies as additional front companies, possibly for money laundering.
When F. W. de Klerk became president in 1990, he ordered the production of the chemicals to be stopped and the lethal agents destroyed. Basson concentrated on non-lethal chemical agents and chemicals the government had not banned. That included a large amount of ecstasy and Mandrax that were apparently exported or allegedly sold to the drug dealers in communities active in the anti-apartheid movement (see Basson brownies). Most of the stockpile disappeared afterwards. Scientists working on the project later stated that they believed it was to be used to create drug-laced tear gas.
In January 1992, Mozambique reported that a South African helicopter had attacked their soldiers by releasing an unknown lethal substance that led to four fatalities. Investigation by the United Nations, U.S. and the United Kingdom identified it as BZ nerve agent. USA and Britain began to pressure the South African government and in January 1993 Project Coast was decelerated. Basson was officially retired and hired to dismantle the project, and allegedly profited when some of the South African front companies were privatised. Later government investigation found that there were large amounts of chemicals and agents missing.
# End of career in military research
In 1993 the Office of Serious Economic Offences (OSEO) began to investigate Basson's business dealings in a seven year forensic audit.
In 1995 the South African government hired Basson to work for Transnet, a transportation and infrastructure company and possibly for other more secretive jobs. The USA and UK governments suspected that during his visits to Libya between 1993-1995, Basson might have sold chemical and biological weapons secrets.
In 1995, the government of Nelson Mandela rehired Basson as an army surgeon, allegedly due to USA and UK pressure and possibly because the government wanted to keep eye on him.
In 1996, South Africa's Truth and Reconciliation Commission (TRC) began to investigate the SADF and determined that the army had probably used lethal toxins against ANC activists. Basson was connected to many of these attacks. In 1997, the CIA told the South African government that Basson intended to leave the country. When Basson was arrested in a sting operation in Pretoria, he had a large quantity of ecstasy pills and various documents with him.
TRC began to investigate Project Coast. Investigation led to suspicion that Basson had sold his secrets to governments of countries like Libya and Iraq. In 1997 they asked the help of the Netherlands Institute for Southern Africa (NIZA). NIZA's investigation report was included in the Truth Commission Files.
At the same time, the Office for Serious Economic Offences, The National Intelligence Agency (NIA) and the Gauteng Attorney-General's Special Investigation Team investigated Basson's affairs. Conflict of interest slowed down the Commission investigation but the TRC gained more information from OSEO.
Basson appeared before the Commission on July 31 1998 and gave evidence for 12 hours. Basson's lawyers constantly interrupted the questioning with legal technicalities. The Commission was, however, able to determine that Basson had been the primary decision maker in the Project Coast.
# Trial
Basson's trial began on October 4 1999 in Pretoria. At the time, the South African media had dubbed him "Doctor Death". Basson faced 67 charges, including drug possession, drug trafficking, fraud and embezzlement of a total of R36,000,000, 229 murders and conspiracy to murder and theft. Basson refused to seek amnesty from the Truth Commission.
The prosecution presented 153 witnesses, but the case soon began to turn against them. On October 11, 1999 Judge Willie Hartzenberg dismissed 6 important charges, including four charges of murder and possible involvement in 200 deaths in Namibia, because he stated that the South African court could not prosecute crimes committed in other countries. Basson was also included in the Namibian amnesty of 1989. Hartzenberg then adjourned the trial for two weeks. After 18 months of trial, he reduced the number of charges to 46.
In July 2001 Basson began to present his own evidence, being the only witness in his own behalf, speaking for 40 days. He stated that he had learned about the weapons of mass destruction from Saddam Hussein, that he had indeed had free rein in the project and that he had exchanged information with foreign governments. However, technically all that was legal. The defence argued that Basson should have immunity for anything that had happened in Namibia.
On April 22 2002 Judge Hartzenberg dismissed all the remaining charges against Basson and granted him amnesty. The trial had lasted 30 months. The state threatened to appeal the judgment due to legal inaccuracies, but the Supreme Court of Appeal refused to order a retrial in 2003.
After his release, Basson has continued to travel all over the world as a guest speaker, and has founded his own private medical practice. In June 2005, a group of Swiss investigators questioned him about illegal trade in weapons and nuclear material and asked the South African government to stop cooperating with them.
Later that year the Constitutional Court, South Africa's highest court, overturned the judgement of the Supreme Court of Appeal. It ruled that crimes allegedly committed outside the country could be prosecuted in South Africa[2]. Since then the National Prosecuting Authority has not instituted proceedings against Basson for crimes against humanity.
# External links
- CrimeLibary article about Wouter Basson
- Retrial for Dr. Death
Template:WikiDoc Sources
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https://www.wikidoc.org/index.php/Wouter_Basson
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7eda3ba1948b8d645418f5ba2cc237488d180327
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wikidoc
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Xerophthalmia
|
Xerophthalmia
# Overview
Xerophthalmia (Greek for dry eyes) is a medical condition in which the eye fails to produce tears. It may be caused by a deficiency in vitamin A and is sometimes used to describe that lack, although there may be other causes.
# Pathophysiology
Xerophthalmia results from inadequate function of the lacrimal glands which produce tears.
# Epidemiology and Demographics
Xerophthalmia is a term that usually implies a destructive dryness of the conjunctival epithelium due to dietary vitamin A deficiency — a rare condition in developed countries, but still causing much damage in developing countries.
# Causes
Xerophthalmia can be associated with systemic diseases such as Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, scleroderma, sarcoidosis, amyloidosis, and hypothyroidism; deficiency of vitamin A; and the use of some medications including antihistamines, nasal decongestants, tranquilizers, and anti-depressant drugs. When xerophthalmia is due to vitamin A deficiency, the condition begins with night blindness and conjunctival xerosis (dryness of the eye membranes) and progresses to corneal xerosis (dryness of the cornea), and, in the late stages, to keratomalacia (softening of the cornea). Other forms of dry eye are associated with aging, poor lid closure, scarring from previous injury, or autoimmune diseases such as rheumatoid arthritis, and these can all cause chronic conjunctivitis.
# Treatment
The treatment depends on the cause. Artificial tears, which lubricate the eye, are the principal symptomatic treatment for dry eye. They are available over-the-counter as eye drops. Using humidifiers, wearing wrap-around glasses when outside, and avoiding outside windy and dry conditions may bring relief. For people with severe cases of dry eye, temporary or permanent closure of the tear drain (small openings at the inner corner of the eyelids where tears drain from the eye) may be helpful. Also known as conjunctivitis arida.
|
Xerophthalmia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Xerophthalmia (Greek for dry eyes) is a medical condition in which the eye fails to produce tears. It may be caused by a deficiency in vitamin A and is sometimes used to describe that lack, although there may be other causes.
# Pathophysiology
Xerophthalmia results from inadequate function of the lacrimal glands which produce tears.
# Epidemiology and Demographics
Xerophthalmia is a term that usually implies a destructive dryness of the conjunctival epithelium due to dietary vitamin A deficiency — a rare condition in developed countries, but still causing much damage in developing countries.
# Causes
Xerophthalmia can be associated with systemic diseases such as Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, scleroderma, sarcoidosis, amyloidosis, and hypothyroidism; deficiency of vitamin A; and the use of some medications including antihistamines, nasal decongestants, tranquilizers, and anti-depressant drugs. When xerophthalmia is due to vitamin A deficiency, the condition begins with night blindness and conjunctival xerosis (dryness of the eye membranes) and progresses to corneal xerosis (dryness of the cornea), and, in the late stages, to keratomalacia (softening of the cornea). Other forms of dry eye are associated with aging, poor lid closure, scarring from previous injury, or autoimmune diseases such as rheumatoid arthritis, and these can all cause chronic conjunctivitis.
# Treatment
The treatment depends on the cause. Artificial tears, which lubricate the eye, are the principal symptomatic treatment for dry eye. They are available over-the-counter as eye drops. Using humidifiers, wearing wrap-around glasses when outside, and avoiding outside windy and dry conditions may bring relief. For people with severe cases of dry eye, temporary or permanent closure of the tear drain (small openings at the inner corner of the eyelids where tears drain from the eye) may be helpful. Also known as conjunctivitis arida.
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https://www.wikidoc.org/index.php/Xerophthalmia
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95c02e8b4d5b6488f866d64dad3cd9c5c9684499
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wikidoc
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Yaws
|
Yaws overview
# Overview
Yaws is a tropical infection of the skin, bones and joints caused by the spirochete bacterium Treponema pertenue. Other treponematosis diseases are bejel (Treponema endemicum), pinta (Treponema carateum), syphilis (Treponema pallidum), and Lyme Disease (Borrelia burgdorferi).
# Causes
Yaws is an infection caused by the spiral-shaped bacteria, Treponema pallidum, subspecies pertenue. It is closely related to the bacterium that causes syphilis, but this disease is not sexually transmitted.
# Diagnosis
## Laboratory Findings
A sample from a skin sore is examined under a special type of microscope called darkfield examination. There is no blood test for yaws. However, the blood test for syphilis is usually positive in people with yaws because the bacteria that cause these two conditions are closely related.
# Treatment
## Medical Therapy
Treatment involves a single dose of one type of penicillin, or 3 weekly doses for later stage disease. It is rare for the disease to return. Anyone who lives in the same house with someone who is infected should be examined for yaws and treated if they are infected.
|
Yaws overview
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Yaws is a tropical infection of the skin, bones and joints caused by the spirochete bacterium Treponema pertenue. Other treponematosis diseases are bejel (Treponema endemicum), pinta (Treponema carateum), syphilis (Treponema pallidum), and Lyme Disease (Borrelia burgdorferi).
# Causes
Yaws is an infection caused by the spiral-shaped bacteria, Treponema pallidum, subspecies pertenue. It is closely related to the bacterium that causes syphilis, but this disease is not sexually transmitted.
# Diagnosis
## Laboratory Findings
A sample from a skin sore is examined under a special type of microscope called darkfield examination. There is no blood test for yaws. However, the blood test for syphilis is usually positive in people with yaws because the bacteria that cause these two conditions are closely related.
# Treatment
## Medical Therapy
Treatment involves a single dose of one type of penicillin, or 3 weekly doses for later stage disease. It is rare for the disease to return. Anyone who lives in the same house with someone who is infected should be examined for yaws and treated if they are infected.
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https://www.wikidoc.org/index.php/Yaws_overview
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5fa1fdd0761690550cffe8ed26cde90be8231429
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wikidoc
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Yeast display
|
Yeast display
Yeast display (or yeast surface display) is a technique used in the field of protein engineering. The yeast display technique was first published by the laboratory of Professor K. Dane Wittrup. The technology was sold to Abbott Laboratories in 2001.
A protein of interest is displayed as a fusion to the Aga2p protein on the surface of yeast. The Aga2p protein is naturally used by yeast to mediate cell-cell contacts during yeast cell mating. As such, display of a protein via Aga2p projects the protein away from the cell surface, minimizing potential interactions with other molecules on the yeast cell wall. The use of magnetic separation and flow cytometry in conjunction with a yeast display library is a highly effective method to isolate high affinity protein ligands against nearly any receptor through directed evolution.
# Advantages and disadvantages of yeast display
Advantages of yeast display over other in vitro evolution methods include eukaryotic expression and processing, quality control mechanisms of the eukaryotic secretory pathway, minimal avidity effects, and quantitative library screening through magnetic separation combined with fluorescent-activated cell sorting (FACS).
Disadvantages include smaller mutagenic library sizes compared to alternative methods and differential glycosylation in yeast compared to mammalian cells. It should be noted that these disadvantages have not limited the success of yeast display for a number of applications, including engineering the highest monovalent ligand-binding affinity reported to date for an engineered protein (Boder, E.T. 2000)
Competing methods for protein evolution in vitro are phage display, ribosome display, bacterial display, and mRNA display.
# Citations
- Boder, E.T., Wittrup, K.D.; Nat. Biotech., 1997, 15, 553-57.
- Boder, E.T., Wittrup, K.D.; Biotechnol. Prog., 1998, 14, 55-62.
- Boder E.T., Midelfort K.S., Wittrup K.D.; Proc Nat Acad Sci, 2000, 97(20):10701-10705.
- Graff, C.P., Chester, K., Begent, R., Wittrup, K.D.; Prot. Eng. Des. Sel., 2004, 17, 293-304.
- Feldhaus M, Siegel R.; Methods in Molecular Biology 263:311-332 (2004).
- Weaver-Feldhaus JM, Lou J, Coleman JR, Siegel RW, Marks JD, Feldhaus MJ. FEBS Lett. 2004 Apr 23;564(1-2):24-34. PMID: 15094038
# Notes
- ↑ First yeast display publication
|
Yeast display
Yeast display (or yeast surface display) is a technique used in the field of protein engineering. The yeast display technique was first published by the laboratory of Professor K. Dane Wittrup.[1] The technology was sold to Abbott Laboratories in 2001.[2]
A protein of interest is displayed as a fusion to the Aga2p protein on the surface of yeast. The Aga2p protein is naturally used by yeast to mediate cell-cell contacts during yeast cell mating. As such, display of a protein via Aga2p projects the protein away from the cell surface, minimizing potential interactions with other molecules on the yeast cell wall. The use of magnetic separation and flow cytometry in conjunction with a yeast display library is a highly effective method to isolate high affinity protein ligands against nearly any receptor through directed evolution.
# Advantages and disadvantages of yeast display
Advantages of yeast display over other in vitro evolution methods include eukaryotic expression and processing, quality control mechanisms of the eukaryotic secretory pathway, minimal avidity effects, and quantitative library screening through magnetic separation combined with fluorescent-activated cell sorting (FACS).
Disadvantages include smaller mutagenic library sizes compared to alternative methods and differential glycosylation in yeast compared to mammalian cells. It should be noted that these disadvantages have not limited the success of yeast display for a number of applications, including engineering the highest monovalent ligand-binding affinity reported to date for an engineered protein (Boder, E.T. 2000)
Competing methods for protein evolution in vitro are phage display, ribosome display, bacterial display, and mRNA display.
# Citations
- Boder, E.T., Wittrup, K.D.; Nat. Biotech., 1997, 15, 553-57.
- Boder, E.T., Wittrup, K.D.; Biotechnol. Prog., 1998, 14, 55-62.
- Boder E.T., Midelfort K.S., Wittrup K.D.; Proc Nat Acad Sci, 2000, 97(20):10701-10705.
- Graff, C.P., Chester, K., Begent, R., Wittrup, K.D.; Prot. Eng. Des. Sel., 2004, 17, 293-304.
- Feldhaus M, Siegel R.; Methods in Molecular Biology 263:311-332 (2004).
- Weaver-Feldhaus JM, Lou J, Coleman JR, Siegel RW, Marks JD, Feldhaus MJ. FEBS Lett. 2004 Apr 23;564(1-2):24-34. PMID: 15094038
# Notes
- ↑ First yeast display publication
- ↑ http://www.news.uiuc.edu/NEWS/01/1221biodisplaytechnology.html
Template:WikiDoc Sources
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https://www.wikidoc.org/index.php/Yeast_display
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1360aafb291610aff2dddb0e3a0b7276845bf31b
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wikidoc
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Yuzpe regimen
|
Yuzpe regimen
The Yuzpe Regimen is a method of emergency contraception using a combination of estrogen and progestogen hormones and started within 72 hours of sexual intercourse. It has subsequently been superseded by a progestogen-only hormonal regimen.
# History
The method was first developed by a Canadian Professor A. Albert Yuzpe who published the first studies demonstrating the method's safety and efficacy in 1974.
# Description
This regimen allows a woman who has had unprotected sex to avoid pregnancy by taking 12 hours apart two sufficient doses of estrogen and progestogen hormones. The sooner this is started, the more effective it is and the effectiveness more than 72 hours after sexual intercourse is greatly reduced. The licensing for emergency Intrauterine device (IUD) insertion allows for up to 5 days and it is highly effective for up to five days after the time of ovulation, which may extend more than five days after the relevant risky intercourse.
These hormones are administered as a number of combined oral contraceptive pills (COCPs). Each dose can vary from 2 to 5 pills depending on the brand of medication being used. Patients concurrently taking certain regular medications (e.g. rifamycin and many anticonvulsant drugs) that enhance the liver's break down of other drugs, must use an even higher hormone dose and may be better advised to use as an alternative the insertion of an IUD.
The standard regime is two tablets each with 50 µg ethinyl estradiol and 250 µg levonorgestrel, to be repeated 12 hours later.
The method is not guaranteed to prevent pregnancy and whilst the hormones may make the subsequent period come a few days early or late, a pregnancy test should be carried out if the period is more than 3 days late. The Yuzpe Regimen does not protect against sexually transmitted diseases.
Subsequently, the World Health Organization (WHO) undertook an investigation into the use of progestogen-only tablets as an Emergency Hormonal Contraceptive (i.e. without any estrogen component). This showed greater efficacy with reduced side effects and has therefore superseded the Yuzpe method. A single dose of 100 mg mifepristone is also more effective than the Yuzpe regime.
# Side effects
Some temporary, but usually minor, reactions include:
- Nausea and/or vomiting
- Breast tenderness
- Irregular Bleeding
- Headache or Dizziness
Should vomiting occur within 3 hours of taking a dose, then insufficient hormones may have been absorbed to provide the full contraceptive cover and an additional dose should be taken. Measures that may help to prevent nausea or vomiting include:
- Take the pills with food.
- Take Dramamine or Bonine an hour before taking the pills, if you are especially sensitive to or bothered by nausea -- however, this step is not necessary.
- Schedule your doses so that you take the second dose before bed.
# Formulations
Many common combined oral contraceptive pills could be used for the Yuzpe regimen, although their manufacturers did not label the pills for this use. Such off-label use of approved medications is legal and commonplace in American medicine. Further, in February 1997, the FDA declared emergency contraceptive use of certain birth control pills, following the Yuzpe regimen, as safe and effective.
Yuzpe regimen dedicated products (Preven in US and Schering-PC4 in UK) were discontinued following the introduction of progestogen-only ECPs (Plan B in US and Levonelle in UK).
|
Yuzpe regimen
The Yuzpe Regimen is a method of emergency contraception using a combination of estrogen and progestogen hormones and started within 72 hours of sexual intercourse. It has subsequently been superseded by a progestogen-only hormonal regimen.
# History
The method was first developed by a Canadian Professor A. Albert Yuzpe who published the first studies demonstrating the method's safety and efficacy in 1974.[1]
# Description
This regimen allows a woman who has had unprotected sex to avoid pregnancy by taking 12 hours apart two sufficient doses of estrogen and progestogen hormones. The sooner this is started, the more effective it is and the effectiveness more than 72 hours after sexual intercourse is greatly reduced. The licensing for emergency Intrauterine device (IUD) insertion allows for up to 5 days and it is highly effective for up to five days after the time of ovulation, which may extend more than five days after the relevant risky intercourse.
These hormones are administered as a number of combined oral contraceptive pills (COCPs). Each dose can vary from 2 to 5 pills depending on the brand of medication being used. Patients concurrently taking certain regular medications (e.g. rifamycin and many anticonvulsant drugs) that enhance the liver's break down of other drugs, must use an even higher hormone dose and may be better advised to use as an alternative the insertion of an IUD.
The standard regime is two tablets each with 50 µg ethinyl estradiol and 250 µg levonorgestrel, to be repeated 12 hours later.
The method is not guaranteed to prevent pregnancy and whilst the hormones may make the subsequent period come a few days early or late, a pregnancy test should be carried out if the period is more than 3 days late. The Yuzpe Regimen does not protect against sexually transmitted diseases.
Subsequently, the World Health Organization (WHO) undertook an investigation into the use of progestogen-only tablets as an Emergency Hormonal Contraceptive (i.e. without any estrogen component). This showed greater efficacy with reduced side effects[2] and has therefore superseded the Yuzpe method. A single dose of 100 mg mifepristone is also more effective than the Yuzpe regime[1].
# Side effects
Some temporary, but usually minor, reactions include:
- Nausea and/or vomiting
- Breast tenderness
- Irregular Bleeding
- Headache or Dizziness
Should vomiting occur within 3 hours of taking a dose, then insufficient hormones may have been absorbed to provide the full contraceptive cover and an additional dose should be taken. Measures that may help to prevent nausea or vomiting include:
- Take the pills with food.
- Take Dramamine or Bonine an hour before taking the pills, if you are especially sensitive to or bothered by nausea -- however, this step is not necessary.
- Schedule your doses so that you take the second dose before bed.
# Formulations
Many common combined oral contraceptive pills could be used for the Yuzpe regimen[3], although their manufacturers did not label the pills for this use. Such off-label use of approved medications is legal and commonplace in American medicine. Further, in February 1997, the FDA declared emergency contraceptive use of certain birth control pills, following the Yuzpe regimen, as safe and effective.
Yuzpe regimen dedicated products (Preven in US and Schering-PC4 in UK) were discontinued following the introduction of progestogen-only ECPs (Plan B in US and Levonelle in UK).
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https://www.wikidoc.org/index.php/Yuzpe_regimen
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1f0777e725fc7bfc1d80294569e1d089162b47fa
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wikidoc
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Ziac overdose
|
Ziac overdose
# Overdosage topics
General
Manifestations
Treatment
- Bradycardia
- Hypotension, Shock
- Heart Block(second or third degree)
- Bronchospasm
## General
There are limited data on overdose with ZIAC. However, several cases of overdose with
bisoprolol fumarate have been reported (maximum: 2000 mg). Bradycardia and/or
hypotension were noted. Sympathomimetic agents were given in some cases, and all
patients recovered. Return to top
## Manifestations
The most frequently observed signs expected with overdosage of a beta-blocker are
bradycardia and hypotension. Lethargy is also common, and with severe overdoses,
delirium, coma, convulsions, and respiratory arrest have been reported to occur.
Congestive heart failure, bronchospasm, and hypoglycemia may occur, particularly in
patients with underlying conditions. With thiazide diuretics, acute intoxication is rare.
The most prominent feature of overdose is acute loss of fluid and electrolytes. Signs and
symptoms include cardiovascular (tachycardia, hypotension, shock), neuromuscular
(weakness, confusion, dizziness, cramps of the calf muscles, paresthesia, fatigue,
impairment of consciousness), gastrointestinal (nausea, vomiting, thirst), renal (polyuria,
-liguria, or anuria ), and laboratory findings (hypokalemia,
hyponatremia, hypochloremia, alkalosis, increased BUN [especially in patients with renal
insufficiency]). Return to top
## Treatment
If overdosage of ZIAC (bisoprolol fumarate and hydrochlorothiazide) is suspected,
therapy with ZIAC should be discontinued and the patient observed closely. Treatment is
symptomatic and supportive; there is no specific antidote. Limited data suggest bisoprolol
fumarate is not dialyzable; similarly, there is no indication that hydrochlorothiazide is
dialyzable. Suggested general measures include induction of emesis and/or gastric lavage,
administration of activated charcoal, respiratory support, correction of fluid and
electrolyte imbalance, and treatment of convulsions. Return to top
## Bradycardia
Administer IV atropine. If the response is inadequate, isoproterenol or
another agent with positive chronotropic properties may be given cautiously. Under some
circumstances, transvenous pacemaker insertion may be necessary. Return to top
## Hypotension, Shock
The patient’s legs should be elevated. IV fluids should be
administered and lost electrolytes (potassium, sodium) replaced. Intravenous glucagon
may be useful. Vasopressors should be considered. Return to top
## Heart Block(second or third degree)
Patients should be carefully monitored and treated
with isoproterenol infusion or transvenous cardiac pacemaker insertion, as appropriate.
Congestive Heart Failure: Initiate conventional therapy (ie, digitalis, diuretics,
vasodilating agents, inotropic agents). Return to top
## Bronchospasm
Administer a bronchodilator such as isoproterenol and/or aminophylline.
Hypoglycemia: Administer IV glucose.
Surveillance: Fluid and electrolyte balance (especially serum potassium) and renal
function should be monitored until normalized. Return to top
Adapted from the FDA Package Insert.
|
Ziac overdose
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overdosage topics
General
Manifestations
Treatment
- Bradycardia
- Hypotension, Shock
- Heart Block(second or third degree)
- Bronchospasm
## General
There are limited data on overdose with ZIAC. However, several cases of overdose with
bisoprolol fumarate have been reported (maximum: 2000 mg). Bradycardia and/or
hypotension were noted. Sympathomimetic agents were given in some cases, and all
patients recovered. Return to top
## Manifestations
The most frequently observed signs expected with overdosage of a beta-blocker are
bradycardia and hypotension. Lethargy is also common, and with severe overdoses,
delirium, coma, convulsions, and respiratory arrest have been reported to occur.
Congestive heart failure, bronchospasm, and hypoglycemia may occur, particularly in
patients with underlying conditions. With thiazide diuretics, acute intoxication is rare.
The most prominent feature of overdose is acute loss of fluid and electrolytes. Signs and
symptoms include cardiovascular (tachycardia, hypotension, shock), neuromuscular
(weakness, confusion, dizziness, cramps of the calf muscles, paresthesia, fatigue,
impairment of consciousness), gastrointestinal (nausea, vomiting, thirst), renal (polyuria,
oliguria, or anuria [due to hemoconcentration]), and laboratory findings (hypokalemia,
hyponatremia, hypochloremia, alkalosis, increased BUN [especially in patients with renal
insufficiency]). Return to top
## Treatment
If overdosage of ZIAC (bisoprolol fumarate and hydrochlorothiazide) is suspected,
therapy with ZIAC should be discontinued and the patient observed closely. Treatment is
symptomatic and supportive; there is no specific antidote. Limited data suggest bisoprolol
fumarate is not dialyzable; similarly, there is no indication that hydrochlorothiazide is
dialyzable. Suggested general measures include induction of emesis and/or gastric lavage,
administration of activated charcoal, respiratory support, correction of fluid and
electrolyte imbalance, and treatment of convulsions. Return to top
## Bradycardia
Administer IV atropine. If the response is inadequate, isoproterenol or
another agent with positive chronotropic properties may be given cautiously. Under some
circumstances, transvenous pacemaker insertion may be necessary. Return to top
## Hypotension, Shock
The patient’s legs should be elevated. IV fluids should be
administered and lost electrolytes (potassium, sodium) replaced. Intravenous glucagon
may be useful. Vasopressors should be considered. Return to top
## Heart Block(second or third degree)
Patients should be carefully monitored and treated
with isoproterenol infusion or transvenous cardiac pacemaker insertion, as appropriate.
Congestive Heart Failure: Initiate conventional therapy (ie, digitalis, diuretics,
vasodilating agents, inotropic agents). Return to top
## Bronchospasm
Administer a bronchodilator such as isoproterenol and/or aminophylline.
Hypoglycemia: Administer IV glucose.
Surveillance: Fluid and electrolyte balance (especially serum potassium) and renal
function should be monitored until normalized. Return to top
Adapted from the FDA Package Insert.
|
https://www.wikidoc.org/index.php/Ziac_overdose
| |
86a81e85665b21a1ee141b611a1d4cb0dcb51324
|
wikidoc
|
Zinc chloride
|
Zinc chloride
# 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
Zinc chloride is an nutritional agent that is FDA approved for the {{{indicationType}}} of zinc deficiency. Common adverse reactions include none known.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Zinc 1 mg/mL (Zinc Chloride Injection, USP) is indicated for use as a supplement to intravenous solutions given for TPN. Administration helps to maintain zinc serum levels and to prevent depletion of endogenous stores, and subsequent deficiency symptoms.
- Zinc 1 mg/mL (Zinc Chloride Injection, USP) contains 1 mg zinc/mL and is administered intravenously only after dilution. The additive should be diluted prior to administration in a volume of fluid not less than 100 mL. For the metabolically stable adult receiving TPN, the suggested intravenous dosage is 2.5 to 4 mg zinc/day (2.5 to 4 mL/day). An additional 2 mg zinc/day (2 mL/day) is suggested for acute catabolic states. For the stable adult with fluid loss from the small bowel, an additional 12.2 mg zinc/liter of small bowel fluid lost (12.2 mL/liter of small bowel fluid lost), or an additional 17.1 mg zinc/kg of stool or ileostomy output (17.1 mL/kg of stool or ileostomy output) is recommended. Frequent monitoring of zinc blood levels is suggested for patients receiving more than the usual maintenance dosage level of zinc.
- For full term infants and children up to 5 years of age, 100 mcg zinc/kg/day (0.1 mL/kg/day) is recommended. For premature infants (birth weight less than 1500 g) up to 3 kg in body weight, 300 mcg zinc/kg/day (0.3 mL/kg/day) is suggested.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Zinc chloride in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Zinc chloride in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Zinc chloride in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Zinc chloride in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Zinc chloride in pediatric patients.
# Contraindications
- None
# Warnings
- Direct intramuscular or intravenous injection of Zinc 1 mg/mL (Zinc Chloride Injection, USP) is contraindicated as the acidic pH of the solution (2) may cause considerable tissue irritation.
- Severe kidney disease may make it necessary to reduce or omit chromium and zinc doses because these elements are primarily eliminated in the urine.
- WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.
- Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.
### Precautions
- Do not use unless the solution is clear and the seal is intact.
- Zinc 1 mg/mL (Zinc Chloride Injection, USP) should only be used in conjunction with a pharmacy directed admixture program using aseptic technique in a laminar flow environment; it should be used promptly and in a single operation without any repeated penetrations. Solution contains no preservatives; discard unused portion immediately after admixture procedure is completed.
- Zinc should not be given undiluted by direct injection into a peripheral vein because of the likelihood of infusion phlebitis and the potential for increased excretory loss of zinc from a bolus injection. Administration of zinc in the absence of copper may cause a decrease in serum copper levels.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Zinc chloride in the drug label.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Zinc chloride in the drug label.
# Drug Interactions
There is limited information regarding Zinc chloride Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Animal reproduction studies have not been conducted with zinc chloride. It is also not known whether zinc chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Zinc chloride 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 Zinc chloride in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Zinc chloride 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 Zinc 1 mg/mL (Zinc Chloride Injection, USP) is administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Zinc chloride with respect to pediatric patients.
### Geriatic Use
- An evaluation of current literature revealed no clinical experience identifying differences in response between 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 Zinc chloride with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Zinc chloride with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Zinc chloride in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Zinc chloride in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Zinc chloride in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Zinc chloride in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Zinc chloride in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Zinc chloride in the drug label.
# Overdosage
## Acute Overdose
- Single intravenous doses of 1 to 2 mg zinc/kg body weight have been given to adult leukemic patients without toxic manifestations. However, acute toxicity was reported in an adult when 10 mg zinc was infused over a period of one hour on each of four consecutive days. Profuse sweating, decreased level of consciousness, blurred vision, tachycardia (140/min), and marked hypothermia (94.2° F) on the fourth day were accompanied by a serum zinc concentration of 207 mcg/dl. Symptoms abated within three hours.
- Hyperamylasemia may be a sign of impending zinc overdosage; patients receiving an inadvertent overdose (25 mg zinc/liter of TPN solution, equivalent to 50 to 70 mg zinc/day) developed hyperamylasemia (557 to 1850 Klein units; normal: 130 to 310).
- Death resulted from an overdosage in which 1683 mg zinc was delivered intravenously over the course of 60 hours to a 72 year old patient.
- Symptoms of zinc toxicity included hypotension (80/40 mm Hg), pulmonary edema, diarrhea, vomiting, jaundice, and oliguria, with a serum zinc level of 4184 mcg/dl.
- Calcium supplements may confer a protective effect against zinc toxicity.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Zinc chloride in the drug label.
# Pharmacology
There is limited information regarding Zinc chloride Pharmacology in the drug label.
## Mechanism of Action
- Zinc is an essential nutritional requirement and serves as a cofactor for more than 70 different enzymes including carbonic anhydrase, alkaline phosphatase, lactic dehydrogenase, and both RNA and DNA polymerase. Zinc facilitates wound healing, helps maintain normal growth rates, normal skin hydration, and the senses of taste and smell.
## Structure
- Zinc 1 mg/mL (Zinc Chloride Injection, USP) is a sterile, nonpyrogenic solution intended for use as an additive to intravenous solutions for total parenteral nutrition (TPN). Each mL of solution contains 2.09 mg zinc chloride and 9 mg sodium chloride. The solution contains no bacteriostat, antimicrobial agent or added buffer. The pH is 2.0 (1.5 to 2.5); product may contain hydrochloric acid and sodium hydroxide for pH adjustment. The osmolarity is 0.354 m0smoL/mL (calc.).
- Zinc Chloride, USP is chemically designated ZnCl2, a white crystalline compound freely soluble in water.
- Sodium Chloride, USP is chemically designated NaCl, a white crystalline compound freely soluble in water.
- The semi-rigid vial is fabricated from a specially formulated polyolefin. It is a copolymer of ethylene and propylene. The safety of the plastic has been confirmed by tests in animals according to USP biological standards for plastic containers. The small amount of water vapor that can pass through the plastic container wall will not significantly alter the drug concentration.
## Pharmacodynamics
- Providing zinc helps prevent development of deficiency symptoms such as: Parakeratosis, hypogeusia, anorexia, dysosmia, geophagia, hypogonadism, growth retardation and hepatosplenomegaly.
- The initial manifestations of hypozincemia in TPN are diarrhea, apathy and depression. At plasma levels below 20 mcg zinc/100 mL dermatitis followed by alopecia has been reported for TPN patients. Normal zinc plasma levels are 100 ± 12 mcg/100 mL.
## Pharmacokinetics
- Zinc resides in muscle, bone, skin, kidney, liver, pancreas, retina, prostate and particularly in the red and white blood cells. Zinc binds to plasma albumin, α2-macroglobulin, and some plasma amino acids including histidine, cysteine, threonine, glycine, and asparagine. Ingested zinc is excreted mainly in the stool (approximately 90%), and to a lesser extent in the urine and in perspiration.
## Nonclinical Toxicology
- Long-term animal studies to evaluate the carcinogenic potential of Zinc 1 mg/mL (Zinc Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.
# Clinical Studies
There is limited information regarding Clinical Studies of Zinc chloride in the drug label.
# How Supplied
- Zinc 1 mg/mL (Zinc Chloride Injection, USP) is supplied in 10 mL Plastic Vials (List No. 4090).
- Store at 20 to 25°C (68 to 77°F).
## Storage
There is limited information regarding Zinc chloride 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 Zinc chloride in the drug label.
# Precautions with Alcohol
- Alcohol-Zinc chloride interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ZINC®
# Look-Alike Drug Names
There is limited information regarding Zinc chloride Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price
|
Zinc chloride
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
Zinc chloride is an nutritional agent that is FDA approved for the {{{indicationType}}} of zinc deficiency. Common adverse reactions include none known.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Zinc 1 mg/mL (Zinc Chloride Injection, USP) is indicated for use as a supplement to intravenous solutions given for TPN. Administration helps to maintain zinc serum levels and to prevent depletion of endogenous stores, and subsequent deficiency symptoms.
- Zinc 1 mg/mL (Zinc Chloride Injection, USP) contains 1 mg zinc/mL and is administered intravenously only after dilution. The additive should be diluted prior to administration in a volume of fluid not less than 100 mL. For the metabolically stable adult receiving TPN, the suggested intravenous dosage is 2.5 to 4 mg zinc/day (2.5 to 4 mL/day). An additional 2 mg zinc/day (2 mL/day) is suggested for acute catabolic states. For the stable adult with fluid loss from the small bowel, an additional 12.2 mg zinc/liter of small bowel fluid lost (12.2 mL/liter of small bowel fluid lost), or an additional 17.1 mg zinc/kg of stool or ileostomy output (17.1 mL/kg of stool or ileostomy output) is recommended. Frequent monitoring of zinc blood levels is suggested for patients receiving more than the usual maintenance dosage level of zinc.
- For full term infants and children up to 5 years of age, 100 mcg zinc/kg/day (0.1 mL/kg/day) is recommended. For premature infants (birth weight less than 1500 g) up to 3 kg in body weight, 300 mcg zinc/kg/day (0.3 mL/kg/day) is suggested.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Zinc chloride in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Zinc chloride in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Zinc chloride in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Zinc chloride in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Zinc chloride in pediatric patients.
# Contraindications
- None
# Warnings
- Direct intramuscular or intravenous injection of Zinc 1 mg/mL (Zinc Chloride Injection, USP) is contraindicated as the acidic pH of the solution (2) may cause considerable tissue irritation.
- Severe kidney disease may make it necessary to reduce or omit chromium and zinc doses because these elements are primarily eliminated in the urine.
- WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.
- Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.
### Precautions
- Do not use unless the solution is clear and the seal is intact.
- Zinc 1 mg/mL (Zinc Chloride Injection, USP) should only be used in conjunction with a pharmacy directed admixture program using aseptic technique in a laminar flow environment; it should be used promptly and in a single operation without any repeated penetrations. Solution contains no preservatives; discard unused portion immediately after admixture procedure is completed.
- Zinc should not be given undiluted by direct injection into a peripheral vein because of the likelihood of infusion phlebitis and the potential for increased excretory loss of zinc from a bolus injection. Administration of zinc in the absence of copper may cause a decrease in serum copper levels.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Zinc chloride in the drug label.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Zinc chloride in the drug label.
# Drug Interactions
There is limited information regarding Zinc chloride Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Animal reproduction studies have not been conducted with zinc chloride. It is also not known whether zinc chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Zinc chloride 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 Zinc chloride in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Zinc chloride 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 Zinc 1 mg/mL (Zinc Chloride Injection, USP) is administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Zinc chloride with respect to pediatric patients.
### Geriatic Use
- An evaluation of current literature revealed no clinical experience identifying differences in response between 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 Zinc chloride with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Zinc chloride with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Zinc chloride in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Zinc chloride in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Zinc chloride in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Zinc chloride in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Zinc chloride in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Zinc chloride in the drug label.
# Overdosage
## Acute Overdose
- Single intravenous doses of 1 to 2 mg zinc/kg body weight have been given to adult leukemic patients without toxic manifestations. However, acute toxicity was reported in an adult when 10 mg zinc was infused over a period of one hour on each of four consecutive days. Profuse sweating, decreased level of consciousness, blurred vision, tachycardia (140/min), and marked hypothermia (94.2° F) on the fourth day were accompanied by a serum zinc concentration of 207 mcg/dl. Symptoms abated within three hours.
- Hyperamylasemia may be a sign of impending zinc overdosage; patients receiving an inadvertent overdose (25 mg zinc/liter of TPN solution, equivalent to 50 to 70 mg zinc/day) developed hyperamylasemia (557 to 1850 Klein units; normal: 130 to 310).
- Death resulted from an overdosage in which 1683 mg zinc was delivered intravenously over the course of 60 hours to a 72 year old patient.
- Symptoms of zinc toxicity included hypotension (80/40 mm Hg), pulmonary edema, diarrhea, vomiting, jaundice, and oliguria, with a serum zinc level of 4184 mcg/dl.
- Calcium supplements may confer a protective effect against zinc toxicity.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Zinc chloride in the drug label.
# Pharmacology
There is limited information regarding Zinc chloride Pharmacology in the drug label.
## Mechanism of Action
- Zinc is an essential nutritional requirement and serves as a cofactor for more than 70 different enzymes including carbonic anhydrase, alkaline phosphatase, lactic dehydrogenase, and both RNA and DNA polymerase. Zinc facilitates wound healing, helps maintain normal growth rates, normal skin hydration, and the senses of taste and smell.
## Structure
- Zinc 1 mg/mL (Zinc Chloride Injection, USP) is a sterile, nonpyrogenic solution intended for use as an additive to intravenous solutions for total parenteral nutrition (TPN). Each mL of solution contains 2.09 mg zinc chloride and 9 mg sodium chloride. The solution contains no bacteriostat, antimicrobial agent or added buffer. The pH is 2.0 (1.5 to 2.5); product may contain hydrochloric acid and sodium hydroxide for pH adjustment. The osmolarity is 0.354 m0smoL/mL (calc.).
- Zinc Chloride, USP is chemically designated ZnCl2, a white crystalline compound freely soluble in water.
- Sodium Chloride, USP is chemically designated NaCl, a white crystalline compound freely soluble in water.
- The semi-rigid vial is fabricated from a specially formulated polyolefin. It is a copolymer of ethylene and propylene. The safety of the plastic has been confirmed by tests in animals according to USP biological standards for plastic containers. The small amount of water vapor that can pass through the plastic container wall will not significantly alter the drug concentration.
## Pharmacodynamics
- Providing zinc helps prevent development of deficiency symptoms such as: Parakeratosis, hypogeusia, anorexia, dysosmia, geophagia, hypogonadism, growth retardation and hepatosplenomegaly.
- The initial manifestations of hypozincemia in TPN are diarrhea, apathy and depression. At plasma levels below 20 mcg zinc/100 mL dermatitis followed by alopecia has been reported for TPN patients. Normal zinc plasma levels are 100 ± 12 mcg/100 mL.
## Pharmacokinetics
- Zinc resides in muscle, bone, skin, kidney, liver, pancreas, retina, prostate and particularly in the red and white blood cells. Zinc binds to plasma albumin, α2-macroglobulin, and some plasma amino acids including histidine, cysteine, threonine, glycine, and asparagine. Ingested zinc is excreted mainly in the stool (approximately 90%), and to a lesser extent in the urine and in perspiration.
## Nonclinical Toxicology
- Long-term animal studies to evaluate the carcinogenic potential of Zinc 1 mg/mL (Zinc Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.
# Clinical Studies
There is limited information regarding Clinical Studies of Zinc chloride in the drug label.
# How Supplied
- Zinc 1 mg/mL (Zinc Chloride Injection, USP) is supplied in 10 mL Plastic Vials (List No. 4090).
- Store at 20 to 25°C (68 to 77°F).
## Storage
There is limited information regarding Zinc chloride 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 Zinc chloride in the drug label.
# Precautions with Alcohol
- Alcohol-Zinc chloride interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ZINC®[1]
# Look-Alike Drug Names
There is limited information regarding Zinc chloride Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price
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https://www.wikidoc.org/index.php/Zinc_chloride
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80ea3b5352f0457d58375287000cac549779eae1
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wikidoc
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Pralatrexate
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Pralatrexate
## Pretreatment Vitamin Supplementation
- Folic Acid: Patients should take folic acid 1.0-1.25 mg orally once daily beginning 10 days before the first dose of Pralatrexate. Continue folic acid during the full course of therapy and for 30 days after the last dose of Pralatrexate.
- Vitamin B12: Administer vitamin B12 1 mg intramuscularly within 10 weeks prior to the first dose of Pralatrexate and every 8-10 weeks thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with Pralatrexate.
## Dosing and Administration
- The recommended dose of Pralatrexate is 30 mg/m2 administered as an intravenous push over 3-5 minutes via the side port of a free-flowing 0.9% Sodium Chloride Injection, intravenous line once weekly for 6 weeks in 7-week cycles until progressive disease or unacceptable toxicity. The calculated dose of Pralatrexate should be aseptically withdrawn into a syringe for immediate use. Do not dilute Pralatrexate.
- Pralatrexate is a clear, yellow solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use any vials exhibiting particulate matter or discoloration.
# Monitoring and Dose Modifications
- Management of severe or intolerable adverse reactions may require dose omission, reduction, or discontinuation of Pralatrexate therapy.
## Monitoring
- Monitor complete blood cell counts and severity of mucositis at baseline and weekly. Perform serum chemistry tests, including renal function and hepatic function, prior to the start of the first and fourth dose of each cycle.
## Dose Modification Recommendations
Prior to administering any dose of Pralatrexate:
- Mucositis should be ≤ Grade 1.
- Platelet count should be ≥ 100,000/mcL for first dose and ≥ 50,000/mcL for all subsequent doses.
- Absolute neutrophil count (ANC) should be ≥ 1,000/mcL.
- Doses may be omitted or reduced based on patient tolerance. Omitted doses will not be made up at the end of the cycle; once a dose reduction occurs for toxicity, do not re-escalate. For dose modifications and omissions, use the guidelines in TABLES 1, 2, and 3.
# Special Handling Precautions
- Pralatrexate is a cytotoxic anticancer agent. Caution should be exercised in handling, preparing, and administering of the solution. The use of gloves and other protective clothing is recommended. If Pralatrexate comes in contact with the skin, immediately and thoroughly wash with soap and water. If Pralatrexate comes in contact with mucous membranes, flush thoroughly with water.
- Several published guidelines for handling and disposal of anticancer agents are available:
- Pralatrexate vials should be refrigerated at 2-8°C (36-46°F) until use.
- Pralatrexate vials should be stored in original carton to protect from light until use.
- Pralatrexate vials contain no preservatives and are intended for single use only. After withdrawal of dose, discard vial including any unused portion.
- Unopened vial(s) of Pralatrexate are stable if stored in the original carton at room temperature for 72 hours. *Any vials left at room temperature for greater than 72 hours should be discarded.
- Pralatrexate can cause bone marrow suppression, manifested by thrombocytopenia, neutropenia, and/or anemia. Monitor complete blood counts and omit and/or reduce the dose based on ANC and platelet count prior to each dose as outlined in Section 2.2 TABLE 2. Administer vitamin B12 and instruct patients to take folic acid to reduce the risk of treatment-related hematological toxicity.
## Mucositis
- Pralatrexate can cause mucositis. Monitor for mucositis weekly and if ≥ Grade 2 mucositis is observed, omit and/or reduce the dose as outlined in Section 2.2 TABLE 1. Administer vitamin B12 and instruct patients to take folic acid to reduce the risk of mucositis.
## Dermatologic Reactions
- Pralatrexate can cause severe dermatologic reactions, which may result in death. These dermatologic reactions have been reported in clinical studies (14/663 patients ) and post marketing experience, and have included skin exfoliation, ulceration, and toxic epidermal necrolysis (TEN). They may be progressive and increase in severity with further treatment, and may involve skin and subcutaneous sites of known lymphoma. Monitor patients with dermatologic reactions closely, and if severe, withhold or discontinue Pralatrexate.
## Tumor Lysis Syndrome
- Pralatrexate can cause tumor lysis syndrome (TLS). Monitor patients who are at increased risk of TLS and treat promptly.
## Hepatic Toxicity
- Pralatrexate can cause hepatic toxicity and liver function test abnormalities. Persistent liver function test abnormalities may be indicators of hepatic toxicity and require dose modification or discontinuation. Monitor liver function tests. Omit dose until recovery, adjust or discontinue therapy based on the severity of the hepatic toxicity.
## Risk of Increased Toxicity in the Presence of Impaired Renal Function
- Patients with moderate to severe renal function impairment may be at greater risk for increased exposure and toxicity. Monitor patients for renal function and systemic toxicity and adjust dosing accordingly.
- Serious adverse drug reactions including toxic epidermal necrolysis and mucositis were reported in patients with end stage renal disease (ESRD) undergoing dialysis who were administered Pralatrexate therapy. Avoid Pralatrexate use in patients with end stage renal disease including those undergoing dialysis unless the potential benefit justifies the potential risk.
## Embryo-Fetal Toxicity
- Pralatrexate can cause fetal harm when administered to a pregnant woman. Pralatrexate was embryotoxic and fetotoxic in rats and rabbits. 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.
- Bone Marrow Suppression
- Mucositis
- Dermatologic Reactions
- Tumor Lysis Syndrome
- Hepatic Toxicity
The most common adverse reactions observed in patients with peripheral T-cell lymphoma (PTCL) treated with Pralatrexate were mucositis, thrombocytopenia, nausea, and fatigue.
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The safety of Pralatrexate was evaluated in 111 PTCL patients in a single-arm clinical study in which patients received a starting dose of 30 mg/m2 once weekly for 6 weeks in 7-week cyc
## Most Frequent Adverse Reactions
TABLE 4 summarizes the most frequent adverse reactions, regardless of causality, using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE, version 3.0).
## Serious Adverse Events
- Forty-four percent of patients (n = 49) experienced a serious adverse event while on study or within 30 days after their last dose of Pralatrexate The most common serious adverse events (> 3%), regardless of causality, were pyrexia, mucositis, sepsis, febrile neutropenia, dehydration, dyspnea, and thrombocytopenia. One death from cardiopulmonary arrest in a patient with mucositis and febrile neutropenia was reported in this trial. Deaths from mucositis, febrile neutropenia, sepsis, and pancytopenia occurred in 1.2% of patients treated on all Pralatrexate trials at doses ranging from 30 to 325 mg/m2.
## Discontinuations
- Twenty-three percent of patients (n = 25) discontinued treatment with Pralatrexate due to adverse reactions. The adverse reactions reported most frequently as the reason for discontinuation of treatment were mucositis (6%, n = 7) and thrombocytopenia (5%, n = 5).
## Dose Modifications
- The target dose of Pralatrexate was 30 mg/m2 once weekly for 6 weeks in 7-week cycles. The majority of patients (69%, n = 77) remained at the target dose for the duration of treatment. Overall, 85% of scheduled doses were administered.
## Dermatologic Reactions
- Toxic epidermal necrolysis, sometimes fatal, has been reported during post-marketing use of Pralatrexate Fatal cases have been reported following the first dose of Pralatrexate including when a reduced dose is given, and have been reported in patients with end-stage renal disease undergoing dialysis.
- When administering Pralatrexate to patients receiving probenecid or other drugs that may affect relevant transporter systems (eg, NSAIDs), monitor patients closely for signs of systemic toxicity due to increased drug exposure.
- The risk for toxicity may be greater when administering Pralatrexate to patients with moderate-to-severe impairment due to the contribution of renal excretion (approximately 34%) to the overall clearance of pralatrexate. Serious adverse drug reactions, including TEN and mucositis have been reported in patients with ESRD undergoing dialysis. Monitor patients for renal function and for systemic toxicity due to increased drug exposure and adjust dosing accordingly. Avoid the use of Pralatrexate in patients with end stage renal disease undergoing dialysis unless the potential benefit justifies the potential risk.
The molecular formula is C23H23N7O5 and the molecular weight is 477.48 g/mol.
- The pharmacokinetics of pralatrexate administered as a single agent at a dose of 30 mg/m2 administered as an intravenous push over 3-5 minutes once weekly for 6 weeks in 7-week cycles have been evaluated in 10 patients with PTCL. The total systemic clearance of pralatrexate diastereomers was 417 mL/min (S-diastereomer) and 191 mL/min (R-diastereomer). The terminal elimination half-life of pralatrexate was 12-18 hours (coefficient of variance = 62-120%). Pralatrexate total systemic exposure (AUC) and maximum plasma concentration (Cmax) increased proportionally with dose (dose range 30-325 mg/m2, including pharmacokinetics data from high-dose solid tumor clinical studies). The pharmacokinetics of pralatrexate did not change significantly over multiple treatment cycles, and no accumulation of pralatrexate was observed.
## Distribution
- Pralatrexate diastereomers showed a steady-state volume of distribution of 105 L (S-diastereomer) and 37 L (R-diastereomer). In vitro studies indicate that pralatrexate is approximately 67% bound to plasma proteins.
## Metabolism
- In vitro studies using human hepatocytes, liver microsomes and S9 fractions, and recombinant human CYP450 isozymes showed that pralatrexate is not significantly metabolized by the phase I hepatic CYP450 isozymes or phase II hepatic glucuronidases.
## Excretion
- A mass balance study has not been performed. The mean fraction of unchanged pralatrexate diastereomers excreted in urine following a pralatrexate dose of 30 mg/m2 administered as an intravenous push over 3-5 minutes was 31% (S-diastereomer) (CV = 47%) and 38% (R-diastereomer) (CV = 45%), respectively.
## Carcinogenesis
- Carcinogenicity studies have not been performed with pralatrexate.
## Mutagenesis
- Pralatrexate did not cause mutations in the Ames test or the Chinese hamster ovary cell chromosome aberration assay. Nevertheless, these tests do not reliably predict genotoxicity for this class of compounds. Pralatrexate did not cause mutations in the mouse micronucleus assay.
## Impairment of Fertility
- No fertility studies have been performed.
- The safety and efficacy of Pralatrexate was evaluated in an open-label, single-arm, multi-center, international trial that enrolled 115 patients with relapsed or refractory PTCL. One hundred and eleven patients were treated with Pralatrexate at 30 mg/m2 once weekly by IV push over 3-5 minutes for 6 weeks in 7-week cycles until disease progression or unacceptable toxicity. Of the 111 patients treated, 109 patients were evaluable for efficacy. Evaluable patients had histologically confirmed PTCL by independent central review using the Revised European American Lymphoma (REAL) World Health Organization (WHO) disease classification, and relapsed or refractory disease after at least one prior treatment.
- The primary efficacy endpoint was overall response rate (complete response, complete response unconfirmed, and partial response) as assessed by International Workshop Criteria (IWC). The key secondary efficacy endpoint was duration of response. Response assessments were scheduled at the end of cycle 1 and then every other cycle (every 14 weeks). Duration of response was measured from the first day of documented response to disease progression or death. Response and disease progression were evaluated by independent central review using the IWC.
- The median age of treated patients was 59.0 years (range 21-85); 68% were male and 32% were female. Most patients were White (72%) and other racial origins included: Black (13%), Hispanic (8%), Asian (5%), other and unknown (<1% each). Patients had an Eastern Cooperative Oncology Group (ECOG) performance status at study entry of 0 (39%), 1 (44%), or 2 (17%). The median time from initial diagnosis to study entry was 15.6 months (range 0.8 – 322.3).
- The median number of prior systemic therapies was 3 (range 1-12). Approximately one-fourth of patients (24%, n = 27) did not have evidence of response to any previous therapy. Approximately two-thirds of patients (63%, n = 70) did not have evidence of response to their most recent prior therapy before entering the study.
- In all evaluable patients (n = 109) treated with Pralatrexate, the response rate, as determined by independent central review by IWC, was 27% (n = 29) (TABLE 5).
- NDC 48818-001-01: 20 mg of pralatrexate in 1 mL solution in a vial (20 mg / 1 mL)
- NDC 48818-001-02: 40 mg of pralatrexate in 2 mL solution in a vial (40 mg / 2 mL)
|
Pralatrexate
### Pretreatment Vitamin Supplementation
- Folic Acid: Patients should take folic acid 1.0-1.25 mg orally once daily beginning 10 days before the first dose of Pralatrexate. Continue folic acid during the full course of therapy and for 30 days after the last dose of Pralatrexate.
- Vitamin B12: Administer vitamin B12 1 mg intramuscularly within 10 weeks prior to the first dose of Pralatrexate and every 8-10 weeks thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with Pralatrexate.
### Dosing and Administration
- The recommended dose of Pralatrexate is 30 mg/m2 administered as an intravenous push over 3-5 minutes via the side port of a free-flowing 0.9% Sodium Chloride Injection, intravenous line once weekly for 6 weeks in 7-week cycles until progressive disease or unacceptable toxicity. The calculated dose of Pralatrexate should be aseptically withdrawn into a syringe for immediate use. Do not dilute Pralatrexate.
- Pralatrexate is a clear, yellow solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use any vials exhibiting particulate matter or discoloration.
## Monitoring and Dose Modifications
- Management of severe or intolerable adverse reactions may require dose omission, reduction, or discontinuation of Pralatrexate therapy.
### Monitoring
- Monitor complete blood cell counts and severity of mucositis at baseline and weekly. Perform serum chemistry tests, including renal function and hepatic function, prior to the start of the first and fourth dose of each cycle.
### Dose Modification Recommendations
Prior to administering any dose of Pralatrexate:
- Mucositis should be ≤ Grade 1.
- Platelet count should be ≥ 100,000/mcL for first dose and ≥ 50,000/mcL for all subsequent doses.
- Absolute neutrophil count (ANC) should be ≥ 1,000/mcL.
- Doses may be omitted or reduced based on patient tolerance. Omitted doses will not be made up at the end of the cycle; once a dose reduction occurs for toxicity, do not re-escalate. For dose modifications and omissions, use the guidelines in TABLES 1, 2, and 3.
## Special Handling Precautions
- Pralatrexate is a cytotoxic anticancer agent. Caution should be exercised in handling, preparing, and administering of the solution. The use of gloves and other protective clothing is recommended. If Pralatrexate comes in contact with the skin, immediately and thoroughly wash with soap and water. If Pralatrexate comes in contact with mucous membranes, flush thoroughly with water.
- Several published guidelines for handling and disposal of anticancer agents are available:
- Pralatrexate vials should be refrigerated at 2-8°C (36-46°F) until use.
- Pralatrexate vials should be stored in original carton to protect from light until use.
- Pralatrexate vials contain no preservatives and are intended for single use only. After withdrawal of dose, discard vial including any unused portion.
- Unopened vial(s) of Pralatrexate are stable if stored in the original carton at room temperature for 72 hours. *Any vials left at room temperature for greater than 72 hours should be discarded.
- Pralatrexate can cause bone marrow suppression, manifested by thrombocytopenia, neutropenia, and/or anemia. Monitor complete blood counts and omit and/or reduce the dose based on ANC and platelet count prior to each dose as outlined in Section 2.2 TABLE 2. Administer vitamin B12 and instruct patients to take folic acid to reduce the risk of treatment-related hematological toxicity.
### Mucositis
- Pralatrexate can cause mucositis. Monitor for mucositis weekly and if ≥ Grade 2 mucositis is observed, omit and/or reduce the dose as outlined in Section 2.2 TABLE 1. Administer vitamin B12 and instruct patients to take folic acid to reduce the risk of mucositis.
### Dermatologic Reactions
- Pralatrexate can cause severe dermatologic reactions, which may result in death. These dermatologic reactions have been reported in clinical studies (14/663 patients [2.1%]) and post marketing experience, and have included skin exfoliation, ulceration, and toxic epidermal necrolysis (TEN). They may be progressive and increase in severity with further treatment, and may involve skin and subcutaneous sites of known lymphoma. Monitor patients with dermatologic reactions closely, and if severe, withhold or discontinue Pralatrexate.
### Tumor Lysis Syndrome
- Pralatrexate can cause tumor lysis syndrome (TLS). Monitor patients who are at increased risk of TLS and treat promptly.
### Hepatic Toxicity
- Pralatrexate can cause hepatic toxicity and liver function test abnormalities. Persistent liver function test abnormalities may be indicators of hepatic toxicity and require dose modification or discontinuation. Monitor liver function tests. Omit dose until recovery, adjust or discontinue therapy based on the severity of the hepatic toxicity.
### Risk of Increased Toxicity in the Presence of Impaired Renal Function
- Patients with moderate to severe renal function impairment may be at greater risk for increased exposure and toxicity. Monitor patients for renal function and systemic toxicity and adjust dosing accordingly.
- Serious adverse drug reactions including toxic epidermal necrolysis and mucositis were reported in patients with end stage renal disease (ESRD) undergoing dialysis who were administered Pralatrexate therapy. Avoid Pralatrexate use in patients with end stage renal disease including those undergoing dialysis unless the potential benefit justifies the potential risk.
### Embryo-Fetal Toxicity
- Pralatrexate can cause fetal harm when administered to a pregnant woman. Pralatrexate was embryotoxic and fetotoxic in rats and rabbits. 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.
- Bone Marrow Suppression
- Mucositis
- Dermatologic Reactions
- Tumor Lysis Syndrome
- Hepatic Toxicity
The most common adverse reactions observed in patients with peripheral T-cell lymphoma (PTCL) treated with Pralatrexate were mucositis, thrombocytopenia, nausea, and fatigue.
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The safety of Pralatrexate was evaluated in 111 PTCL patients in a single-arm clinical study in which patients received a starting dose of 30 mg/m2 once weekly for 6 weeks in 7-week cyc
### Most Frequent Adverse Reactions
TABLE 4 summarizes the most frequent adverse reactions, regardless of causality, using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE, version 3.0).
### Serious Adverse Events
- Forty-four percent of patients (n = 49) experienced a serious adverse event while on study or within 30 days after their last dose of Pralatrexate The most common serious adverse events (> 3%), regardless of causality, were pyrexia, mucositis, sepsis, febrile neutropenia, dehydration, dyspnea, and thrombocytopenia. One death from cardiopulmonary arrest in a patient with mucositis and febrile neutropenia was reported in this trial. Deaths from mucositis, febrile neutropenia, sepsis, and pancytopenia occurred in 1.2% of patients treated on all Pralatrexate trials at doses ranging from 30 to 325 mg/m2.
### Discontinuations
- Twenty-three percent of patients (n = 25) discontinued treatment with Pralatrexate due to adverse reactions. The adverse reactions reported most frequently as the reason for discontinuation of treatment were mucositis (6%, n = 7) and thrombocytopenia (5%, n = 5).
### Dose Modifications
- The target dose of Pralatrexate was 30 mg/m2 once weekly for 6 weeks in 7-week cycles. The majority of patients (69%, n = 77) remained at the target dose for the duration of treatment. Overall, 85% of scheduled doses were administered.
### Dermatologic Reactions
- Toxic epidermal necrolysis, sometimes fatal, has been reported during post-marketing use of Pralatrexate Fatal cases have been reported following the first dose of Pralatrexate including when a reduced dose is given, and have been reported in patients with end-stage renal disease undergoing dialysis.
- When administering Pralatrexate to patients receiving probenecid or other drugs that may affect relevant transporter systems (eg, NSAIDs), monitor patients closely for signs of systemic toxicity due to increased drug exposure.
- The risk for toxicity may be greater when administering Pralatrexate to patients with moderate-to-severe impairment due to the contribution of renal excretion (approximately 34%) to the overall clearance of pralatrexate. Serious adverse drug reactions, including TEN and mucositis have been reported in patients with ESRD undergoing dialysis. Monitor patients for renal function and for systemic toxicity due to increased drug exposure and adjust dosing accordingly. Avoid the use of Pralatrexate in patients with end stage renal disease undergoing dialysis unless the potential benefit justifies the potential risk.
The molecular formula is C23H23N7O5 and the molecular weight is 477.48 g/mol.
- The pharmacokinetics of pralatrexate administered as a single agent at a dose of 30 mg/m2 administered as an intravenous push over 3-5 minutes once weekly for 6 weeks in 7-week cycles have been evaluated in 10 patients with PTCL. The total systemic clearance of pralatrexate diastereomers was 417 mL/min (S-diastereomer) and 191 mL/min (R-diastereomer). The terminal elimination half-life of pralatrexate was 12-18 hours (coefficient of variance [CV] = 62-120%). Pralatrexate total systemic exposure (AUC) and maximum plasma concentration (Cmax) increased proportionally with dose (dose range 30-325 mg/m2, including pharmacokinetics data from high-dose solid tumor clinical studies). The pharmacokinetics of pralatrexate did not change significantly over multiple treatment cycles, and no accumulation of pralatrexate was observed.
### Distribution
- Pralatrexate diastereomers showed a steady-state volume of distribution of 105 L (S-diastereomer) and 37 L (R-diastereomer). In vitro studies indicate that pralatrexate is approximately 67% bound to plasma proteins.
### Metabolism
- In vitro studies using human hepatocytes, liver microsomes and S9 fractions, and recombinant human CYP450 isozymes showed that pralatrexate is not significantly metabolized by the phase I hepatic CYP450 isozymes or phase II hepatic glucuronidases.
### Excretion
- A mass balance study has not been performed. The mean fraction of unchanged pralatrexate diastereomers excreted in urine following a pralatrexate dose of 30 mg/m2 administered as an intravenous push over 3-5 minutes was 31% (S-diastereomer) (CV = 47%) and 38% (R-diastereomer) (CV = 45%), respectively.
### Carcinogenesis
- Carcinogenicity studies have not been performed with pralatrexate.
### Mutagenesis
- Pralatrexate did not cause mutations in the Ames test or the Chinese hamster ovary cell chromosome aberration assay. Nevertheless, these tests do not reliably predict genotoxicity for this class of compounds. Pralatrexate did not cause mutations in the mouse micronucleus assay.
### Impairment of Fertility
- No fertility studies have been performed.
- The safety and efficacy of Pralatrexate was evaluated in an open-label, single-arm, multi-center, international trial that enrolled 115 patients with relapsed or refractory PTCL. One hundred and eleven patients were treated with Pralatrexate at 30 mg/m2 once weekly by IV push over 3-5 minutes for 6 weeks in 7-week cycles until disease progression or unacceptable toxicity. Of the 111 patients treated, 109 patients were evaluable for efficacy. Evaluable patients had histologically confirmed PTCL by independent central review using the Revised European American Lymphoma (REAL) World Health Organization (WHO) disease classification, and relapsed or refractory disease after at least one prior treatment.
- The primary efficacy endpoint was overall response rate (complete response, complete response unconfirmed, and partial response) as assessed by International Workshop Criteria (IWC). The key secondary efficacy endpoint was duration of response. Response assessments were scheduled at the end of cycle 1 and then every other cycle (every 14 weeks). Duration of response was measured from the first day of documented response to disease progression or death. Response and disease progression were evaluated by independent central review using the IWC.
- The median age of treated patients was 59.0 years (range 21-85); 68% were male and 32% were female. Most patients were White (72%) and other racial origins included: Black (13%), Hispanic (8%), Asian (5%), other and unknown (<1% each). Patients had an Eastern Cooperative Oncology Group (ECOG) performance status at study entry of 0 (39%), 1 (44%), or 2 (17%). The median time from initial diagnosis to study entry was 15.6 months (range 0.8 – 322.3).
- The median number of prior systemic therapies was 3 (range 1-12). Approximately one-fourth of patients (24%, n = 27) did not have evidence of response to any previous therapy. Approximately two-thirds of patients (63%, n = 70) did not have evidence of response to their most recent prior therapy before entering the study.
- In all evaluable patients (n = 109) treated with Pralatrexate, the response rate, as determined by independent central review by IWC, was 27% (n = 29) (TABLE 5).
- NDC 48818-001-01: 20 mg of pralatrexate in 1 mL solution in a vial (20 mg / 1 mL)
- NDC 48818-001-02: 40 mg of pralatrexate in 2 mL solution in a vial (40 mg / 2 mL)
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https://www.wikidoc.org/index.php/10-propargyl-10-deazaaminopterin
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b4548b5b6b45a81888c1b909111b08a611d337fb
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wikidoc
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100% English
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100% English
100% English was a Channel 4 television programme shown in November 2006 in the United Kingdom. It looked at the genetic makeup of English people who considered themselves to be ethnically English and found that while all had an ethnic makeup similar to people of European descent, a minority discovered genetic markers from North Africa and the Middle East from several generations before they were born. The presenter was Andrew Graham-DixonThe test results were interpreted by DNAPrint Genomics, based in Sarasota, Florida.
The concept of the show was to:
Take eight people - all of whom are convinced they are 100% English. Then submit a sample of their DNA to a series of state-of-the-art tests... Lord Tebbit, Garry Bushell and Carol Thatcher are among the participants who have agreed to place their genetic make-up under the microscope..
Gary Bushell, who appeared on the show in good-faith, later criticised the slant of the programme and the portrayal of English people. On his website he stated: "Only Nazis, and it appears C4, think of national identity in terms of racial purity... Besides, you could apply the same tests to the French or Italians and get similar results, but no-one questions their right to nationhood."
Bushell also criticised DNAPrint Genomics stating their tests had a 28% error margin for European DNA and that the same DNA sample often produced radically different results. He also stated that most anthropologists disagreed with DNAPrint Genomic's racial classifications and questioned the reliability of the markers that they had used to designate African DNA.
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100% English
100% English was a Channel 4 television programme shown in November 2006 in the United Kingdom. It looked at the genetic makeup of English people who considered themselves to be ethnically English and found that while all had an ethnic makeup similar to people of European descent, a minority discovered genetic markers from North Africa and the Middle East from several generations before they were born. The presenter was Andrew Graham-DixonThe test results were interpreted by DNAPrint Genomics, based in Sarasota, Florida[1].
The concept of the show was to:
Take eight people - all of whom are convinced they are 100% English. Then submit a sample of their DNA to a series of state-of-the-art tests... Lord Tebbit, Garry Bushell and Carol Thatcher are among the participants who have agreed to place their genetic make-up under the microscope.. [2]
Gary Bushell, who appeared on the show in good-faith, later criticised the slant of the programme and the portrayal of English people. On his website he stated: "Only Nazis, and it appears C4, think of national identity in terms of racial purity... Besides, you could apply the same tests to the French or Italians and get similar results, but no-one questions their right to nationhood."
Bushell also criticised DNAPrint Genomics stating their tests had a 28% error margin for European DNA and that the same DNA sample often produced radically different results. He also stated that most anthropologists disagreed with DNAPrint Genomic's racial classifications and questioned the reliability of the markers that they had used to designate African DNA.[3]
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https://www.wikidoc.org/index.php/100%25_English
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86fe94b60a67c41974ee7d8148b98eea2b77f76a
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wikidoc
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Isotretinoin
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Isotretinoin
# 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
Isotretinoin is a dermatologic agent that is FDA approved for the treatment of severe recalcitrant nodular acne in patients 12 years of age and older. There is a Black Box Warning for this drug as shown here. Common adverse reactions include lip dry, dry skin, back pain, dry eye, arthralgia, epistaxis, headache, nasopharyngitis, chapped lips, dermatitis, blood creatine kinase increased, cheilitis, musculoskeletal discomfort, upper respiratory tract infection, visual acuity reduced.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- ABSORICA is a retinoid indicated for the treatment of severe recalcitrant nodular acne in patients 12 years of age and older. Nodules are inflammatory lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic. “Severe,” by definition, means “many” as opposed to “few or several” nodules. Because of significant adverse reactions associated with its use, ABSORICA should be reserved for patients with multiple severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, ABSORICA is indicated only for those female patients who are not pregnant, because ABSORICA can cause severe birth defects.
- Dosing Information
- Healthcare professionals who prescribe ABSORICA must be certified in the iPLEDGE program and must comply with the required monitoring to ensure safe use of ABSORICA.
- The required laboratory testing must be completed prior to dosing ABSORICA.
- Pregnancy Testing, and Contraceptive measures must be followed prior to dosing ABSORICA.
- Recommended Dosage
- The recommended dosage range for ABSORICA is 0.5 to 1 mg/kg/day given in two divided doses without regard to meals for 15 to 20 weeks (see Table 1). To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid.
- The safety of once daily dosing with ABSORICA has not been established. Once daily dosing is not recommended.
- Dosage Range
- In trials comparing 0.1, 0.5, and 1 mg/kg/day, it was found that all dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted according to response of the disease and/or the appearance of clinical side effects, some of which may be dose-related. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to 2 mg/kg/day, as tolerated.
- Duration of Use
- A normal course of treatment is 15 – 20 weeks. If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of ABSORICA, even in low doses, has not been studied, and is not recommended. It is important that ABSORICA be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of ABSORICA on bone loss is unknown.
- Laboratory Testing
- Pregnancy Testing:
- Lipid Profile:
- Perform a fasting lipid profile including triglycerides prior to use of ABSORICA.
- Liver Function Test:
- Perform liver function tests prior to use of ABSORICA.
Limitations of Use
- A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged remission of disease in many patients. If a second course of therapy is needed, it should not be initiated until at least 8 weeks after completion of the first course, because experience with isotretinoin has shown that patients may continue to improve following treatment with isotretinoin. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth.
- As a part of the iPLEDGE program, ABSORICA may only be administered to patients enrolled in the program.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Isotretinoin in adult patients.
### Non–Guideline-Supported Use
- Acne vulgaris
- Rosacea
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Healthcare professionals who prescribe ABSORICA must be certified in the iPLEDGE program and must comply with the required monitoring to ensure safe use of ABSORICA.
- The required laboratory testing must be completed prior to dosing ABSORICA.
- Pregnancy Testing, and Contraceptive measures must be followed prior to dosing ABSORICA.
- Recommended Dosage:
- The recommended dosage range for ABSORICA is 0.5 to 1 mg/kg/day given in two divided doses without regard to meals for 15 to 20 weeks (see Table 1). To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid.
- The safety of once daily dosing with ABSORICA has not been established. Once daily dosing is not recommended.
- Dosage Range:
- In trials comparing 0.1, 0.5, and 1 mg/kg/day, it was found that all dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted according to response of the disease and/or the appearance of clinical side effects, some of which may be dose-related. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to 2 mg/kg/day, as tolerated.
- Duration of Use:
- A normal course of treatment is 15 – 20 weeks. If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of ABSORICA, even in low doses, has not been studied, and is not recommended. It is important that ABSORICA be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of ABSORICA on bone loss is unknown.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Isotretinoin in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Isotretinoin in pediatric patients.
# Contraindications
Pregnancy
- ABSORICA can cause fetal harm when administered to a pregnant woman. Major congenital malformations, spontaneous abortions, and premature births have been documented following pregnancy exposure to isotretinoin in any amount and even for short periods of time. ABSORICA is contraindicated in females who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, treatment should be discontinued and the patient should be apprised of the potential hazard to the fetus.
Hypersensitivity
- Hypersensitivity to this product (or Vitamin A, given the chemical similarity to isotretinoin) or to any of its components.
# Warnings
- ABSORICA must not be used by female patients who are or may become pregnant. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking ABSORICA in any amount, even for short periods of time.
Embryofetal Toxicity
Teratogenicity
- Major congenital malformations, spontaneous abortions, and premature births have been documented following pregnancy exposure to isotretinoin. Females of childbearing potential must comply with the pregnancy testing and contraception requirements described in the iPLEDGE program. There are no accurate means of determining whether an exposed fetus has been affected.
No Blood Donation
- Patients must be informed not to donate blood during isotretinoin therapy and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to isotretinoin.
iPLEDGE Program
- Because of the risk of teratogenicity and to minimize fetal exposure, ABSORICA is available only through a restricted program under a REMS called iPLEDGE. Under the ABSORICA REMS, prescribers, patients, pharmacies, and distributors must enroll and be registered in the program. ABSORICA must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE program. Only FDA-approved isotretinoin products must be distributed, prescribed, dispensed, and used.
Required components of the iPLEDGE Program are:
- ABSORICA must only be prescribed by prescribers who are registered and activated with the iPLEDGE program and agree to comply with the REMS requirements described in the booklets entitled The Guide to Best Practices for the iPLEDGE Program, The iPLEDGE Program Prescriber Contraception Counseling Guide, and Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin.
- Male patients and Female patients not of childbearing potential: To obtain ABSORICA, these patients must understand the risks and benefits of ABSORICA, comply with the REMS requirements described in the booklet entitled The iPLEDGE Program Guide to Isotretinoin for Male Patients and Female Patients Who Cannot Get Pregnant, and sign a Patient Information/Informed Consent form.
- Female patients of childbearing potential: ABSORICA is contraindicated in female patients who are or may become pregnant.
- Female patients of childbearing potential who are not pregnant must understand the risks and benefits, comply with the REMS requirements described in the booklet entitled The iPLEDGE Program Guide to Isotretinoin for Female Patients Who Can Get Pregnant and The iPLEDGE Program Birth Control Workbook (including the pregnancy testing and contraception requirements, and sign a Patient Information/Informed Consent form and Patient Information/Informed Consent About Birth Defects form. Additionally, the patient must answer questions about the iPLEDGE program and pregnancy prevention monthly.
- Pharmacies that dispense ABSORICA must be registered and activated with iPLEDGE, must only dispense to patients who are authorized to receive ABSORICA, and agree to comply with the REMS requirements described in the booklet entitled The Pharmacist Guide for the iPLEDGE Program.
- Female patients of childbearing potential must fill and pick up the prescription within 7 days of the specimen collection for the pregnancy test; male patients and female patients not of childbearing potential must fill and pick up the prescription within 30 days of the office visit.
- ABSORICA must only be dispensed in no more than a 30-day supply with a Medication Guide. Refills require a new prescription and a new authorization from the iPLEDGE system.
- Wholesalers and distributors that distribute ABSORICA must be registered with iPLEDGE and agree to comply with the REMS requirements.
- If a pregnancy does occur during ABSORICA treatment, ABSORICA must be discontinued immediately. The patient should be referred to an obstetrician-gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure during or 1 month after ABSORICA therapy must be reported immediately to the FDA via the MedWatch telephone number 1-800-FDA-1088 and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com).
- Further information, including a list of qualified pharmacies, is available at www.ipledgeprogram.com or 1-866-495-0654.
Unacceptable Contraception
Micro-dosed Progesterone Preparations
- Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) are an inadequate method of contraception during ABSORICA therapy.
Psychiatric Disorders
- Isotretinoin may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. No mechanism of action has been established for these reactions. Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin. Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of ABSORICA therapy, patients and family members should be asked about any history of psychiatric disorder, and at each visit during therapy patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary. Signs and symptoms of depression, as described in the brochure (Recognizing Psychiatric Disorders in Adolescents and Young Adults), include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment. Patients should stop ABSORICA and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. Discontinuation of ABSORICA therapy may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient's family. A referral to a mental health professional may be necessary. The physician should consider whether ABSORICA therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of ABSORICA therapy.
Pseudotumor Cerebri
- Isotretinoin use has been associated with cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. Concomitant treatment with tetracyclines should therefore be avoided. Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea and vomiting, and visual disturbances. Patients with these symptoms should be screened for papilledema and, if present, they should be told to discontinue ABSORICA immediately and be referred to a neurologist for further diagnosis and care.
Serious Skin Reactions
- There have been post-marketing reports of erythema multiforme and severe skin reactions associated with isotretinoin use. These reactions may be serious and result in death, life-threatening events, hospitalization, or disability. Patients should be monitored closely for severe skin reactions, and discontinuation of ABSORICA should be considered if warranted.
Pancreatitis
- Acute pancreatitis has been reported in isotretinoin-treated patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. ABSORICA should be stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur.
Lipid Abnormalities
- Elevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with isotretinoin. Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving isotretinoin in clinical trials. In addition, approximately 15% developed a decrease in high-density lipoproteins and about 7% showed an increase in cholesterol levels. In clinical trials, the effects of triglycerides, HDL and cholesterol were reversible upon cessation of isotretinoin therapy. Some patients have been able to reverse triglyceride elevation by reduction in weight, restriction of dietary fat and alcohol, and reduction in the dose while continuing isotretinoin.
- Blood lipid determinations should be performed before ABSORICA is given and then at intervals until the lipid response to ABSORICA is established, which usually occurs within 4 weeks. Especially careful consideration must be given to risk/benefit for patients who may be at high risk of triglyceridemia during ABSORICA therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If ABSORICA therapy is instituted, more frequent checks of serum values for lipids and/or blood sugar are recommended.
- The cardiovascular consequences of hypertriglyceridemia associated with isotretinoin are unknown.
Hearing Impairment
- Impaired hearing has been reported in patients taking isotretinoin; in some cases, the hearing impairment has been reported to persist after therapy has been discontinued. Mechanism(s) and causality for this reaction have not been established. Patients who experience tinnitus or hearing impairment should discontinue ABSORICA treatment and be referred for specialized care for further evaluation.
Hepatotoxicity
- Clinical hepatitis considered to be possibly or probably related to isotretinoin therapy has been reported. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials with isotretinoin, some of which normalized with dosage reduction or continued administration of the drug. If normalization does not readily occur or if hepatitis is suspected during treatment with ABSORICA, the drug should be discontinued and the etiology further investigated.
Inflammatory Bowel Disease
- Isotretinoin has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. In some instances, symptoms have been reported to persist after isotretinoin treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue ABSORICA immediately.
Skeletal Abnormalities
Bone Mineral Density Changes
- Isotretinoin may have a negative effect on bone mineral density (BMD) in some patients. In a clinical trial of ABSORICA and a generic product of Accutane® (isotretinoin), 27/306 (8.8%) of adolescents had BMD declines, defined as ≥ 4% lumbar spine or total hip, or ≥ 5% femoral neck, during the 20 week treatment period. Repeat scans conducted within 2-3 months after the post-treatment scan showed no recovery of BMD. Longer term data at 4-11 months showed that 3 out of 7 patients had total hip and femoral neck BMD below pre-treatment baseline, and 2 others did not show the increase in BMD above baseline expected in this adolescent population. Therefore, physicians should use caution when prescribing ABSORICA to patients with a history of childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism. This would include patients diagnosed with anorexia nervosa and those who are on chronic drug therapy that causes drug-induced osteoporosis/osteomalacia and/or affects vitamin D metabolism, such as systemic corticosteroids and any anticonvulsant.
Musculoskeletal Abnormalities
- Approximately 16% of patients treated with isotretinoin in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these symptoms were mild to moderate, but occasionally required discontinuation of the drug.
- In a trial of pediatric patients treated with isotretinoin, approximately 29% (104/358) developed back pain. Back pain was severe in 13.5% (14/104) of the cases and occurred at a higher frequency in female patients than male patients. Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of ABSORICA. Consideration should be given to discontinuation of ABSORICA if any significant abnormality is found.
- There have been spontaneous reports of osteoporosis, osteopenia, bone fractures and/or delayed healing of bone fractures in patients while on therapy with isotretinoin or following cessation of therapy with isotretinoin. While causality to isotretinoin has not been established, an effect cannot be ruled out.
- Patients may be at an increased risk when participating in sports with repetitive impact where the risks of spondylolisthesis with and without pars fractures and hip growth plate injures in early and late adolescence are known.
- Effects of multiple courses of isotretinoin on the developing musculoskeletal system are unknown. There is some evidence that long-term, high-dose, or multiple courses of therapy with isotretinoin have more of an effect than a single course of therapy on the musculoskeletal system.
- Longer term effects have not been studied. It is important that ABSORICA be given at the recommended doses for no longer than the recommended duration.
Hyperostosis
- A high prevalence of skeletal hyperostosis was noted in clinical trials for disorders of keratinization with a mean dose of 2.24 mg/kg/day of isotretinoin. Additionally, skeletal hyperostosis was noted in 6 of 8 patients in a prospective trial of disorders of keratinization. Minimal skeletal hyperostosis and calcification of ligaments and tendons have also been observed by x-ray in prospective trials of nodular acne patients treated with a single course of therapy at recommended doses. The skeletal effects of multiple isotretinoin treatment courses for acne are unknown.
- In a clinical trial of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, hyperostosis was not observed after 16 to 20 weeks of treatment with approximately 1 mg/kg/day of isotretinoin given in two divided doses. Hyperostosis may require a longer time frame to appear. The clinical course and significance remain unknown.
Premature Epiphyseal Closure
- There are spontaneous literature reports of premature epiphyseal closure in acne patients receiving recommended doses of isotretinoin. The effect of multiple courses of isotretinoin on epiphyseal closure is unknown.
- In a 20-week clinical trial that included 289 adolescents on ABSORICA or a generic product of Accutane® (isotretinoin) who had hand radiographs taken to assess bone age, a total of 9 (3.11%) patients had bone age changes that were clinically significant and for which a drug-related effect cannot be excluded.
Ocular Abnormalities
- Visual problems should be carefully monitored. All ABSORICA patients experiencing visual difficulties should discontinue ABSORICA treatment and have an ophthalmological examination.
Corneal Opacities
- Corneal opacities have occurred in patients receiving isotretinoin for acne and more frequently when higher drug dosages were used in patients with disorders of keratinization. The corneal opacities that have been observed in clinical trial patients treated with isotretinoin have either completely resolved or were resolving at follow-up 6 to 7 weeks after discontinuation of the drug.
Decreased Night Vision
- Decreased night vision has been reported during isotretinoin therapy and in some instances the event has persisted after therapy was discontinued. Because the onset in some patients was sudden, patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night.
Dry Eye
- Dry eye has been reported in subjects during isotretinoin therapy. Patients who wear contact lenses may have trouble wearing them while on ABSORICA treatment and afterwards.
Hypersensitivity
- Anaphylactic reactions and other allergic reactions have been reported in isotretinoin-treated patients. Cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement (including renal) have been reported. Severe allergic reaction necessitates discontinuation of therapy and appropriate medical management.
Laboratory Monitoring for Adverse Reactions
Lipids Test
- Pretreatment and follow-up blood lipids should be obtained under fasting conditions. After consumption of alcohol, at least 36 hours should elapse before these determinations are made. It is recommended that these tests be performed at weekly or biweekly intervals until the lipid response to ABSORICA is established. The incidence of hypertriglyceridemia is 1 patient in 4 on isotretinoin.
Liver Function Test
- Since elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported in patients on isotretinoin, pretreatment and follow-up liver function tests should be performed at weekly or biweekly intervals until the response to ABSORICA has been established.
Glucose
- Some patients receiving isotretinoin have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during isotretinoin therapy, although no causal relationship has been established.
CPK
- Some patients undergoing vigorous physical activity while on isotretinoin therapy have experienced elevated CPK levels; however, the clinical significance is unknown. There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity. In an isotretinoin clinical trial of 924 patients, marked elevations in CPK (≥350 U/L) were observed in approximately 24% of patients. In another clinical trial of 217 pediatric patients (12 – 17 years) elevations in CPK were observed in 12% of patients, including those undergoing strenuous physical activity in association with reported musculoskeletal adverse events such as back pain, arthralgia, limb injury, or muscle sprain. In these patients, approximately half of the CPK elevations returned to normal within 2 weeks and half returned to normal within 4 weeks. No cases of rhabdomyolysis were reported in this clinical trial.
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions with ABSORICA or other isotretinoin products are described in more detail in other sections of the labeling:
- Embryofetal Toxicity
- Psychiatric Disorders
- Pseudotumor Cerebri
- Serious Skin Reactions
- Pancreatitis
- Lipid Abnormalities
- Hearing Impairment
- Hepatotoxicity
- Inflammatory Bowel Disease
- Skeletal Abnormalities
- Ocular Abnormalities
- Hypersensitivity
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of ABSORICA cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice.
- The adverse reactions listed below reflect both clinical experience with ABSORICA, and consider other adverse reactions that are known from clinical trials and the post-marketing surveillance with oral isotretinoin. The relationship of some of these events to isotretinoin therapy is unknown. Many of the side effects and adverse events seen in patients receiving isotretinoin are similar to those described in patients taking very high doses of vitamin A (dryness of the skin and mucous membranes, e.g., of the lips, nasal passage, and eyes).
Dose Relationship
- Cheilitis and hypertriglyceridemia are adverse reactions that are usually dose related. Most adverse reactions reported in clinical trials with isotretinoin were reversible when therapy was discontinued; however, some persisted after cessation of therapy.
Body as a Whole
- The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): fatigue, irritability, pain. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: allergic reactions, including vasculitis, systemic hypersensitivity, edema, lymphadenopathy, weight loss.
Cardiovascular
- The following adverse reactions have been reported with isotretinoin: vascular thrombotic disease, stroke, palpitation, tachycardia.
Endocrine/Metabolism and Nutritional
- The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): decreased appetite, weight fluctuation, hyperlipidaemia. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: hypertriglyceridemia, alterations in blood sugar.
Gastrointestinal
- The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): lip dry, chapped lips, cheilitis, nausea, constipation, diarrhea, abdominal pain, vomiting. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: inflammatory bowel disease, hepatitis, pancreatitis, bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, and other nonspecific gastrointestinal symptoms.
Hematologic
- The following adverse reactions have been reported with isotretinoin: allergic reactions, anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis.
Infections and infestations
- The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): nasopharyngitis, hordeolum, upper respiratory tract infection. In addition to the above adverse reactions, the following adverse reaction has been reported with isotretinoin: infections (including disseminated herpes simplex).
Laboratory Abnormalities
- The following changes in laboratory tests have been noted in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): blood creatine phosphokinase (CPK) increased, blood triglycerides increased, alanine aminotransferase (SGPT) increased, aspartate aminotransferase (SGOT) increased, gamma-glutamyltransferase (GGTP) increased, blood cholesterol increased, low density lipoprotein (LDL) increased, white blood cell count decreased, blood alkaline phosphatase increased, blood bilirubin increased, blood glucose increased, high density lipopoprotein (HDL) decreased, bone mineral density decreased. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: increased LDH, elevation of fasting blood sugar, hyperuricemia, decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis), elevated sedimentation rates, elevated platelet counts, thrombocytopenia, white cells in the urine, proteinuria, microscopic or gross hematuria.
Musculoskeletal and Connective Tissue
- The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): decreases in bone mineral density, musculoskeletal symptoms (sometimes severe) including back pain, athralgia, musculoskeletal discomfort, musculoskeletal pain, neck pain, pain in extremity, myalgia, musculoskeletal stiffness. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, tendonitis, arthritis, transient pain in the chest, and rare reports of rhabdomyolysis.
Neurological
- The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): headache, syncope. In addition to the above adverse reactions, other adverse reactions reported with isotretinoin include: pseudotumor cerebri, dizziness, drowsiness, lethargy, malaise, nervousness, paresthesias, seizures, stroke, weakness.
Psychiatric
- The following adverse reactions have been reported in clinical trials conducted with ABSORICA and a generic product of Accutane® (isotretinoin): suicidal ideation, insomnia, anxiety, depression, irritability, panic attack, anger, euphoria, violent behaviors, emotional instability. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: suicide attempts, suicide, aggression, psychosis and hallucination auditory. Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.
Reproductive System
- The following adverse reaction has been reported with isotretinoin: abnormal menses.
Respiratory
- The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): epistaxis, nasal dryness. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: bronchospasms (with or without a history of asthma), respiratory infection, voice alteration.
Skin and Subcutaneous Tissue
- The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): dry skin, dermatitis, eczema, rash, dermatitis contact, alopecia, pruritus, sunburn, erythema. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: acne fulminans, alopecia (which in some cases persists), bruising, dry nose, eruptive xanthomas, erythema multiforme, flushing, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), Stevens-Johnson syndrome, sunburn susceptibility increased, sweating, toxic epidermal necrolysis, urticaria, vasculitis(including Wegener's granulomatosis), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting).
Special Senses
- Hearing: The following adverse reactions have been reported with isotretinoin: tinnitus and hearing impairment.
- Ocular: The following adverse reactions have been reported in clinical trials conducted with ABSORICA and a generic product of Accutane® (isotretinoin): dry eye, visual acuity reduced, vision blurred, eye pruritis, eye irritation, asthenopia, decreased night vision, ocular hyperemia, increased lacrimation, and conjunctivitis. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: corneal opacities, decreased night vision which may persist, cataracts, color vision disorder, conjunctivitis, eyelid inflammation, keratitis, optic neuritis, photobia, visual disturbances.
Renal and Urinary
- The following adverse reactions have been reported in clinical trials conducted with isotretinoin: glomerulonephritis, nonspecific urogenital findings.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Isotretinoin in the drug label
# Drug Interactions
Vitamin A
- ABSORICA is closely related to vitamin A. Therefore, the use of both vitamin A and ABSORICA at the same time may lead to vitamin A side effects. Patients should be advised against taking vitamin supplements containing Vitamin A to avoid additive toxic effects.
Tetracyclines
- Concomitant treatment with ABSORICA and tetracyclines should be avoided because isotretinoin use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines.
Phenytoin
- Isotretinoin has not been shown to alter the pharmacokinetics of phenytoin in a trial in seven healthy volunteers. These results are consistent with the in vitro finding that neither isotretinoin nor its metabolites induce or inhibit the activity of the CYP2C9 human hepatic P450 enzyme. Phenytoin is known to cause osteomalacia. No formal clinical trials have been conducted to assess if there is an interactive effect on bone loss between phenytoin and isotretinoin. Therefore, caution should be exercised when using these drugs together.
St. John's Wort
- Isotretinoin use is associated with depression in some patients. Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John's Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John's Wort.
Systemic Corticosteroids
- Systemic corticosteroids are known to cause osteoporosis. No formal clinical trials have been conducted to assess if there is an interactive effect on bone loss between systemic corticosteroids and isotretinoin. Therefore, caution should be exercised when using these drugs together.
Norethindrone/ethinyl estradiol
- In a trial of 31 premenopausal female patients with severe recalcitrant nodular acne receiving Norethindrone/ethinyl estradiol as an oral contraceptive agent, isotretinoin at the recommended dose of 1 mg/kg/day, did not induce clinically relevant changes in the pharmacokinetics of ethinyl estradiol and norethindrone and in the serum levels of progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Prescribers are advised to consult the package insert of medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
Pregnancy Category X
Risk Summary
- ABSORICA is contraindicated during pregnancy because isotretinoin can cause can cause fetal harm when administered to a pregnant woman. There is an increased risk of major congenital malformations, spontaneous abortions, and premature births following isotretinoin exposure during pregnancy in humans. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to a fetus.
Clinical Considerations
- If pregnancy does occur during treatment of a female patient who is taking ABSORICA, ABSORICA must be discontinued immediately and she should be referred to an obstetrician-gynecologist experienced in reproductive toxicity for further evaluation and counseling.
Human Data
- Major congenital malformations that have been documented following isotretinoin exposure include malformations of the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and parathyroid glands. External malformations include: skull; ear (including anotia, micropinna, small or absent external auditory canals); eye (including microphthalmia); facial dysmorphia and cleft palate. Internal abnormalities include: CNS (including cerebral and cerebellar malformations, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular; thymus gland; parathyroid hormone deficiency. In some cases death has occurred as a result of the malformations.
- Isotretinoin is found in the semen of male patients taking isotretinoin, but the amount delivered to a female partner would be about one million times lower than an oral dose of 40 mg. While the no-effect limit for isotretinoin induced embryopathy is unknown and 20 years of post-marketing reports include four reports with isolated defects compatible with features of retinoid exposed fetuses, two of these reports were incomplete and two had other possible explanations for the defects observed.
- Cases of IQ scores less than 85 with or without other abnormalities have been reported. An increased risk of spontaneous abortion and premature births have been documented with isotretinoin exposure during pregnancy.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Isotretinoin in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Isotretinoin during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from ABSORICA, 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 use of ABSORICA in pediatric patients less than 12 years of age has not been studied. The use of ABSORICA for the treatment of severe recalcitrant nodular acne in pediatric patients ages 12 to 17 years should be given careful consideration, especially for those patients where a known metabolic or structural bone disease exists. Use of ABSORICA in this age group for severe recalcitrant nodular acne is supported by evidence from a clinical trial of ABSORICA compared to a generic product of Accutane® (isotretinoin) in 397 pediatric patients (12 to 17 years). Results from this trial demonstrated that both ABSORICA and the other isotretinoin drug product, at a dose of 1 mg/kg/day given in two divided doses, was effective in treating severe recalcitrant nodular acne in pediatric patients.
- In trials with isotretinoin, adverse reactions reported in pediatric patients were similar to those described in adults except for the increased incidence of back pain and arthralgia (both of which were sometimes severe) and myalgia in pediatric patients. In a trial of pediatric patients treated with isotretinoin, approximately 29% (104/358) developed back pain. Back pain was severe in 13.5% (14/104) of the cases and occurred at a higher frequency in female patients than male patients. Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of ABSORICA. Consideration should be given to discontinuation of ABSORICA if any significant abnormality is found.
- The effect on bone mineral density (BMD) of a 20-week course of therapy with ABSORICA or a generic product of Accutane® (isotretinoin) was evaluated in a double-blind, randomized clinical trial involving 396 adolescents with severe recalcitrant nodular acne (mean age 15.4, range 12-17, 80% males). Following 20 weeks of treatment, there were no statistically significant differences between the treatment groups. The mean changes in BMD from baseline for the overall trial population were 1.8% for lumbar spine, -0.1% for total hip and -0.3% for femoral neck. Mean BMD Z-scores declined from baseline at each of these sites (-0.053, -0.109 and -0.104 respectively). Out of 306 adolescents, 27 (8.8%) had clinically significant BMD declines defined as ≥4% lumbar spine or total hip, or ≥5% femoral neck, including 2 subjects for lumbar spine, 17 for total hip and 20 for femoral neck. Repeat DXA scans within 2-3 months after the post treatment scan showed no recovery of BMD. Longer-term follow up at 4-11 months showed that 3 out of 7 patients had total hip and femoral neck BMD below pre-treatment baseline, and 2 others did not show the increase in BMD above baseline expected in this adolescent population. The significance of these changes in regard to long-term bone health and future fracture risk is unknown.
- In an open-label clinical trial (N=217) of a single course of therapy with isotretinoin for adolescents with severe recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly decreased (lumbar spine change >-4% and total hip change >-5%) or were increased in the majority of patients. One patient had a decrease in lumbar spine bone mineral density >4% based on unadjusted data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density >4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%) had a decrease in total hip bone mineral density >5% based on unadjusted data. Twenty-one (10.6%) patients had decreases in total hip bone mineral density >5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up trials performed in 8 of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in 5 patients at the lumbar spine, while the other 3 patients had lumbar spine bone density measurements below baseline values. Total hip bone mineral densities remained below baseline (range −1.6% to −7.6%) in 5 of 8 patients (62.5%).
- In a separate open-label extension trial of 10 patients, ages 13 to 18 years, who started a second course of isotretinoin 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25%.
- There are spontaneous literature reports of premature epiphyseal closure in acne patients receiving recommended doses of isotretinoin. The effect of multiple courses of isotretinoin on epiphyseal closure is unknown. In a 20-week clinical trial that included 289 adolescents who had hand radiographs taken to assess bone age, a total of 9 patients had bone age changes that were clinically significant and for which a drug-related effect cannot be excluded.
### Geriatic Use
- Clinical trials of ABSORICA did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Although reported clinical experience has not identified differences in responses between elderly and younger patients, effects of aging might be expected to increase some risks associated with ABSORICA therapy.
### Gender
- There is no FDA guidance on the use of Isotretinoin with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Isotretinoin with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Isotretinoin in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Isotretinoin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Isotretinoin in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Isotretinoin in patients who are immunocompromised.
### Females of Childbearing Potential
- All females of childbearing potential must comply with the iPLEDGE program requirements.
Pregnancy Testing
- ABSORICA must only be prescribed to female patients who are known not to be pregnant as confirmed by a negative CLIA-certified laboratory conducted pregnancy test. Female patients of childbearing potential must have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial ABSORICA prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for ABSORICA. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests must be at least 19 days.
- For patients with regular menstrual cycles, perform the second pregnancy test during the first 5 days of the menstrual period immediately preceding the beginning of ABSORICA therapy and after the patient has used 2 forms of contraception for 1 month.
- For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, perform the second pregnancy test immediately preceding the beginning of ABSORICA therapy and after the patient has used 2 forms of contraception for 1 month.
- Each month of continued ABSORICA therapy, patients must have a negative result from a urine or serum pregnancy test. A pregnancy test must be repeated each month, in a CLIA-certified laboratory, prior to the female patient receiving each prescription. A pregnancy test must also be completed at the end of the entire course of isotretinoin therapy and 1 month after the discontinuation of isotretinoin.
Contraception
- Females of childbearing potential must use 2 forms of effective contraception simultaneously, at least 1 of which must be a primary form, unless the patient commits to continuous abstinence from heterosexual contact, or the patient has undergone a hysterectomy or bilateral oophorectomy, or has been medically confirmed to be post-menopausal. Patients must use 2 forms of effective contraception for at least 1 month prior to initiation of ABSORICA therapy, during ABSORICA therapy, and for 1 month after discontinuing ABSORICA therapy. Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) are an inadequate method of contraception during isotretinoin therapy.
- Effective forms of contraception include both primary and secondary forms of contraception:
- Any birth control method can fail. There have been reports of pregnancy from female patients who have used combination oral contraceptives, as well as transdermal patch/ injectable/ implantable/ vaginal ring hormonal birth control products; these pregnancies occurred while taking isotretinoin. These reports are more frequent for female patients who use only a single method of contraception. Therefore, it is critically important for female patients of childbearing potential use 2 effective forms of contraception simultaneously.
- Using two forms of contraception simultaneously substantially reduces the chances that a female will become pregnant over the risk of pregnancy with either form alone. A drug interaction that decreases effectiveness of hormonal contraceptives has not been entirely ruled out for isotretinoin. Although hormonal contraceptives are highly effective, prescribers are advised to consult the package insert of any medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products.
- Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John's Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John's Wort.
- If the patient has unprotected heterosexual intercourse at any time 1 month before, during, or 1 month after therapy, she must:
- Stop taking ABSORICA immediately, if on therapy
- Have a pregnancy test at least 19 days after the last act of unprotected heterosexual intercourse
- Start using 2 forms of effective contraception simultaneously again for 1 month before resuming ABSORICA therapy
- If a pregnancy does occur during ABSORICA treatment, ABSORICA must be discontinued immediately. The patient should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure during or 1 month after ABSORICA therapy must be reported immediately to the FDA via the MedWatch number 1-800-FDA-1088 and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com).
# Administration and Monitoring
### Administration
- Healthcare professionals who prescribe ABSORICA must be certified in the iPLEDGE program and must comply with the required monitoring to ensure safe use of ABSORICA
- The required laboratory testing must be completed prior to dosing ABSORICA.
- Pregnancy Testing, and Contraceptive measures must be followed prior to dosing ABSORICA.
- Recommended Dosage
- The recommended dosage range for ABSORICA is 0.5 to 1 mg/kg/day given in two divided doses without regard to meals for 15 to 20 weeks (see Table 1). To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid.
- The safety of once daily dosing with ABSORICA has not been established. Once daily dosing is not recommended.
- Dosage Range
- In trials comparing 0.1, 0.5, and 1 mg/kg/day, it was found that all dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted according to response of the disease and/or the appearance of clinical side effects, some of which may be dose-related. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to 2 mg/kg/day, as tolerated.
- Duration of Use
- A normal course of treatment is 15 – 20 weeks. If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of ABSORICA, even in low doses, has not been studied, and is not recommended. It is important that ABSORICA be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of ABSORICA on bone loss is unknown.
- Laboratory Testing
- Pregnancy Testing
- Lipid Profile
- Perform a fasting lipid profile including triglycerides prior to use of ABSORICA.
- Liver Function Test
- Perform liver function tests prior to use of ABSORICA.
### DOSAGE FORMS AND STRENGTHS
- ABSORICA is available in 10 mg, 20 mg, 25 mg, 30 mg, 35 mg and 40 mg capsules.
- 10 mg: Dark yellow, opaque, capsule imprinted with black ink “ G 240” on cap and “ 10” on the body
- 20 mg: Red, opaque, capsule imprinted with black ink “ G 241” on cap and “ 20” on the body
- 25 mg: Green, opaque, capsule imprinted with white ink “ G 342” on cap and “ 25” on the body
- 30 mg: Brown, opaque, capsule imprinted with white ink “ G 242” on cap and “ 30” on the body
- 35 mg: Dark blue, opaque, capsule imprinted with white ink “ G 343” on cap and “ 35” on the body
- 40 mg: Brown and red, capsule imprinted with white ink “ G 325” on cap and “ 40” on the body
### Monitoring
- There is limited information regarding Monitoring of Isotretinoin in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Isotretinoin in the drug label.
# Overdosage
- In humans, overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. These symptoms quickly resolve without apparent residual effects.
- ABSORICA causes serious birth defects at any dosage (see Boxed CONTRAINDICATIONS AND WARNINGS). Female patients of childbearing potential who present with ABSORICA overdose must be evaluated for pregnancy. Patients who are pregnant should receive counseling about the risks to the fetus, as described in the Boxed CONTRAINDICATIONS AND WARNINGS. Non-pregnant patients must be warned to avoid pregnancy for at least one month and receive contraceptive counseling as described in Warnings and Precautions. Educational materials for such patients can be obtained by calling the manufacturer. Because an overdose would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, male patients should use a condom, or avoid reproductive sexual activity with a female patient who is or might become pregnant, for 1 month after the overdose. All patients with ABSORICA overdose should not donate blood for at least 1 month.
# Pharmacology
## Mechanism of Action
- ABSORICA is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1 mg/kg/day, inhibits sebaceous gland function and keratinization. Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and is related to the dose and duration of treatment with isotretinoin and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation. The exact mechanism of action of ABSORICA is unknown.
## Structure
- ABSORICA (isotretinoin) Capsules contain 10 mg, 20 mg, 25 mg, 30 mg, 35 mg or 40 mg of isotretinoin (a retinoid) in hard gelatin capsules for oral administration. In addition to the active ingredient, isotretinoin, each capsule contains the following inactive ingredients: propyl gallate, sorbitan monooleate, soybean oil and stearoyl polyoxylglycerides. The gelatin capsules contain the following dye systems:
- 10 mg – iron oxide (yellow) and titanium dioxide;
- 20 mg – iron oxide (red), and titanium dioxide;
- 25 mg – FD&C Blue #1, FD&C Yellow #5, FD&C Yellow #6 and titanium dioxide;
- 30 mg – iron oxide (black, red and yellow) and titanium dioxide;
- 35 mg – FD&C Blue #2, iron oxide (black, red and yellow) and titanium dioxide;
- 40 mg – iron oxide (black, red and yellow) and titanium dioxide.
- Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a yellow to orange crystalline powder with a molecular weight of 300.44. It is practically insoluble in water, soluble in chloroform and sparingly soluble in alcohol and in isopropyl alcohol. The structural formula is:
## Pharmacodynamics
- The pharmacodynamics of ABSORICA are unknown.
## Pharmacokinetics
Absorption
- Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high-fat meal. ABSORICA is bioequivalent to Accutane® (isotretinoin) capsule when both drugs are taken with a high-fat meal. ABSORICA is more bioavailable than Accutane® (isotretinoin) capsules when both drugs are taken fasted; the AUC0-t of ABSORICA is approximately 83% greater than that of Accutane®. ABSORICA is therefore not interchangeable with generic products of Accutane®.
- A single dose two-way crossover pharmacokinetic trial was conducted in 14 healthy adult male subjects comparing ABSORICA 40 mg (1 x 40 mg capsules), dosed under fasted and fed conditions. Under fed conditions after a high-fat meal, it was observed that the mean AUC0-t and Cmax were approximately 50% and 26% higher, than that observed under fasting conditions (Table 2). The observed elimination half-life (T1/2) was slightly lower in the fed state versus fasted. The time to peak concentration (Tmax) increased with food and this may be related to a longer absorption phase.
- Published clinical literature has shown that there is no difference in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects with normal skin.
Distribution
- Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.
Metabolism
- Following oral administration of isotretinoin, at least three metabolites have been identified in human plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). Retinoic acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. The administration of one isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin.
- After a single 40 mg oral dose of ABSORICA to 57 healthy adult subjects, concurrent administration of food increased the extent of formation of all metabolites in plasma when compared to the extent of formation under fasted conditions.
- All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. However, the clinical significance of these models is unknown.
- In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4, and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces.
Elimination
- Following oral administration of an 80 mg dose of 14C-isotretinoin as a liquid suspension, 14C-activity in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%).
- After a single 40 mg (2 x 20 mg) oral dose of ABSORICA to 57 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (T1/2) of isotretinoin and 4-oxo-isotretinoin under fed states were 18 hours and 38 hours, respectively.
Special Patient Populations
- The pharmacokinetics of isotretinoin were evaluated after single and multiple doses in 38 pediatric patients (12 to 15 years) and 19 adult patients (≥18 years) who received isotretinoin for the treatment of severe recalcitrant nodular acne. In both age groups, 4-oxo-isotretinoin was the major metabolite; tretinoin and 4-oxo-tretinoin were also observed. There were no statistically significant differences in the pharmacokinetics of isotretinoin between pediatric and adult patients.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis and Impairment of Fertility
- In male and female Fischer 344 rats given oral isotretinoin at dosages of 8 or 32 mg/kg/day (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area) for greater than 18 months, there was a dose-related increased incidence of pheochromocytoma relative to controls. The incidence of adrenal medullary hyperplasia was also increased at the higher dosage in both sexes. The relatively high level of spontaneous pheochromocytomas occurring in the male Fischer 344 rat makes it an equivocal model for study of this tumor; therefore, the relevance of this tumor to the human population is uncertain.
- The Ames test was conducted with isotretinoin in two laboratories. The results of the tests in one laboratory were negative while in the second laboratory a weakly positive response (less than 1.6 x background) was noted in S. typhimurium TA100 when the assay was conducted with metabolic activation. No dose response effect was seen and all other strains were negative. Additionally, other tests designed to assess genotoxicity (Chinese hamster cell assay, mouse micronucleus test, S. cerevisiae D7 assay, in vitro clastogenesis assay with human-derived lymphocytes, and unscheduled DNA synthesis assay) were all negative.
- In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at oral dosages of isotretinoin of 2, 8, or 32 mg/kg/day (0.3, 1.3, or 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area).
- In dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks at dosages of 20 or 60 mg/kg/day (10 or 30 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area). In general, there was microscopic evidence for appreciable depression of spermatogenesis but some sperm were observed in all testes examined and in no instance were completely atrophic tubules seen.
- In trials of 66 men, 30 of whom were patients with nodular acne under treatment with oral isotretinoin, no significant changes were noted in the count or motility of spermatozoa in the ejaculate. In a study of 50 men (ages 17 to 32 years) receiving isotretinoin therapy for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose.
Animal Toxicology
- In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day after normalization for total body surface area) for 18 months or longer, the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of coronary, pulmonary and mesenteric arteries, and metastatic calcification of the gastric mucosa were greater than in control rats of similar age. Focal endocardial and myocardial calcifications associated with calcification of the coronary arteries were observed in two dogs after approximately 6 to 7 months of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area).
# Clinical Studies
- A double-blind, randomized, parallel group trial (Study 1) was conducted in patients with severe recalcitrant nodular acne to evaluate the efficacy and safety of ABSORICA compared to a generic product of Accutane® under fed conditions. Enrolled patients had a weight of 40 to 110 kg with at least 10 nodular lesions on the face and/or trunk. A total of 925 patients were randomized 1:1 to receive ABSORICA or a generic product of Accutane® (isotretinoin). Study patients ranged from 12 to 54 years of age, were approximately 60% male, 40% female, and were 87% White, 4% Black, 6% Asian, and 3% Other. Patients were treated an initial dose of 0.5 mg/kg/day in two divided doses for the first 4 weeks followed by 1 mg/kg/day in two divided doses for the following 16 weeks.
- Change from Baseline to Week 20 in total nodular lesion count and proportion of patients with at least a 90% reduction in total nodular lesion count from Baseline to Week 20 are presented in Table 3. Total nodular lesion counts by visit are presented in Figure 1.
# How Supplied
- ABSORICA (isotretinoin) Capsules are supplied as follows:
- 10 mg: Dark yellow, opaque, capsule imprinted with black ink “ G 240” on cap and “ 10” on the body
- Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-115-31
- 20 mg: Red, opaque, capsule imprinted with black ink “ G 241” on cap and “ 20” on the body
- Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-116-31
- 25 mg: Green, opaque, capsule imprinted with white ink “ G 342” on cap and “ 25” on the body
- Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-133-31
- 30 mg: Brown, opaque, capsule imprinted with white ink “ G 242” on cap and “ 30” on the body
- Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-117-31
- 35 mg: Dark blue, opaque, capsule imprinted with white ink “ G 343” on cap and “ 35” on the body
- Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-134-31
- 40 mg: Brown and red, capsule imprinted with white ink “ G 325” on cap and “ 40” on the body
- Box of 30 capsules (3 x 10 Prescription Packs): NDC10631-118-31
## Storage
- Store at 20° C - 25° C (68° F - 77° F), excursion permitted between 15° C - 30° C (59° F - 86° F) . *Protect from light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient that ABSORICA is only available through a restricted program called iPLEDGE.
- As a component of the iPLEDGE program, prescribers must instruct patients to read the Medication Guide, the iPLEDGE program patient educational booklets, and watch the DVD with the following videos — “Be Prepared, Be Protected” and “Be Aware: The Risk of Pregnancy While on Isotretinoin”. The DVD includes information about contraception, the most common reasons that contraception fails, and the importance of using 2 forms of effective contraception when taking teratogenic drugs and comprehensive information about types of potential birth defects which could occur if a female patient who is pregnant takes ABSORICA at any time during pregnancy.
- Male patients and Female patients not of childbearing potential must understand the risks and benefits of ABSORICA, comply with the REMS requirements described in the booklet entitled The iPLEDGE Program Guide to Isotretinoin for Male Patients and Female Patients Who Cannot Get Pregnant, and sign a Patient Information/Informed Consent form.
- Female patients of childbearing potential must be instructed that they must not be pregnant when ABSORICA therapy is initiated or plan to become pregnant while receiving ABSORICA therapy. Additionally, they must use 2 forms of effective contraception simultaneously for 1 month before starting ABSORICA, while taking ABSORICA, and for 1 month after ABSORICA has been stopped, unless they commit to continuous abstinence from heterosexual intercourse. They should also sign a Patient Information/Informed Consent form and Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form prior to beginning ABSORICA therapy. Female patients should be seen by their prescribers monthly and have a urine or serum pregnancy test, in a CLIA-certified laboratory, performed each month during treatment to confirm negative pregnancy status before another ABSORICA prescription is written. Additionally, a pregnancy test must be completed at the end of the entire course of ABSORICA therapy and 1 month after discontinuation of therapy.
- Advise the patient that isotretinoin is found in the semen of male patients taking isotretinoin, but the amount delivered to a female partner would be about one million times lower than an oral dose of 40 mg. While the no-effect limit for isotretinoin induced embryopathy is unknown, 20 years of post-marketing reports include four with isolated defects compatible with features of retinoid exposed fetuses; however two of these reports were incomplete and two had other possible explanations for the defects observed.
- Advise the patient that ABSORICA is available only from pharmacies that are certified in the iPLEDGE program, and provide them with the telephone number (1-866-495-0654) and website ( www.ipledgeprogram.com) for information on how to obtain.
- Advise patients that they may be requested to participate in a survey to evaluate the effectiveness of the iPLEDGE program.
- Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of ABSORICA treatment, patients and family members should be asked about any history of psychiatric disorder, and at each visit during treatment patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary. Inform patients that symptoms of depression include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment. Patients should stop treatment and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. Discontinuation of ABSORICA treatment may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient's family. A referral to a mental health professional may be necessary. The physician should consider whether ABSORICA therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of ABSORICA therapy.
- Patients must be informed that some patients, while taking isotretinoin or soon after stopping isotretinoin, have become depressed or developed other serious mental problems. Symptoms of depression include sad, “anxious” or empty mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating. Some patients taking isotretinoin have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts), some have tried to end their own lives, and some have ended their own lives. There were reports that some of these people did not appear depressed. There have been reports of patients on isotretinoin becoming aggressive or violent. There have also been reports of psychotic symptoms, which indicate a loss of contact with reality. Psychotic symptoms include feelings of suspiciousness toward others, strange beliefs, hearing voices or other noises without an obvious source, and seeing unusual objects or people with no explanation. No one knows if isotretinoin caused these behaviors and symptoms or if they would have happened even if the person did not take isotretinoin. If any of these behaviors or symptoms occur, the patient should stop treatment and the patient or family member should contact the prescriber promptly without waiting until the next visit. Some people have had other signs of depression while taking isotretinoin.
- Patients must be informed that they must not share ABSORICA with anyone else because of the risk of birth defects and other serious adverse reactions.
- Patients must be informed not to donate blood during therapy and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to ABSORICA.
- ABSORICA may be taken without regard to meals. To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid.
- Patients should be informed that inflammatory bowel disease (including regional ileitis) may occur without a prior history of intestinal disorders. In rare instances, symptoms have been reported to persist after treatment has stopped. Patients should be informed that if they experience abdominal pain, rectal bleeding or severe diarrhea, they should discontinue ABSORICA immediately.
- Patients should be informed that transient exacerbation (flare) of acne has been seen, generally during the initial period of therapy.
- Wax epilation and skin resurfacing procedures (such as dermabrasion, laser) should be avoided during ABSORICA therapy and for at least 6 months thereafter due to the possibility of scarring.
- Patients should be advised to avoid prolonged exposure to UV rays or sunlight.
- Patients should be informed that they may experience dry eye, corneal opacities, and decreased night vision. Contact lens wearers may experience decreased tolerance to contact lenses during and after therapy.
- Patients should be informed that 16% of patients treated with isotretinoin in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these symptoms were mild to moderate, but occasionally required discontinuation of the drug. Transient pain in the chest has been reported less frequently. In the clinical trial, these symptoms generally cleared rapidly after discontinuation of therapy, but in some cases persisted.
- There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity.
- Pediatric patients and their caregivers should be informed that approximately 17% to 29% of pediatric patients treated with isotretinoin developed back pain. In a clinical trial, back pain was severe in 13.5% of the cases and occurred at a higher frequency in female patients than male patients. Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of treatment. Consideration should be given to discontinuation of isotretinoin if any significant abnormality is found.
- Neutropenia and rare cases of agranulocytosis have been reported in patients treated with isotretinoin. ABSORICA should be discontinued if clinically significant decreases in white cell counts occur.
- Patients should be advised that severe skin reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported in post marketing data in patients treated with isotretinoin. Treatment with ABSORICA should be discontinued if clinically significant skin reactions occur.
- Adolescent patients who participate in sports with repetitive impact should be informed that isotretinoin use may increase their risk of spondylolisthesis or hip growth plate injuries. There are spontaneous reports of fractures and/or delayed healing in patients while on therapy with isotretinoin or following cessation of therapy with isotretinoin while involved in these activities.
# Precautions with Alcohol
- Alcohol-Isotretinoin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Accutane,
Amnesteem,
Claravis,
Sotret,
Myorisan,
Absorica.
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price
|
Isotretinoin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]
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# Black Box Warning
# Overview
Isotretinoin is a dermatologic agent that is FDA approved for the treatment of severe recalcitrant nodular acne in patients 12 years of age and older. There is a Black Box Warning for this drug as shown here. Common adverse reactions include lip dry, dry skin, back pain, dry eye, arthralgia, epistaxis, headache, nasopharyngitis, chapped lips, dermatitis, blood creatine kinase increased, cheilitis, musculoskeletal discomfort, upper respiratory tract infection, visual acuity reduced.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- ABSORICA is a retinoid indicated for the treatment of severe recalcitrant nodular acne in patients 12 years of age and older. Nodules are inflammatory lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic. “Severe,” by definition, means “many” as opposed to “few or several” nodules. Because of significant adverse reactions associated with its use, ABSORICA should be reserved for patients with multiple severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, ABSORICA is indicated only for those female patients who are not pregnant, because ABSORICA can cause severe birth defects.
- Dosing Information
- Healthcare professionals who prescribe ABSORICA must be certified in the iPLEDGE program and must comply with the required monitoring to ensure safe use of ABSORICA.
- The required laboratory testing must be completed prior to dosing ABSORICA.
- Pregnancy Testing, and Contraceptive measures must be followed prior to dosing ABSORICA.
- Recommended Dosage
- The recommended dosage range for ABSORICA is 0.5 to 1 mg/kg/day given in two divided doses without regard to meals for 15 to 20 weeks (see Table 1). To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid.
- The safety of once daily dosing with ABSORICA has not been established. Once daily dosing is not recommended.
- Dosage Range
- In trials comparing 0.1, 0.5, and 1 mg/kg/day, it was found that all dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted according to response of the disease and/or the appearance of clinical side effects, some of which may be dose-related. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to 2 mg/kg/day, as tolerated.
- Duration of Use
- A normal course of treatment is 15 – 20 weeks. If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of ABSORICA, even in low doses, has not been studied, and is not recommended. It is important that ABSORICA be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of ABSORICA on bone loss is unknown.
- Laboratory Testing
- Pregnancy Testing:
- [See Use in Specific Populations]
- Lipid Profile:
- Perform a fasting lipid profile including triglycerides prior to use of ABSORICA.
- Liver Function Test:
- Perform liver function tests prior to use of ABSORICA.
Limitations of Use
- A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged remission of disease in many patients. If a second course of therapy is needed, it should not be initiated until at least 8 weeks after completion of the first course, because experience with isotretinoin has shown that patients may continue to improve following treatment with isotretinoin. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth.
- As a part of the iPLEDGE program, ABSORICA may only be administered to patients enrolled in the program.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Isotretinoin in adult patients.
### Non–Guideline-Supported Use
- Acne vulgaris
- Rosacea
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Healthcare professionals who prescribe ABSORICA must be certified in the iPLEDGE program and must comply with the required monitoring to ensure safe use of ABSORICA.
- The required laboratory testing must be completed prior to dosing ABSORICA.
- Pregnancy Testing, and Contraceptive measures must be followed prior to dosing ABSORICA.
- Recommended Dosage:
- The recommended dosage range for ABSORICA is 0.5 to 1 mg/kg/day given in two divided doses without regard to meals for 15 to 20 weeks (see Table 1). To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid.
- The safety of once daily dosing with ABSORICA has not been established. Once daily dosing is not recommended.
- Dosage Range:
- In trials comparing 0.1, 0.5, and 1 mg/kg/day, it was found that all dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted according to response of the disease and/or the appearance of clinical side effects, some of which may be dose-related. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to 2 mg/kg/day, as tolerated.
- Duration of Use:
- A normal course of treatment is 15 – 20 weeks. If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of ABSORICA, even in low doses, has not been studied, and is not recommended. It is important that ABSORICA be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of ABSORICA on bone loss is unknown.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Isotretinoin in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Isotretinoin in pediatric patients.
# Contraindications
Pregnancy
- ABSORICA can cause fetal harm when administered to a pregnant woman. Major congenital malformations, spontaneous abortions, and premature births have been documented following pregnancy exposure to isotretinoin in any amount and even for short periods of time. ABSORICA is contraindicated in females who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, treatment should be discontinued and the patient should be apprised of the potential hazard to the fetus.
Hypersensitivity
- Hypersensitivity to this product (or Vitamin A, given the chemical similarity to isotretinoin) or to any of its components.
# Warnings
- ABSORICA must not be used by female patients who are or may become pregnant. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking ABSORICA in any amount, even for short periods of time.
Embryofetal Toxicity
Teratogenicity
- Major congenital malformations, spontaneous abortions, and premature births have been documented following pregnancy exposure to isotretinoin. Females of childbearing potential must comply with the pregnancy testing and contraception requirements described in the iPLEDGE program. There are no accurate means of determining whether an exposed fetus has been affected.
No Blood Donation
- Patients must be informed not to donate blood during isotretinoin therapy and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to isotretinoin.
iPLEDGE Program
- Because of the risk of teratogenicity and to minimize fetal exposure, ABSORICA is available only through a restricted program under a REMS called iPLEDGE. Under the ABSORICA REMS, prescribers, patients, pharmacies, and distributors must enroll and be registered in the program. ABSORICA must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE program. Only FDA-approved isotretinoin products must be distributed, prescribed, dispensed, and used.
Required components of the iPLEDGE Program are:
- ABSORICA must only be prescribed by prescribers who are registered and activated with the iPLEDGE program and agree to comply with the REMS requirements described in the booklets entitled The Guide to Best Practices for the iPLEDGE Program, The iPLEDGE Program Prescriber Contraception Counseling Guide, and Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin.
- Male patients and Female patients not of childbearing potential: To obtain ABSORICA, these patients must understand the risks and benefits of ABSORICA, comply with the REMS requirements described in the booklet entitled The iPLEDGE Program Guide to Isotretinoin for Male Patients and Female Patients Who Cannot Get Pregnant, and sign a Patient Information/Informed Consent form.
- Female patients of childbearing potential: ABSORICA is contraindicated in female patients who are or may become pregnant.
- Female patients of childbearing potential who are not pregnant must understand the risks and benefits, comply with the REMS requirements described in the booklet entitled The iPLEDGE Program Guide to Isotretinoin for Female Patients Who Can Get Pregnant and The iPLEDGE Program Birth Control Workbook (including the pregnancy testing and contraception requirements, and sign a Patient Information/Informed Consent form and Patient Information/Informed Consent About Birth Defects form. Additionally, the patient must answer questions about the iPLEDGE program and pregnancy prevention monthly.
- Pharmacies that dispense ABSORICA must be registered and activated with iPLEDGE, must only dispense to patients who are authorized to receive ABSORICA, and agree to comply with the REMS requirements described in the booklet entitled The Pharmacist Guide for the iPLEDGE Program.
- Female patients of childbearing potential must fill and pick up the prescription within 7 days of the specimen collection for the pregnancy test; male patients and female patients not of childbearing potential must fill and pick up the prescription within 30 days of the office visit.
- ABSORICA must only be dispensed in no more than a 30-day supply with a Medication Guide. Refills require a new prescription and a new authorization from the iPLEDGE system.
- Wholesalers and distributors that distribute ABSORICA must be registered with iPLEDGE and agree to comply with the REMS requirements.
- If a pregnancy does occur during ABSORICA treatment, ABSORICA must be discontinued immediately. The patient should be referred to an obstetrician-gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure during or 1 month after ABSORICA therapy must be reported immediately to the FDA via the MedWatch telephone number 1-800-FDA-1088 and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com).
- Further information, including a list of qualified pharmacies, is available at www.ipledgeprogram.com or 1-866-495-0654.
Unacceptable Contraception
Micro-dosed Progesterone Preparations
- Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) are an inadequate method of contraception during ABSORICA therapy.
Psychiatric Disorders
- Isotretinoin may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. No mechanism of action has been established for these reactions. Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin. Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of ABSORICA therapy, patients and family members should be asked about any history of psychiatric disorder, and at each visit during therapy patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary. Signs and symptoms of depression, as described in the brochure (Recognizing Psychiatric Disorders in Adolescents and Young Adults), include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment. Patients should stop ABSORICA and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. Discontinuation of ABSORICA therapy may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient's family. A referral to a mental health professional may be necessary. The physician should consider whether ABSORICA therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of ABSORICA therapy.
Pseudotumor Cerebri
- Isotretinoin use has been associated with cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. Concomitant treatment with tetracyclines should therefore be avoided. Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea and vomiting, and visual disturbances. Patients with these symptoms should be screened for papilledema and, if present, they should be told to discontinue ABSORICA immediately and be referred to a neurologist for further diagnosis and care.
Serious Skin Reactions
- There have been post-marketing reports of erythema multiforme and severe skin reactions [e.g., Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)] associated with isotretinoin use. These reactions may be serious and result in death, life-threatening events, hospitalization, or disability. Patients should be monitored closely for severe skin reactions, and discontinuation of ABSORICA should be considered if warranted.
Pancreatitis
- Acute pancreatitis has been reported in isotretinoin-treated patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. ABSORICA should be stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur.
Lipid Abnormalities
- Elevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with isotretinoin. Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving isotretinoin in clinical trials. In addition, approximately 15% developed a decrease in high-density lipoproteins and about 7% showed an increase in cholesterol levels. In clinical trials, the effects of triglycerides, HDL and cholesterol were reversible upon cessation of isotretinoin therapy. Some patients have been able to reverse triglyceride elevation by reduction in weight, restriction of dietary fat and alcohol, and reduction in the dose while continuing isotretinoin.
- Blood lipid determinations should be performed before ABSORICA is given and then at intervals until the lipid response to ABSORICA is established, which usually occurs within 4 weeks. Especially careful consideration must be given to risk/benefit for patients who may be at high risk of triglyceridemia during ABSORICA therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If ABSORICA therapy is instituted, more frequent checks of serum values for lipids and/or blood sugar are recommended.
- The cardiovascular consequences of hypertriglyceridemia associated with isotretinoin are unknown.
Hearing Impairment
- Impaired hearing has been reported in patients taking isotretinoin; in some cases, the hearing impairment has been reported to persist after therapy has been discontinued. Mechanism(s) and causality for this reaction have not been established. Patients who experience tinnitus or hearing impairment should discontinue ABSORICA treatment and be referred for specialized care for further evaluation.
Hepatotoxicity
- Clinical hepatitis considered to be possibly or probably related to isotretinoin therapy has been reported. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials with isotretinoin, some of which normalized with dosage reduction or continued administration of the drug. If normalization does not readily occur or if hepatitis is suspected during treatment with ABSORICA, the drug should be discontinued and the etiology further investigated.
Inflammatory Bowel Disease
- Isotretinoin has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. In some instances, symptoms have been reported to persist after isotretinoin treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue ABSORICA immediately.
Skeletal Abnormalities
Bone Mineral Density Changes
- Isotretinoin may have a negative effect on bone mineral density (BMD) in some patients. In a clinical trial of ABSORICA and a generic product of Accutane® (isotretinoin), 27/306 (8.8%) of adolescents had BMD declines, defined as ≥ 4% lumbar spine or total hip, or ≥ 5% femoral neck, during the 20 week treatment period. Repeat scans conducted within 2-3 months after the post-treatment scan showed no recovery of BMD. Longer term data at 4-11 months showed that 3 out of 7 patients had total hip and femoral neck BMD below pre-treatment baseline, and 2 others did not show the increase in BMD above baseline expected in this adolescent population. Therefore, physicians should use caution when prescribing ABSORICA to patients with a history of childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism. This would include patients diagnosed with anorexia nervosa and those who are on chronic drug therapy that causes drug-induced osteoporosis/osteomalacia and/or affects vitamin D metabolism, such as systemic corticosteroids and any anticonvulsant.
Musculoskeletal Abnormalities
- Approximately 16% of patients treated with isotretinoin in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these symptoms were mild to moderate, but occasionally required discontinuation of the drug.
- In a trial of pediatric patients treated with isotretinoin, approximately 29% (104/358) developed back pain. Back pain was severe in 13.5% (14/104) of the cases and occurred at a higher frequency in female patients than male patients. Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of ABSORICA. Consideration should be given to discontinuation of ABSORICA if any significant abnormality is found.
- There have been spontaneous reports of osteoporosis, osteopenia, bone fractures and/or delayed healing of bone fractures in patients while on therapy with isotretinoin or following cessation of therapy with isotretinoin. While causality to isotretinoin has not been established, an effect cannot be ruled out.
- Patients may be at an increased risk when participating in sports with repetitive impact where the risks of spondylolisthesis with and without pars fractures and hip growth plate injures in early and late adolescence are known.
- Effects of multiple courses of isotretinoin on the developing musculoskeletal system are unknown. There is some evidence that long-term, high-dose, or multiple courses of therapy with isotretinoin have more of an effect than a single course of therapy on the musculoskeletal system.
- Longer term effects have not been studied. It is important that ABSORICA be given at the recommended doses for no longer than the recommended duration.
Hyperostosis
- A high prevalence of skeletal hyperostosis was noted in clinical trials for disorders of keratinization with a mean dose of 2.24 mg/kg/day of isotretinoin. Additionally, skeletal hyperostosis was noted in 6 of 8 patients in a prospective trial of disorders of keratinization. Minimal skeletal hyperostosis and calcification of ligaments and tendons have also been observed by x-ray in prospective trials of nodular acne patients treated with a single course of therapy at recommended doses. The skeletal effects of multiple isotretinoin treatment courses for acne are unknown.
- In a clinical trial of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, hyperostosis was not observed after 16 to 20 weeks of treatment with approximately 1 mg/kg/day of isotretinoin given in two divided doses. Hyperostosis may require a longer time frame to appear. The clinical course and significance remain unknown.
Premature Epiphyseal Closure
- There are spontaneous literature reports of premature epiphyseal closure in acne patients receiving recommended doses of isotretinoin. The effect of multiple courses of isotretinoin on epiphyseal closure is unknown.
- In a 20-week clinical trial that included 289 adolescents on ABSORICA or a generic product of Accutane® (isotretinoin) who had hand radiographs taken to assess bone age, a total of 9 (3.11%) patients had bone age changes that were clinically significant and for which a drug-related effect cannot be excluded.
Ocular Abnormalities
- Visual problems should be carefully monitored. All ABSORICA patients experiencing visual difficulties should discontinue ABSORICA treatment and have an ophthalmological examination.
Corneal Opacities
- Corneal opacities have occurred in patients receiving isotretinoin for acne and more frequently when higher drug dosages were used in patients with disorders of keratinization. The corneal opacities that have been observed in clinical trial patients treated with isotretinoin have either completely resolved or were resolving at follow-up 6 to 7 weeks after discontinuation of the drug.
Decreased Night Vision
- Decreased night vision has been reported during isotretinoin therapy and in some instances the event has persisted after therapy was discontinued. Because the onset in some patients was sudden, patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night.
Dry Eye
- Dry eye has been reported in subjects during isotretinoin therapy. Patients who wear contact lenses may have trouble wearing them while on ABSORICA treatment and afterwards.
Hypersensitivity
- Anaphylactic reactions and other allergic reactions have been reported in isotretinoin-treated patients. Cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement (including renal) have been reported. Severe allergic reaction necessitates discontinuation of therapy and appropriate medical management.
Laboratory Monitoring for Adverse Reactions
Lipids Test
- Pretreatment and follow-up blood lipids should be obtained under fasting conditions. After consumption of alcohol, at least 36 hours should elapse before these determinations are made. It is recommended that these tests be performed at weekly or biweekly intervals until the lipid response to ABSORICA is established. The incidence of hypertriglyceridemia is 1 patient in 4 on isotretinoin.
Liver Function Test
- Since elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported in patients on isotretinoin, pretreatment and follow-up liver function tests should be performed at weekly or biweekly intervals until the response to ABSORICA has been established.
Glucose
- Some patients receiving isotretinoin have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during isotretinoin therapy, although no causal relationship has been established.
CPK
- Some patients undergoing vigorous physical activity while on isotretinoin therapy have experienced elevated CPK levels; however, the clinical significance is unknown. There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity. In an isotretinoin clinical trial of 924 patients, marked elevations in CPK (≥350 U/L) were observed in approximately 24% of patients. In another clinical trial of 217 pediatric patients (12 – 17 years) elevations in CPK were observed in 12% of patients, including those undergoing strenuous physical activity in association with reported musculoskeletal adverse events such as back pain, arthralgia, limb injury, or muscle sprain. In these patients, approximately half of the CPK elevations returned to normal within 2 weeks and half returned to normal within 4 weeks. No cases of rhabdomyolysis were reported in this clinical trial.
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions with ABSORICA or other isotretinoin products are described in more detail in other sections of the labeling:
- Embryofetal Toxicity
- Psychiatric Disorders
- Pseudotumor Cerebri
- Serious Skin Reactions
- Pancreatitis
- Lipid Abnormalities
- Hearing Impairment
- Hepatotoxicity
- Inflammatory Bowel Disease
- Skeletal Abnormalities
- Ocular Abnormalities
- Hypersensitivity
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of ABSORICA cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice.
- The adverse reactions listed below reflect both clinical experience with ABSORICA, and consider other adverse reactions that are known from clinical trials and the post-marketing surveillance with oral isotretinoin. The relationship of some of these events to isotretinoin therapy is unknown. Many of the side effects and adverse events seen in patients receiving isotretinoin are similar to those described in patients taking very high doses of vitamin A (dryness of the skin and mucous membranes, e.g., of the lips, nasal passage, and eyes).
Dose Relationship
- Cheilitis and hypertriglyceridemia are adverse reactions that are usually dose related. Most adverse reactions reported in clinical trials with isotretinoin were reversible when therapy was discontinued; however, some persisted after cessation of therapy.
Body as a Whole
- The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): fatigue, irritability, pain. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: allergic reactions, including vasculitis, systemic hypersensitivity, edema, lymphadenopathy, weight loss.
Cardiovascular
- The following adverse reactions have been reported with isotretinoin: vascular thrombotic disease, stroke, palpitation, tachycardia.
Endocrine/Metabolism and Nutritional
- The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): decreased appetite, weight fluctuation, hyperlipidaemia. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: hypertriglyceridemia, alterations in blood sugar.
Gastrointestinal
- The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): lip dry, chapped lips, cheilitis, nausea, constipation, diarrhea, abdominal pain, vomiting. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: inflammatory bowel disease, hepatitis, pancreatitis, bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, and other nonspecific gastrointestinal symptoms.
Hematologic
- The following adverse reactions have been reported with isotretinoin: allergic reactions, anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis.
Infections and infestations
- The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): nasopharyngitis, hordeolum, upper respiratory tract infection. In addition to the above adverse reactions, the following adverse reaction has been reported with isotretinoin: infections (including disseminated herpes simplex).
Laboratory Abnormalities
- The following changes in laboratory tests have been noted in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): blood creatine phosphokinase (CPK) increased, blood triglycerides increased, alanine aminotransferase (SGPT) increased, aspartate aminotransferase (SGOT) increased, gamma-glutamyltransferase (GGTP) increased, blood cholesterol increased, low density lipoprotein (LDL) increased, white blood cell count decreased, blood alkaline phosphatase increased, blood bilirubin increased, blood glucose increased, high density lipopoprotein (HDL) decreased, bone mineral density decreased. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: increased LDH, elevation of fasting blood sugar, hyperuricemia, decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis), elevated sedimentation rates, elevated platelet counts, thrombocytopenia, white cells in the urine, proteinuria, microscopic or gross hematuria.
Musculoskeletal and Connective Tissue
- The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): decreases in bone mineral density, musculoskeletal symptoms (sometimes severe) including back pain, athralgia, musculoskeletal discomfort, musculoskeletal pain, neck pain, pain in extremity, myalgia, musculoskeletal stiffness. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, tendonitis, arthritis, transient pain in the chest, and rare reports of rhabdomyolysis.
Neurological
- The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): headache, syncope. In addition to the above adverse reactions, other adverse reactions reported with isotretinoin include: pseudotumor cerebri, dizziness, drowsiness, lethargy, malaise, nervousness, paresthesias, seizures, stroke, weakness.
Psychiatric
- The following adverse reactions have been reported in clinical trials conducted with ABSORICA and a generic product of Accutane® (isotretinoin): suicidal ideation, insomnia, anxiety, depression, irritability, panic attack, anger, euphoria, violent behaviors, emotional instability. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: suicide attempts, suicide, aggression, psychosis and hallucination auditory. Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.
Reproductive System
- The following adverse reaction has been reported with isotretinoin: abnormal menses.
Respiratory
- The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): epistaxis, nasal dryness. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: bronchospasms (with or without a history of asthma), respiratory infection, voice alteration.
Skin and Subcutaneous Tissue
- The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): dry skin, dermatitis, eczema, rash, dermatitis contact, alopecia, pruritus, sunburn, erythema. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: acne fulminans, alopecia (which in some cases persists), bruising, dry nose, eruptive xanthomas, erythema multiforme, flushing, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), Stevens-Johnson syndrome, sunburn susceptibility increased, sweating, toxic epidermal necrolysis, urticaria, vasculitis(including Wegener's granulomatosis), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting).
Special Senses
- Hearing: The following adverse reactions have been reported with isotretinoin: tinnitus and hearing impairment.
- Ocular: The following adverse reactions have been reported in clinical trials conducted with ABSORICA and a generic product of Accutane® (isotretinoin): dry eye, visual acuity reduced, vision blurred, eye pruritis, eye irritation, asthenopia, decreased night vision, ocular hyperemia, increased lacrimation, and conjunctivitis. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: corneal opacities, decreased night vision which may persist, cataracts, color vision disorder, conjunctivitis, eyelid inflammation, keratitis, optic neuritis, photobia, visual disturbances.
Renal and Urinary
- The following adverse reactions have been reported in clinical trials conducted with isotretinoin: glomerulonephritis, nonspecific urogenital findings.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Isotretinoin in the drug label
# Drug Interactions
Vitamin A
- ABSORICA is closely related to vitamin A. Therefore, the use of both vitamin A and ABSORICA at the same time may lead to vitamin A side effects. Patients should be advised against taking vitamin supplements containing Vitamin A to avoid additive toxic effects.
Tetracyclines
- Concomitant treatment with ABSORICA and tetracyclines should be avoided because isotretinoin use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines.
Phenytoin
- Isotretinoin has not been shown to alter the pharmacokinetics of phenytoin in a trial in seven healthy volunteers. These results are consistent with the in vitro finding that neither isotretinoin nor its metabolites induce or inhibit the activity of the CYP2C9 human hepatic P450 enzyme. Phenytoin is known to cause osteomalacia. No formal clinical trials have been conducted to assess if there is an interactive effect on bone loss between phenytoin and isotretinoin. Therefore, caution should be exercised when using these drugs together.
St. John's Wort
- Isotretinoin use is associated with depression in some patients. Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John's Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John's Wort.
Systemic Corticosteroids
- Systemic corticosteroids are known to cause osteoporosis. No formal clinical trials have been conducted to assess if there is an interactive effect on bone loss between systemic corticosteroids and isotretinoin. Therefore, caution should be exercised when using these drugs together.
Norethindrone/ethinyl estradiol
- In a trial of 31 premenopausal female patients with severe recalcitrant nodular acne receiving Norethindrone/ethinyl estradiol as an oral contraceptive agent, isotretinoin at the recommended dose of 1 mg/kg/day, did not induce clinically relevant changes in the pharmacokinetics of ethinyl estradiol and norethindrone and in the serum levels of progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Prescribers are advised to consult the package insert of medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
Pregnancy Category X
Risk Summary
- ABSORICA is contraindicated during pregnancy because isotretinoin can cause can cause fetal harm when administered to a pregnant woman. There is an increased risk of major congenital malformations, spontaneous abortions, and premature births following isotretinoin exposure during pregnancy in humans. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to a fetus.
Clinical Considerations
- If pregnancy does occur during treatment of a female patient who is taking ABSORICA, ABSORICA must be discontinued immediately and she should be referred to an obstetrician-gynecologist experienced in reproductive toxicity for further evaluation and counseling.
Human Data
- Major congenital malformations that have been documented following isotretinoin exposure include malformations of the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and parathyroid glands. External malformations include: skull; ear (including anotia, micropinna, small or absent external auditory canals); eye (including microphthalmia); facial dysmorphia and cleft palate. Internal abnormalities include: CNS (including cerebral and cerebellar malformations, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular; thymus gland; parathyroid hormone deficiency. In some cases death has occurred as a result of the malformations.
- Isotretinoin is found in the semen of male patients taking isotretinoin, but the amount delivered to a female partner would be about one million times lower than an oral dose of 40 mg. While the no-effect limit for isotretinoin induced embryopathy is unknown and 20 years of post-marketing reports include four reports with isolated defects compatible with features of retinoid exposed fetuses, two of these reports were incomplete and two had other possible explanations for the defects observed.
- Cases of IQ scores less than 85 with or without other abnormalities have been reported. An increased risk of spontaneous abortion and premature births have been documented with isotretinoin exposure during pregnancy.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Isotretinoin in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Isotretinoin during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from ABSORICA, 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 use of ABSORICA in pediatric patients less than 12 years of age has not been studied. The use of ABSORICA for the treatment of severe recalcitrant nodular acne in pediatric patients ages 12 to 17 years should be given careful consideration, especially for those patients where a known metabolic or structural bone disease exists. Use of ABSORICA in this age group for severe recalcitrant nodular acne is supported by evidence from a clinical trial of ABSORICA compared to a generic product of Accutane® (isotretinoin) in 397 pediatric patients (12 to 17 years). Results from this trial demonstrated that both ABSORICA and the other isotretinoin drug product, at a dose of 1 mg/kg/day given in two divided doses, was effective in treating severe recalcitrant nodular acne in pediatric patients.
- In trials with isotretinoin, adverse reactions reported in pediatric patients were similar to those described in adults except for the increased incidence of back pain and arthralgia (both of which were sometimes severe) and myalgia in pediatric patients. In a trial of pediatric patients treated with isotretinoin, approximately 29% (104/358) developed back pain. Back pain was severe in 13.5% (14/104) of the cases and occurred at a higher frequency in female patients than male patients. Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of ABSORICA. Consideration should be given to discontinuation of ABSORICA if any significant abnormality is found.
- The effect on bone mineral density (BMD) of a 20-week course of therapy with ABSORICA or a generic product of Accutane® (isotretinoin) was evaluated in a double-blind, randomized clinical trial involving 396 adolescents with severe recalcitrant nodular acne (mean age 15.4, range 12-17, 80% males). Following 20 weeks of treatment, there were no statistically significant differences between the treatment groups. The mean changes in BMD from baseline for the overall trial population were 1.8% for lumbar spine, -0.1% for total hip and -0.3% for femoral neck. Mean BMD Z-scores declined from baseline at each of these sites (-0.053, -0.109 and -0.104 respectively). Out of 306 adolescents, 27 (8.8%) had clinically significant BMD declines defined as ≥4% lumbar spine or total hip, or ≥5% femoral neck, including 2 subjects for lumbar spine, 17 for total hip and 20 for femoral neck. Repeat DXA scans within 2-3 months after the post treatment scan showed no recovery of BMD. Longer-term follow up at 4-11 months showed that 3 out of 7 patients had total hip and femoral neck BMD below pre-treatment baseline, and 2 others did not show the increase in BMD above baseline expected in this adolescent population. The significance of these changes in regard to long-term bone health and future fracture risk is unknown.
- In an open-label clinical trial (N=217) of a single course of therapy with isotretinoin for adolescents with severe recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly decreased (lumbar spine change >-4% and total hip change >-5%) or were increased in the majority of patients. One patient had a decrease in lumbar spine bone mineral density >4% based on unadjusted data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density >4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%) had a decrease in total hip bone mineral density >5% based on unadjusted data. Twenty-one (10.6%) patients had decreases in total hip bone mineral density >5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up trials performed in 8 of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in 5 patients at the lumbar spine, while the other 3 patients had lumbar spine bone density measurements below baseline values. Total hip bone mineral densities remained below baseline (range −1.6% to −7.6%) in 5 of 8 patients (62.5%).
- In a separate open-label extension trial of 10 patients, ages 13 to 18 years, who started a second course of isotretinoin 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25%.
- There are spontaneous literature reports of premature epiphyseal closure in acne patients receiving recommended doses of isotretinoin. The effect of multiple courses of isotretinoin on epiphyseal closure is unknown. In a 20-week clinical trial that included 289 adolescents who had hand radiographs taken to assess bone age, a total of 9 patients had bone age changes that were clinically significant and for which a drug-related effect cannot be excluded.
### Geriatic Use
- Clinical trials of ABSORICA did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Although reported clinical experience has not identified differences in responses between elderly and younger patients, effects of aging might be expected to increase some risks associated with ABSORICA therapy.
### Gender
- There is no FDA guidance on the use of Isotretinoin with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Isotretinoin with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Isotretinoin in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Isotretinoin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Isotretinoin in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Isotretinoin in patients who are immunocompromised.
### Females of Childbearing Potential
- All females of childbearing potential must comply with the iPLEDGE program requirements.
Pregnancy Testing
- ABSORICA must only be prescribed to female patients who are known not to be pregnant as confirmed by a negative CLIA-certified laboratory conducted pregnancy test. Female patients of childbearing potential must have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial ABSORICA prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for ABSORICA. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests must be at least 19 days.
- For patients with regular menstrual cycles, perform the second pregnancy test during the first 5 days of the menstrual period immediately preceding the beginning of ABSORICA therapy and after the patient has used 2 forms of contraception for 1 month.
- For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, perform the second pregnancy test immediately preceding the beginning of ABSORICA therapy and after the patient has used 2 forms of contraception for 1 month.
- Each month of continued ABSORICA therapy, patients must have a negative result from a urine or serum pregnancy test. A pregnancy test must be repeated each month, in a CLIA-certified laboratory, prior to the female patient receiving each prescription. A pregnancy test must also be completed at the end of the entire course of isotretinoin therapy and 1 month after the discontinuation of isotretinoin.
Contraception
- Females of childbearing potential must use 2 forms of effective contraception simultaneously, at least 1 of which must be a primary form, unless the patient commits to continuous abstinence from heterosexual contact, or the patient has undergone a hysterectomy or bilateral oophorectomy, or has been medically confirmed to be post-menopausal. Patients must use 2 forms of effective contraception for at least 1 month prior to initiation of ABSORICA therapy, during ABSORICA therapy, and for 1 month after discontinuing ABSORICA therapy. Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) are an inadequate method of contraception during isotretinoin therapy.
- Effective forms of contraception include both primary and secondary forms of contraception:
- Any birth control method can fail. There have been reports of pregnancy from female patients who have used combination oral contraceptives, as well as transdermal patch/ injectable/ implantable/ vaginal ring hormonal birth control products; these pregnancies occurred while taking isotretinoin. These reports are more frequent for female patients who use only a single method of contraception. Therefore, it is critically important for female patients of childbearing potential use 2 effective forms of contraception simultaneously.
- Using two forms of contraception simultaneously substantially reduces the chances that a female will become pregnant over the risk of pregnancy with either form alone. A drug interaction that decreases effectiveness of hormonal contraceptives has not been entirely ruled out for isotretinoin. Although hormonal contraceptives are highly effective, prescribers are advised to consult the package insert of any medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products.
- Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John's Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John's Wort.
- If the patient has unprotected heterosexual intercourse at any time 1 month before, during, or 1 month after therapy, she must:
- Stop taking ABSORICA immediately, if on therapy
- Have a pregnancy test at least 19 days after the last act of unprotected heterosexual intercourse
- Start using 2 forms of effective contraception simultaneously again for 1 month before resuming ABSORICA therapy
- If a pregnancy does occur during ABSORICA treatment, ABSORICA must be discontinued immediately. The patient should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure during or 1 month after ABSORICA therapy must be reported immediately to the FDA via the MedWatch number 1-800-FDA-1088 and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com).
# Administration and Monitoring
### Administration
- Healthcare professionals who prescribe ABSORICA must be certified in the iPLEDGE program and must comply with the required monitoring to ensure safe use of ABSORICA
- The required laboratory testing must be completed prior to dosing ABSORICA.
- Pregnancy Testing, and Contraceptive measures must be followed prior to dosing ABSORICA.
- Recommended Dosage
- The recommended dosage range for ABSORICA is 0.5 to 1 mg/kg/day given in two divided doses without regard to meals for 15 to 20 weeks (see Table 1). To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid.
- The safety of once daily dosing with ABSORICA has not been established. Once daily dosing is not recommended.
- Dosage Range
- In trials comparing 0.1, 0.5, and 1 mg/kg/day, it was found that all dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted according to response of the disease and/or the appearance of clinical side effects, some of which may be dose-related. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to 2 mg/kg/day, as tolerated.
- Duration of Use
- A normal course of treatment is 15 – 20 weeks. If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of ABSORICA, even in low doses, has not been studied, and is not recommended. It is important that ABSORICA be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of ABSORICA on bone loss is unknown.
- Laboratory Testing
- Pregnancy Testing
- [SeeUse in Specific Populations]
- Lipid Profile
- Perform a fasting lipid profile including triglycerides prior to use of ABSORICA.
- Liver Function Test
- Perform liver function tests prior to use of ABSORICA.
### DOSAGE FORMS AND STRENGTHS
- ABSORICA is available in 10 mg, 20 mg, 25 mg, 30 mg, 35 mg and 40 mg capsules.
- 10 mg: Dark yellow, opaque, capsule imprinted with black ink “ G 240” on cap and “ 10” on the body
- 20 mg: Red, opaque, capsule imprinted with black ink “ G 241” on cap and “ 20” on the body
- 25 mg: Green, opaque, capsule imprinted with white ink “ G 342” on cap and “ 25” on the body
- 30 mg: Brown, opaque, capsule imprinted with white ink “ G 242” on cap and “ 30” on the body
- 35 mg: Dark blue, opaque, capsule imprinted with white ink “ G 343” on cap and “ 35” on the body
- 40 mg: Brown and red, capsule imprinted with white ink “ G 325” on cap and “ 40” on the body
### Monitoring
- There is limited information regarding Monitoring of Isotretinoin in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Isotretinoin in the drug label.
# Overdosage
- In humans, overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. These symptoms quickly resolve without apparent residual effects.
- ABSORICA causes serious birth defects at any dosage (see Boxed CONTRAINDICATIONS AND WARNINGS). Female patients of childbearing potential who present with ABSORICA overdose must be evaluated for pregnancy. Patients who are pregnant should receive counseling about the risks to the fetus, as described in the Boxed CONTRAINDICATIONS AND WARNINGS. Non-pregnant patients must be warned to avoid pregnancy for at least one month and receive contraceptive counseling as described in Warnings and Precautions. Educational materials for such patients can be obtained by calling the manufacturer. Because an overdose would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, male patients should use a condom, or avoid reproductive sexual activity with a female patient who is or might become pregnant, for 1 month after the overdose. All patients with ABSORICA overdose should not donate blood for at least 1 month.
# Pharmacology
## Mechanism of Action
- ABSORICA is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1 mg/kg/day, inhibits sebaceous gland function and keratinization. Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and is related to the dose and duration of treatment with isotretinoin and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation. The exact mechanism of action of ABSORICA is unknown.
## Structure
- ABSORICA (isotretinoin) Capsules contain 10 mg, 20 mg, 25 mg, 30 mg, 35 mg or 40 mg of isotretinoin (a retinoid) in hard gelatin capsules for oral administration. In addition to the active ingredient, isotretinoin, each capsule contains the following inactive ingredients: propyl gallate, sorbitan monooleate, soybean oil and stearoyl polyoxylglycerides. The gelatin capsules contain the following dye systems:
- 10 mg – iron oxide (yellow) and titanium dioxide;
- 20 mg – iron oxide (red), and titanium dioxide;
- 25 mg – FD&C Blue #1, FD&C Yellow #5, FD&C Yellow #6 and titanium dioxide;
- 30 mg – iron oxide (black, red and yellow) and titanium dioxide;
- 35 mg – FD&C Blue #2, iron oxide (black, red and yellow) and titanium dioxide;
- 40 mg – iron oxide (black, red and yellow) and titanium dioxide.
- Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a yellow to orange crystalline powder with a molecular weight of 300.44. It is practically insoluble in water, soluble in chloroform and sparingly soluble in alcohol and in isopropyl alcohol. The structural formula is:
## Pharmacodynamics
- The pharmacodynamics of ABSORICA are unknown.
## Pharmacokinetics
Absorption
- Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high-fat meal. ABSORICA is bioequivalent to Accutane® (isotretinoin) capsule when both drugs are taken with a high-fat meal. ABSORICA is more bioavailable than Accutane® (isotretinoin) capsules when both drugs are taken fasted; the AUC0-t of ABSORICA is approximately 83% greater than that of Accutane®. ABSORICA is therefore not interchangeable with generic products of Accutane®.
- A single dose two-way crossover pharmacokinetic trial was conducted in 14 healthy adult male subjects comparing ABSORICA 40 mg (1 x 40 mg capsules), dosed under fasted and fed conditions. Under fed conditions after a high-fat meal, it was observed that the mean AUC0-t and Cmax were approximately 50% and 26% higher, than that observed under fasting conditions (Table 2). The observed elimination half-life (T1/2) was slightly lower in the fed state versus fasted. The time to peak concentration (Tmax) increased with food and this may be related to a longer absorption phase.
- Published clinical literature has shown that there is no difference in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects with normal skin.
Distribution
- Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.
Metabolism
- Following oral administration of isotretinoin, at least three metabolites have been identified in human plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). Retinoic acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. The administration of one isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin.
- After a single 40 mg oral dose of ABSORICA to 57 healthy adult subjects, concurrent administration of food increased the extent of formation of all metabolites in plasma when compared to the extent of formation under fasted conditions.
- All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. However, the clinical significance of these models is unknown.
- In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4, and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces.
Elimination
- Following oral administration of an 80 mg dose of 14C-isotretinoin as a liquid suspension, 14C-activity in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%).
- After a single 40 mg (2 x 20 mg) oral dose of ABSORICA to 57 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (T1/2) of isotretinoin and 4-oxo-isotretinoin under fed states were 18 hours and 38 hours, respectively.
Special Patient Populations
- The pharmacokinetics of isotretinoin were evaluated after single and multiple doses in 38 pediatric patients (12 to 15 years) and 19 adult patients (≥18 years) who received isotretinoin for the treatment of severe recalcitrant nodular acne. In both age groups, 4-oxo-isotretinoin was the major metabolite; tretinoin and 4-oxo-tretinoin were also observed. There were no statistically significant differences in the pharmacokinetics of isotretinoin between pediatric and adult patients.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis and Impairment of Fertility
- In male and female Fischer 344 rats given oral isotretinoin at dosages of 8 or 32 mg/kg/day (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area) for greater than 18 months, there was a dose-related increased incidence of pheochromocytoma relative to controls. The incidence of adrenal medullary hyperplasia was also increased at the higher dosage in both sexes. The relatively high level of spontaneous pheochromocytomas occurring in the male Fischer 344 rat makes it an equivocal model for study of this tumor; therefore, the relevance of this tumor to the human population is uncertain.
- The Ames test was conducted with isotretinoin in two laboratories. The results of the tests in one laboratory were negative while in the second laboratory a weakly positive response (less than 1.6 x background) was noted in S. typhimurium TA100 when the assay was conducted with metabolic activation. No dose response effect was seen and all other strains were negative. Additionally, other tests designed to assess genotoxicity (Chinese hamster cell assay, mouse micronucleus test, S. cerevisiae D7 assay, in vitro clastogenesis assay with human-derived lymphocytes, and unscheduled DNA synthesis assay) were all negative.
- In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at oral dosages of isotretinoin of 2, 8, or 32 mg/kg/day (0.3, 1.3, or 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area).
- In dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks at dosages of 20 or 60 mg/kg/day (10 or 30 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area). In general, there was microscopic evidence for appreciable depression of spermatogenesis but some sperm were observed in all testes examined and in no instance were completely atrophic tubules seen.
- In trials of 66 men, 30 of whom were patients with nodular acne under treatment with oral isotretinoin, no significant changes were noted in the count or motility of spermatozoa in the ejaculate. In a study of 50 men (ages 17 to 32 years) receiving isotretinoin therapy for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose.
Animal Toxicology
- In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day after normalization for total body surface area) for 18 months or longer, the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of coronary, pulmonary and mesenteric arteries, and metastatic calcification of the gastric mucosa were greater than in control rats of similar age. Focal endocardial and myocardial calcifications associated with calcification of the coronary arteries were observed in two dogs after approximately 6 to 7 months of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area).
# Clinical Studies
- A double-blind, randomized, parallel group trial (Study 1) was conducted in patients with severe recalcitrant nodular acne to evaluate the efficacy and safety of ABSORICA compared to a generic product of Accutane® under fed conditions. Enrolled patients had a weight of 40 to 110 kg with at least 10 nodular lesions on the face and/or trunk. A total of 925 patients were randomized 1:1 to receive ABSORICA or a generic product of Accutane® (isotretinoin). Study patients ranged from 12 to 54 years of age, were approximately 60% male, 40% female, and were 87% White, 4% Black, 6% Asian, and 3% Other. Patients were treated an initial dose of 0.5 mg/kg/day in two divided doses for the first 4 weeks followed by 1 mg/kg/day in two divided doses for the following 16 weeks.
- Change from Baseline to Week 20 in total nodular lesion count and proportion of patients with at least a 90% reduction in total nodular lesion count from Baseline to Week 20 are presented in Table 3. Total nodular lesion counts by visit are presented in Figure 1.
# How Supplied
- ABSORICA (isotretinoin) Capsules are supplied as follows:
- 10 mg: Dark yellow, opaque, capsule imprinted with black ink “ G 240” on cap and “ 10” on the body
- Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-115-31
- 20 mg: Red, opaque, capsule imprinted with black ink “ G 241” on cap and “ 20” on the body
- Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-116-31
- 25 mg: Green, opaque, capsule imprinted with white ink “ G 342” on cap and “ 25” on the body
- Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-133-31
- 30 mg: Brown, opaque, capsule imprinted with white ink “ G 242” on cap and “ 30” on the body
- Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-117-31
- 35 mg: Dark blue, opaque, capsule imprinted with white ink “ G 343” on cap and “ 35” on the body
- Box of 30 capsules (3 x 10 Prescription Packs): NDC 10631-134-31
- 40 mg: Brown and red, capsule imprinted with white ink “ G 325” on cap and “ 40” on the body
- Box of 30 capsules (3 x 10 Prescription Packs): NDC10631-118-31
## Storage
- Store at 20° C - 25° C (68° F - 77° F), excursion permitted between 15° C - 30° C (59° F - 86° F) [see USP controlled room temperature]. *Protect from light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient that ABSORICA is only available through a restricted program called iPLEDGE.
- As a component of the iPLEDGE program, prescribers must instruct patients to read the Medication Guide, the iPLEDGE program patient educational booklets, and watch the DVD with the following videos — “Be Prepared, Be Protected” and “Be Aware: The Risk of Pregnancy While on Isotretinoin”. The DVD includes information about contraception, the most common reasons that contraception fails, and the importance of using 2 forms of effective contraception when taking teratogenic drugs and comprehensive information about types of potential birth defects which could occur if a female patient who is pregnant takes ABSORICA at any time during pregnancy.
- Male patients and Female patients not of childbearing potential must understand the risks and benefits of ABSORICA, comply with the REMS requirements described in the booklet entitled The iPLEDGE Program Guide to Isotretinoin for Male Patients and Female Patients Who Cannot Get Pregnant, and sign a Patient Information/Informed Consent form.
- Female patients of childbearing potential must be instructed that they must not be pregnant when ABSORICA therapy is initiated or plan to become pregnant while receiving ABSORICA therapy. Additionally, they must use 2 forms of effective contraception simultaneously for 1 month before starting ABSORICA, while taking ABSORICA, and for 1 month after ABSORICA has been stopped, unless they commit to continuous abstinence from heterosexual intercourse. They should also sign a Patient Information/Informed Consent form and Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form prior to beginning ABSORICA therapy. Female patients should be seen by their prescribers monthly and have a urine or serum pregnancy test, in a CLIA-certified laboratory, performed each month during treatment to confirm negative pregnancy status before another ABSORICA prescription is written. Additionally, a pregnancy test must be completed at the end of the entire course of ABSORICA therapy and 1 month after discontinuation of therapy.
- Advise the patient that isotretinoin is found in the semen of male patients taking isotretinoin, but the amount delivered to a female partner would be about one million times lower than an oral dose of 40 mg. While the no-effect limit for isotretinoin induced embryopathy is unknown, 20 years of post-marketing reports include four with isolated defects compatible with features of retinoid exposed fetuses; however two of these reports were incomplete and two had other possible explanations for the defects observed.
- Advise the patient that ABSORICA is available only from pharmacies that are certified in the iPLEDGE program, and provide them with the telephone number (1-866-495-0654) and website ( www.ipledgeprogram.com) for information on how to obtain.
- Advise patients that they may be requested to participate in a survey to evaluate the effectiveness of the iPLEDGE program.
- Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of ABSORICA treatment, patients and family members should be asked about any history of psychiatric disorder, and at each visit during treatment patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary. Inform patients that symptoms of depression include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment. Patients should stop treatment and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. Discontinuation of ABSORICA treatment may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient's family. A referral to a mental health professional may be necessary. The physician should consider whether ABSORICA therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of ABSORICA therapy.
- Patients must be informed that some patients, while taking isotretinoin or soon after stopping isotretinoin, have become depressed or developed other serious mental problems. Symptoms of depression include sad, “anxious” or empty mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating. Some patients taking isotretinoin have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts), some have tried to end their own lives, and some have ended their own lives. There were reports that some of these people did not appear depressed. There have been reports of patients on isotretinoin becoming aggressive or violent. There have also been reports of psychotic symptoms, which indicate a loss of contact with reality. Psychotic symptoms include feelings of suspiciousness toward others, strange beliefs, hearing voices or other noises without an obvious source, and seeing unusual objects or people with no explanation. No one knows if isotretinoin caused these behaviors and symptoms or if they would have happened even if the person did not take isotretinoin. If any of these behaviors or symptoms occur, the patient should stop treatment and the patient or family member should contact the prescriber promptly without waiting until the next visit. Some people have had other signs of depression while taking isotretinoin.
- Patients must be informed that they must not share ABSORICA with anyone else because of the risk of birth defects and other serious adverse reactions.
- Patients must be informed not to donate blood during therapy and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to ABSORICA.
- ABSORICA may be taken without regard to meals. To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid.
- Patients should be informed that inflammatory bowel disease (including regional ileitis) may occur without a prior history of intestinal disorders. In rare instances, symptoms have been reported to persist after treatment has stopped. Patients should be informed that if they experience abdominal pain, rectal bleeding or severe diarrhea, they should discontinue ABSORICA immediately.
- Patients should be informed that transient exacerbation (flare) of acne has been seen, generally during the initial period of therapy.
- Wax epilation and skin resurfacing procedures (such as dermabrasion, laser) should be avoided during ABSORICA therapy and for at least 6 months thereafter due to the possibility of scarring.
- Patients should be advised to avoid prolonged exposure to UV rays or sunlight.
- Patients should be informed that they may experience dry eye, corneal opacities, and decreased night vision. Contact lens wearers may experience decreased tolerance to contact lenses during and after therapy.
- Patients should be informed that 16% of patients treated with isotretinoin in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these symptoms were mild to moderate, but occasionally required discontinuation of the drug. Transient pain in the chest has been reported less frequently. In the clinical trial, these symptoms generally cleared rapidly after discontinuation of therapy, but in some cases persisted.
- There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity.
- Pediatric patients and their caregivers should be informed that approximately 17% to 29% of pediatric patients treated with isotretinoin developed back pain. In a clinical trial, back pain was severe in 13.5% of the cases and occurred at a higher frequency in female patients than male patients. Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of treatment. Consideration should be given to discontinuation of isotretinoin if any significant abnormality is found.
- Neutropenia and rare cases of agranulocytosis have been reported in patients treated with isotretinoin. ABSORICA should be discontinued if clinically significant decreases in white cell counts occur.
- Patients should be advised that severe skin reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported in post marketing data in patients treated with isotretinoin. Treatment with ABSORICA should be discontinued if clinically significant skin reactions occur.
- Adolescent patients who participate in sports with repetitive impact should be informed that isotretinoin use may increase their risk of spondylolisthesis or hip growth plate injuries. There are spontaneous reports of fractures and/or delayed healing in patients while on therapy with isotretinoin or following cessation of therapy with isotretinoin while involved in these activities.
# Precautions with Alcohol
- Alcohol-Isotretinoin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Accutane,
Amnesteem,
Claravis,
Sotret,
Myorisan,
Absorica.
# Look-Alike Drug Names
- A® — B®[1]
# Drug Shortage Status
# Price
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https://www.wikidoc.org/index.php/13-cis_retinoic_acid
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24a58a59ac2052f9a6acb9813cf3be0029a2adf1
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Heart sounds
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Heart sounds
# Overview
The heart sounds are the noises (sound) generated by the beating heart and the resultant flow of blood through it. This is also called a heartbeat. In cardiac auscultation, an examiner uses a stethoscope to listen for these sounds, which provide important information about the condition of the heart.
In healthy adults, there are two normal heart sounds often described as a lub and a dub (or dup), that occur in sequence with each heart beat. These are the first heart sound (S1) and second heart sound (S2), produced by the closure of the AV valves and semilunar valves respectively. In addition to these normal sounds, a variety of other sounds may be present including heart murmurs and adventitious sounds.
Heart murmurs are generated by turbulent flow of blood, which may occur inside or outside the heart. Murmurs may be physiological (benign) or pathological (abnormal). Abnormal murmurs can be caused by stenosis restricting the opening of a heart valve, causing turbulence as blood flows through it. Valve insufficiency (or regurgitation) allows backflow of blood when the incompetent valve is supposed to be closed. Different murmurs are audible in different parts of the cardiac cycle, depending on the cause of the murmur.
# Normal heart sounds
# First heart tone S1, the "lub"(components M1 and T1)
The first heart tone, or S1, is caused by the sudden block of reverse blood flow due to closure of the atrioventricular valves, mitral and tricuspid, at the beginning of ventricular contraction, or systole. When the pressure in the ventricles rises above the pressure in the atria, venous blood flow entering the ventricles is pushed back toward the atria, catching the valve leaflets, closing the inlet valves and preventing regurgitation of blood from the ventricles back into the atria. The S1 sound results from reverberation within the blood associated with the sudden block of flow reversal by the valves.
# Second heart tone S2 the "dub"(components A2 and P2)
The second heart tone, or S2, is caused by the sudden block of reversing blood flow due to closure of the aortic valve and pulmonary valve at the end of ventricular systole, i.e beginning of ventricular diastole. As the left ventricle empties, its pressure falls below the pressure in the aorta, aortic blood flow quickly reverses back toward the left ventricle, catching the aortic valve leaflets and is stopped by aortic (outlet) valve closure. Similarly, as the pressure in the right ventricle falls below the pressure in the pulmonary artery, the pulmonary (outlet) valve closes. The S2 sound results from reverberation within the blood associated with the sudden block of flow reversal.
## Splitting of the second heart sound
### Physiologic Splitting
During inspiration, negative intrathoracic pressure causes increased blood return into the right side of the heart, yet some slowing of emptying from the left side. The increased blood volume in the right ventricle causes the pulmonary valve to stay open longer during ventricular systole. This causes an increased delay in the P2 component of S2 relative to the A2 component. This is defined as physiologic splitting of S2. During expiration, the positive intrathoracic pressure causes decreased blood return to the right side of the heart. The reduced volume in the right ventricle allows the pulmonary valve to close earlier at the end of ventricular systole, causing P2 to occur earlier, and "closer" to A2. It is physiological to hear a "splitting" of the second heart tone in younger people, during inspiration and in the "pulmonary area", i.e. the 2nd ICS (intercostal space) at the left edge of the sternum. During expiration, the interval between the two components normally shortens and the S2 sounds becomes merged.
### Persistent Splitting
Persistent splitting of S2 is seen in right bundle branch block (RBBB) and pulmonary hypertension. Because of the delayed activation of the right heart in RBBB the pulmonary valve closure is delayed causing a split in the second heart sound which is persistent in both inspiration and expiration.
### Paradoxical Splitting
This phenomenon is seen in left bundle branch block (LBBB), aortic stenosis, severe heart failure and hypertrophic cardiomyopathy. Delayed activation of the left ventricle and in turn delayed closure of the aortic valve causes the pulmonic component of the second heart sound to occur before the aortic component. This split is better appreciated while expiration than during inspiration.
### Fixed Splitting
If this splitting does not vary with inspiration, it is termed "fixed split S2" and is usually due to an atrial septal defect (ASD) or ventricular septal defect (VSD). The ASD or VSD creates a left to right shunt that increases the blood flow to the right side of the heart, thereby causing the pulmonic valve to close later than the aortic valve independent of inspiration/expiration.
## Loud P2
Pulmonary hypertension is the most common cause of a loud P2. When the pulmonary artery pressures are more than 50 mm Hg a loud pulmonic component of S2 is heard in the left second intercostal space (pulmonic area). Pulmonary hypertension is also a caiuse of persistent splitting of S2.
# Extra heart sounds
Infrequently extra heart sounds are heard in both normal and abnormal situations. A gallop rhythm refers to a (usually abnormal) rhythm of the heart on auscultation. The normal heart rhythm contains two audible sounds, called S1 and S2, giving the well-known "lub-dub" rhythm. They are caused by the closing of valves in the heart. A gallop rhythm contains another sound, called S3 or S4, dependent upon where in the cycle this added sound comes; it can also contain both of these sounds.
# Third heart sound S3
Rarely, there may be a third heart sound S3. S3 (or third heart sound) is the name of the vibration which occurs during early diastole, shortly after the second heart sound S2, giving a rhythm much like the cadence in the word 'Kentucky'. It can be a normal finding in people under 40 years of age, but over this age is usually a sign of heart failure. It is usually low-pitched and difficult to hear, and is best heard with the bell of the stethoscope. An S3 rhythm is also known as ventricular gallop. The third heart sound or protodiastolic sound is not of valvular origin, as it occurs at the beginning of diastole just after S2. This sound occurs when the left ventricle is not very compliant, and at the beginning of diastole the rush of blood into the left ventricle suddenly is halted, resulting in a vibration of the ventricle and surrounding structures.
The third heart sound is normal in children and young adults, but disappears before middle age. Abnormal reemergence of this sound late in life indicates a pathological state, often a sign of a failing left ventricle as in dilated congestive heart failure (CHF). This sound is called a protodiastolic gallop or ventricular gallop, a type of gallop rhythm.
## Pathophysiology and Etiology
It is caused by the sudden slowing of blood rushing in from the atrium into the ventricle as it is relaxing.
## Differential Diagnosis of Causes of an S3
It is associated with heart failure, caused by conditions which have:
- Mitral regurgitation - this is when one of the heart valves that usually stops blood going from the left ventricle to the left atria fails, allowing blood into the atria during systole. This means they will be overfilled when they come to contract, leading to the rapid ventricular filling.
- Elevated left atrial and left ventricular filling pressures, usually a result of a stiffened and dilated left ventricle
- Ventricular septal defect - this is a hole in the wall between the two ventricles, which allows rapid filling from the other ventricle.
- Elevated atrial pressure
- High-output states
### Poor Left Ventricular Function
- Post-MI - the death of tissue in the ventricular wall due to loss of blood supply causes areas which do not move as well, if at all (hypokinetic and akinetic), meaning they do not relax quickly enough so the ventricular filling is relatively too quick.
- Dilated cardiomyopathy - the ventricular walls are abnormal for a variety of reasons, and become thin and stiff so do not relax well.
- Hypertrophic obstructive cardiomyopathy
- Cardiomegaly of a variety of causes
In conditions affecting the pericardium or diseases that primarily affect the heart muscle (restrictive cardiomyopathies) a similar sound can be heard, but is usually more high-pitched and is called a 'pericardial knock'.
The S3 can also be confused with a widely split S2, or a mitral opening snap, but these sounds are typically of much higher pitch and occur closer to the onset of S2.
## Treatment
The gallop rhythm itself does not need to be treated; the underlying cause requires correction; depending on the etiology the gallop rhythm may resolve following treatment.
# Fourth heart sound S4
S4 (or fourth heart sound) occurs just before S1 (thus right at the end of one whole cycle), giving a cadence like the word 'Tennessee'. It is never normal. If the problem lies with the left ventricle, the gallop rhythm will be heard best at the cardiac apex (the point of the two ventricles). It will become more apparent with exercise, with the patient lying on their left-hand side, or with the patient holding expiration. If the culprit is the right ventricle, the abnormal rhythm will be most evident on the lower left hand side of the sternum, and will get louder with exercise and quick, deep inspiration . The fourth heart sound S4 is sometimes audible in healthy children, but when audible in an adult is called a presystolic gallop or atrial gallop. This gallop is a sign of a pathologic state, usually a failing left ventricle. This sound occurs just after atrial contraction ("atrial kick") and is the sound of blood being forced into a stiff/hypertrophic left ventricle. The combined presence of S3 and S4 is a quadruple gallop. At rapid heart rates, S3 and S4 may merge to produce a summation gallop.
## Pathophysiology and Etiology
It is caused by the atria contracting forcefully in an effort to overcome an abnormally-stiff ventricle.
## Differential Diagnosis of Causes of an S4
The S4 rhythm is associated with disorders that increases the stiffness of the ventricle, including:
- Long-standing hypertension
- Aortic stenosis
- Overload of the ventricle
- Fibrosis of the ventricle
- Left ventricular hypertrophy
- Coronary Artery Disease
- Hypertrophic Cardiomyopathy
- Pulmonary Hypertension
## Treatment
Again, the rhythm itself does not require treatment; the underlying cause of ventricular stiffness or dysfunction does.
# Summation Gallop
If a fast heart rate (tachycardia) is present along and S3 and S4 both occur, the rate may become high enough so that the distinction between the two sounds is lost, and they summate into a single sound.
# Abnormal sounds
Aortic area, pulmonic area, tricuspid area and mitral area are the area where we auscultate the heart.
Heart murmurs are produced as a result of turbulent flow of blood, turbulence sufficient to produce audible noise. They usually are heard as a whooshing sound. The term murmur only refers to a sound believed to originating within blood flow through or near the heart; rapid blood velocity is necessary to produce a murmur. Though not fully reliable, soft murmurs are less likely to reflect a serious, if any, health problem; loud murmurs essentially always reflect a problem. Yet most heart problems do not produce any murmur and most valve problems also do not produce an audible murmur.
The following paragraphs overview the murmurs most commonly heard in adults, adults who do not have major congenital heart abnormalities.
- Regurgitation through the mitral valve is by far the most commonly heard murmur, sometimes fairly loud to a practiced ear, even though the volume of regurgitant blood flow may be quite small. Yet, though often obvious, probably about 20% of cases of mitral regurgitation, though obvious using echocardiography visualization, do not produce an audible murmur.
- Stenosis of the aortic valve is typically the next most commonly heart murmur, a systolic ejection murmur. This is more common in older adults or in those individuals having a two, not a three leaflet aortic valve.
- Regurgitation through the aortic valve, if marked, is sometimes audible to a practiced ear with a high quality, especially electronically amplified, stethoscope. Generally, this is a very rarely heard murmur, even though aortic valve regurgitation is not so rare. Aortic regurgition, though obvious using echocardiography visualization, usually does not produce an audible murmur.
- Stenosis of the mitral valve, if severe, also rarely produces an audible, low frequency soft rumbling murmur, best recognized by a practiced ear using a high quality, especially electronically amplified, stethoscope.
- Either regurgitation through, or stenosis of, the tricuspid or pulmonary valves essentially never produces audible murmurs.
- Other audible murmurs are associated with abnormal openings between the left ventricle and right heart or from the aortic or pulmonary arteries back into a lower pressure heart chamber.
As noted, several different cardiac conditions can cause heart murmurs. However, the murmurs produced often change in complex ways with the severity of the cardiac disease. An astute physician can sometimes diagnose cardiac conditions with some accuracy based largely on the murmur, related physical examination and experience with the relative frequency of different heart conditions. However, with the advent of better quality and wider availability of echocardiography and other techniques, heart status can be recognized and quantified much more accurately than formerly possible with only a stethoscope, examination and experience.
Clicks: With the advent of newer, non-invasive imaging techniques, the origin of other, so-called adventitial sounds or "clicks" has been appreciated. These are short, high-pitched sounds. There are two types of clicks, ejection click and non-ejection click.
- Ejection clicks are caused by bicuspid aortic valve and bicuspid pulmonary valve early in the systole.
- Non-ejection clicks are seen in mitral valve prolapse, ventricular septal aneurysm, atrial septal aneurysm, cardiac tumors, pulmonary hypertension and systemic hypertension. Patients with mitral valve prolapse may have a mid-systolic click along with a murmur.
- The atrioventricular valves of patients with mitral stenosis may open with an opening snap on the beginning of diastole.
Rubs: Patients with pericarditis, an inflammation of the sac surrounding the heart (pericardium), may have an audible pericardial friction rub. This is a characteristic scratching, creaking, high-pitched sound emanating from the rubbing of both layers of inflammated pericardium. It is the loudest in systole, but can often be heard also at the beginning and at the end of diastole. It is very dependent on body position and breathing, and changes from hour to hour.
There are a number of interventions that can be performed that alter the intensity and characteristics of abnormal heart sounds. These interventions can be performed to differentiate the different heart sounds and obtain a diagnosis of the cardiac anomaly that causes the heart sound. (See Heart murmur#Interventions that change murmur sounds.)
Inhalation pressure also causes an increase in the venous blood return to the right side of the heart. Therefore, right-sided murmurs generally increase in intensity with inspiration. The increased volume of blood entering the right sided chambers of the heart restricts the amount of blood entering the left sided chambers of the heart. This causes left-sided murmurs to generally decrease in intensity during inspiration.
With expiration, the opposite haemodynamic changes occur. This means that left-sided murmurs generally increase in intensity with expiration.
Having the patient lie supine and raising their legs up to a 45 degree angle facilitates an increase in venous return to the right side of the heart producing effects similar to inhalation-increased blood flow.
# Surface anatomy
The opening and closing of the valves is usually much less loud than the sound of the blood rushing through the valve and "colliding" with the subsequent barrier. Because of this, auscultation to determine function of a valve is usually not performed at the position of the valve, but at a downstream position where the listener can best hear the blood colliding after the valve is closed.
One can remember the positions of the sounds by the mnemonic "All The Presidents Men".
- A - Aortic - Right second intercostal space
- T - Tricuspid - Left fourth intercostal space sternal border
- P - Pulmonic - Left second intercostal space sternal border
- M - Mitral - Fifth intercostal space lateral to left midclavicular line
# Recording heart sounds
With the advent of electronic stethoscopes, it is now possible to conveniently record heart sounds. One electronic stethoscope provides a port to output stethoscope sounds to an external recording device, such as a notebook computer or MP3 recorder. The same connection can then be used to listen to the recordings through the stethoscope headphones, allowing for faithful reproduction of low-frequency murmurs and other heart sounds.
# Related Chapters
- Physical examination
- Precordial examination
- Anatomy
Heart
Heart valve
Aortic valve
Pulmonary valve
Mitral valve
Tricuspid valve
- Heart
- Heart valve
Aortic valve
Pulmonary valve
Mitral valve
Tricuspid valve
- Aortic valve
- Pulmonary valve
- Mitral valve
- Tricuspid valve
- Pathophysiology
Mitral stenosis
Mitral regurgitation
Aortic stenosis
Aortic insufficiency
Pulmonary stenosis
Pulmonary insufficiency
Tricuspid stenosis
Tricuspid insufficiency
- Mitral stenosis
- Mitral regurgitation
- Aortic stenosis
- Aortic insufficiency
- Pulmonary stenosis
- Pulmonary insufficiency
- Tricuspid stenosis
- Tricuspid insufficiency
- Heart murmur
- Benign paediatric heart murmur
- Pulsatile Tinnitus - hearing a heartbeat sound in one or both ears
|
Heart sounds
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
# Overview
The heart sounds are the noises (sound) generated by the beating heart and the resultant flow of blood through it. This is also called a heartbeat. In cardiac auscultation, an examiner uses a stethoscope to listen for these sounds, which provide important information about the condition of the heart.
In healthy adults, there are two normal heart sounds often described as a lub and a dub (or dup), that occur in sequence with each heart beat. These are the first heart sound (S1) and second heart sound (S2), produced by the closure of the AV valves and semilunar valves respectively. In addition to these normal sounds, a variety of other sounds may be present including heart murmurs and adventitious sounds.
Heart murmurs are generated by turbulent flow of blood, which may occur inside or outside the heart. Murmurs may be physiological (benign) or pathological (abnormal). Abnormal murmurs can be caused by stenosis restricting the opening of a heart valve, causing turbulence as blood flows through it. Valve insufficiency (or regurgitation) allows backflow of blood when the incompetent valve is supposed to be closed. Different murmurs are audible in different parts of the cardiac cycle, depending on the cause of the murmur.
# Normal heart sounds
# First heart tone S1, the "lub"(components M1 and T1)
The first heart tone, or S1, is caused by the sudden block of reverse blood flow due to closure of the atrioventricular valves, mitral and tricuspid, at the beginning of ventricular contraction, or systole. When the pressure in the ventricles rises above the pressure in the atria, venous blood flow entering the ventricles is pushed back toward the atria, catching the valve leaflets, closing the inlet valves and preventing regurgitation of blood from the ventricles back into the atria. The S1 sound results from reverberation within the blood associated with the sudden block of flow reversal by the valves. [1]
# Second heart tone S2 the "dub"(components A2 and P2)
The second heart tone, or S2, is caused by the sudden block of reversing blood flow due to closure of the aortic valve and pulmonary valve at the end of ventricular systole, i.e beginning of ventricular diastole. As the left ventricle empties, its pressure falls below the pressure in the aorta, aortic blood flow quickly reverses back toward the left ventricle, catching the aortic valve leaflets and is stopped by aortic (outlet) valve closure. Similarly, as the pressure in the right ventricle falls below the pressure in the pulmonary artery, the pulmonary (outlet) valve closes. The S2 sound results from reverberation within the blood associated with the sudden block of flow reversal.
## Splitting of the second heart sound
### Physiologic Splitting
During inspiration, negative intrathoracic pressure causes increased blood return into the right side of the heart, yet some slowing of emptying from the left side. The increased blood volume in the right ventricle causes the pulmonary valve to stay open longer during ventricular systole. This causes an increased delay in the P2 component of S2 relative to the A2 component. This is defined as physiologic splitting of S2. During expiration, the positive intrathoracic pressure causes decreased blood return to the right side of the heart. The reduced volume in the right ventricle allows the pulmonary valve to close earlier at the end of ventricular systole, causing P2 to occur earlier, and "closer" to A2. It is physiological to hear a "splitting" of the second heart tone in younger people, during inspiration and in the "pulmonary area", i.e. the 2nd ICS (intercostal space) at the left edge of the sternum. During expiration, the interval between the two components normally shortens and the S2 sounds becomes merged.
### Persistent Splitting
Persistent splitting of S2 is seen in right bundle branch block (RBBB) and pulmonary hypertension. Because of the delayed activation of the right heart in RBBB the pulmonary valve closure is delayed causing a split in the second heart sound which is persistent in both inspiration and expiration.
### Paradoxical Splitting
This phenomenon is seen in left bundle branch block (LBBB), aortic stenosis, severe heart failure and hypertrophic cardiomyopathy. Delayed activation of the left ventricle and in turn delayed closure of the aortic valve causes the pulmonic component of the second heart sound to occur before the aortic component. This split is better appreciated while expiration than during inspiration.
### Fixed Splitting
If this splitting does not vary with inspiration, it is termed "fixed split S2" and is usually due to an atrial septal defect (ASD) or ventricular septal defect (VSD). The ASD or VSD creates a left to right shunt that increases the blood flow to the right side of the heart, thereby causing the pulmonic valve to close later than the aortic valve independent of inspiration/expiration.
## Loud P2
Pulmonary hypertension is the most common cause of a loud P2. When the pulmonary artery pressures are more than 50 mm Hg a loud pulmonic component of S2 is heard in the left second intercostal space (pulmonic area). Pulmonary hypertension is also a caiuse of persistent splitting of S2.
# Extra heart sounds
Infrequently extra heart sounds are heard in both normal and abnormal situations. A gallop rhythm refers to a (usually abnormal) rhythm of the heart on auscultation. The normal heart rhythm contains two audible sounds, called S1 and S2, giving the well-known "lub-dub" rhythm. They are caused by the closing of valves in the heart. A gallop rhythm contains another sound, called S3 or S4, dependent upon where in the cycle this added sound comes; it can also contain both of these sounds.
# Third heart sound S3
Rarely, there may be a third heart sound S3. S3 (or third heart sound) is the name of the vibration which occurs during early diastole, shortly after the second heart sound S2, giving a rhythm much like the cadence in the word 'Kentucky'. It can be a normal finding in people under 40 years of age, but over this age is usually a sign of heart failure. It is usually low-pitched and difficult to hear, and is best heard with the bell of the stethoscope. An S3 rhythm is also known as ventricular gallop. The third heart sound or protodiastolic sound is not of valvular origin, as it occurs at the beginning of diastole just after S2. This sound occurs when the left ventricle is not very compliant, and at the beginning of diastole the rush of blood into the left ventricle suddenly is halted, resulting in a vibration of the ventricle and surrounding structures.
The third heart sound is normal in children and young adults, but disappears before middle age. Abnormal reemergence of this sound late in life indicates a pathological state, often a sign of a failing left ventricle as in dilated congestive heart failure (CHF). This sound is called a protodiastolic gallop or ventricular gallop, a type of gallop rhythm.
## Pathophysiology and Etiology
It is caused by the sudden slowing of blood rushing in from the atrium into the ventricle as it is relaxing.
## Differential Diagnosis of Causes of an S3
It is associated with heart failure, caused by conditions which have:
- Mitral regurgitation - this is when one of the heart valves that usually stops blood going from the left ventricle to the left atria fails, allowing blood into the atria during systole. This means they will be overfilled when they come to contract, leading to the rapid ventricular filling.
- Elevated left atrial and left ventricular filling pressures, usually a result of a stiffened and dilated left ventricle
- Ventricular septal defect - this is a hole in the wall between the two ventricles, which allows rapid filling from the other ventricle.
- Elevated atrial pressure
- High-output states
### Poor Left Ventricular Function
- Post-MI - the death of tissue in the ventricular wall due to loss of blood supply causes areas which do not move as well, if at all (hypokinetic and akinetic), meaning they do not relax quickly enough so the ventricular filling is relatively too quick.
- Dilated cardiomyopathy - the ventricular walls are abnormal for a variety of reasons, and become thin and stiff so do not relax well.
- Hypertrophic obstructive cardiomyopathy
- Cardiomegaly of a variety of causes
In conditions affecting the pericardium or diseases that primarily affect the heart muscle (restrictive cardiomyopathies) a similar sound can be heard, but is usually more high-pitched and is called a 'pericardial knock'.
The S3 can also be confused with a widely split S2, or a mitral opening snap, but these sounds are typically of much higher pitch and occur closer to the onset of S2.
## Treatment
The gallop rhythm itself does not need to be treated; the underlying cause requires correction; depending on the etiology the gallop rhythm may resolve following treatment.
# Fourth heart sound S4
S4 (or fourth heart sound) occurs just before S1 (thus right at the end of one whole cycle), giving a cadence like the word 'Tennessee'. It is never normal. If the problem lies with the left ventricle, the gallop rhythm will be heard best at the cardiac apex (the point of the two ventricles). It will become more apparent with exercise, with the patient lying on their left-hand side, or with the patient holding expiration. If the culprit is the right ventricle, the abnormal rhythm will be most evident on the lower left hand side of the sternum, and will get louder with exercise and quick, deep inspiration [2]. The fourth heart sound S4 is sometimes audible in healthy children, but when audible in an adult is called a presystolic gallop or atrial gallop. This gallop is a sign of a pathologic state, usually a failing left ventricle. This sound occurs just after atrial contraction ("atrial kick") and is the sound of blood being forced into a stiff/hypertrophic left ventricle. The combined presence of S3 and S4 is a quadruple gallop. At rapid heart rates, S3 and S4 may merge to produce a summation gallop.
## Pathophysiology and Etiology
It is caused by the atria contracting forcefully in an effort to overcome an abnormally-stiff ventricle.
## Differential Diagnosis of Causes of an S4
The S4 rhythm is associated with disorders that increases the stiffness of the ventricle, including:
- Long-standing hypertension
- Aortic stenosis
- Overload of the ventricle
- Fibrosis of the ventricle
- Left ventricular hypertrophy
- Coronary Artery Disease
- Hypertrophic Cardiomyopathy
- Pulmonary Hypertension
## Treatment
Again, the rhythm itself does not require treatment; the underlying cause of ventricular stiffness or dysfunction does.
# Summation Gallop
If a fast heart rate (tachycardia) is present along and S3 and S4 both occur, the rate may become high enough so that the distinction between the two sounds is lost, and they summate into a single sound.
# Abnormal sounds
Aortic area, pulmonic area, tricuspid area and mitral area are the area where we auscultate the heart.
Heart murmurs are produced as a result of turbulent flow of blood, turbulence sufficient to produce audible noise. They usually are heard as a whooshing sound. The term murmur only refers to a sound believed to originating within blood flow through or near the heart; rapid blood velocity is necessary to produce a murmur. Though not fully reliable, soft murmurs are less likely to reflect a serious, if any, health problem; loud murmurs essentially always reflect a problem. Yet most heart problems do not produce any murmur and most valve problems also do not produce an audible murmur.
The following paragraphs overview the murmurs most commonly heard in adults, adults who do not have major congenital heart abnormalities.
- Regurgitation through the mitral valve is by far the most commonly heard murmur, sometimes fairly loud to a practiced ear, even though the volume of regurgitant blood flow may be quite small. Yet, though often obvious, probably about 20% of cases of mitral regurgitation, though obvious using echocardiography visualization, do not produce an audible murmur.
- Stenosis of the aortic valve is typically the next most commonly heart murmur, a systolic ejection murmur. This is more common in older adults or in those individuals having a two, not a three leaflet aortic valve.
- Regurgitation through the aortic valve, if marked, is sometimes audible to a practiced ear with a high quality, especially electronically amplified, stethoscope. Generally, this is a very rarely heard murmur, even though aortic valve regurgitation is not so rare. Aortic regurgition, though obvious using echocardiography visualization, usually does not produce an audible murmur.
- Stenosis of the mitral valve, if severe, also rarely produces an audible, low frequency soft rumbling murmur, best recognized by a practiced ear using a high quality, especially electronically amplified, stethoscope.
- Either regurgitation through, or stenosis of, the tricuspid or pulmonary valves essentially never produces audible murmurs.
- Other audible murmurs are associated with abnormal openings between the left ventricle and right heart or from the aortic or pulmonary arteries back into a lower pressure heart chamber.
As noted, several different cardiac conditions can cause heart murmurs. However, the murmurs produced often change in complex ways with the severity of the cardiac disease. An astute physician can sometimes diagnose cardiac conditions with some accuracy based largely on the murmur, related physical examination and experience with the relative frequency of different heart conditions. However, with the advent of better quality and wider availability of echocardiography and other techniques, heart status can be recognized and quantified much more accurately than formerly possible with only a stethoscope, examination and experience.
Clicks: With the advent of newer, non-invasive imaging techniques, the origin of other, so-called adventitial sounds or "clicks" has been appreciated. These are short, high-pitched sounds. There are two types of clicks, ejection click and non-ejection click.
- Ejection clicks are caused by bicuspid aortic valve and bicuspid pulmonary valve early in the systole.
- Non-ejection clicks are seen in mitral valve prolapse, ventricular septal aneurysm, atrial septal aneurysm, cardiac tumors, pulmonary hypertension and systemic hypertension. Patients with mitral valve prolapse may have a mid-systolic click along with a murmur.
- The atrioventricular valves of patients with mitral stenosis may open with an opening snap on the beginning of diastole.
Rubs: Patients with pericarditis, an inflammation of the sac surrounding the heart (pericardium), may have an audible pericardial friction rub. This is a characteristic scratching, creaking, high-pitched sound emanating from the rubbing of both layers of inflammated pericardium. It is the loudest in systole, but can often be heard also at the beginning and at the end of diastole. It is very dependent on body position and breathing, and changes from hour to hour.
There are a number of interventions that can be performed that alter the intensity and characteristics of abnormal heart sounds. These interventions can be performed to differentiate the different heart sounds and obtain a diagnosis of the cardiac anomaly that causes the heart sound. (See Heart murmur#Interventions that change murmur sounds.)
Inhalation pressure also causes an increase in the venous blood return to the right side of the heart. Therefore, right-sided murmurs generally increase in intensity with inspiration. The increased volume of blood entering the right sided chambers of the heart restricts the amount of blood entering the left sided chambers of the heart. This causes left-sided murmurs to generally decrease in intensity during inspiration.
With expiration, the opposite haemodynamic changes occur. This means that left-sided murmurs generally increase in intensity with expiration.
Having the patient lie supine and raising their legs up to a 45 degree angle facilitates an increase in venous return to the right side of the heart producing effects similar to inhalation-increased blood flow.
# Surface anatomy
The opening and closing of the valves is usually much less loud than the sound of the blood rushing through the valve and "colliding" with the subsequent barrier. Because of this, auscultation to determine function of a valve is usually not performed at the position of the valve, but at a downstream position where the listener can best hear the blood colliding after the valve is closed.
One can remember the positions of the sounds by the mnemonic "All The Presidents Men". [3]
- A - Aortic - Right second intercostal space
- T - Tricuspid - Left fourth intercostal space sternal border
- P - Pulmonic - Left second intercostal space sternal border
- M - Mitral - Fifth intercostal space lateral to left midclavicular line
# Recording heart sounds
With the advent of electronic stethoscopes, it is now possible to conveniently record heart sounds. One electronic stethoscope provides a port to output stethoscope sounds to an external recording device, such as a notebook computer or MP3 recorder. The same connection can then be used to listen to the recordings through the stethoscope headphones, allowing for faithful reproduction of low-frequency murmurs and other heart sounds.
# Related Chapters
- Physical examination
- Precordial examination
- Anatomy
Heart
Heart valve
Aortic valve
Pulmonary valve
Mitral valve
Tricuspid valve
- Heart
- Heart valve
Aortic valve
Pulmonary valve
Mitral valve
Tricuspid valve
- Aortic valve
- Pulmonary valve
- Mitral valve
- Tricuspid valve
- Pathophysiology
Mitral stenosis
Mitral regurgitation
Aortic stenosis
Aortic insufficiency
Pulmonary stenosis
Pulmonary insufficiency
Tricuspid stenosis
Tricuspid insufficiency
- Mitral stenosis
- Mitral regurgitation
- Aortic stenosis
- Aortic insufficiency
- Pulmonary stenosis
- Pulmonary insufficiency
- Tricuspid stenosis
- Tricuspid insufficiency
- Heart murmur
- Benign paediatric heart murmur
- Pulsatile Tinnitus - hearing a heartbeat sound in one or both ears
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https://www.wikidoc.org/index.php/3rd_heart_sound
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0097de7980192eb128fcdfcd74f014173e622493
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wikidoc
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XYY syndrome
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XYY syndrome
# Overview
XYY syndrome is an aneuploidy of the sex chromosomes in which a human male receives an extra Y chromosome,producing a 47,XYY karyotype.
Some medical geneticists question whether the term "syndrome" is appropriate for this condition because its phenotype is normal and the vast majority (an estimated 97% in the UK) of 47,XYY males do not know their karyotype.
# Etiology
47,XYY is not inherited, but usually occurs as a random event during the formation of sperm cells. An error in chromosome separation during metaphase II (of meiosis II) called nondisjunction can result in sperm cells with an extra copy of the Y chromosome. If one of these atypical sperm cells contributes to the genetic makeup of a child, the child will have an extra Y chromosome in each of the body's cells.
In some cases, the addition of an extra Y chromosome results from nondisjunction during cell division during a post-zygotic mitosis in early embryonic development. This can produce 46,XY/47,XYY mosaics.
# Incidence
About 1 in 1,000 boys are born with a 47,XYY karyotype. The incidence of 47,XYY is not affected by advanced paternal or maternal age.
# First case
The first published report of a man with a 47,XYY karyotype was by Avery A. Sandberg and colleagues at Roswell Park Memorial Institute in Buffalo, New York in 1961. It was an incidental finding in a normal 44-year-old, 6 ft. tall man of average intelligence who was karyotyped because he had a daughter with Down syndrome.
47,XYY was the last of the common sex chromosome aneuploidies to be discovered, two years after the discoveries of 47,XXY, 45,X, and 47,XXX in 1959. Even the much less common 48,XXYY had been discovered in 1960, a year before 47,XYY. Screening for these X chromosome aneuploidies was possible by noting the presence or absence of "female" sex chromatin bodies (Barr bodies) in the nuclei of interphase cells in buccal smears, a technique developed a decade before the first reported sex chromosome aneuploidy.
An analogous technique to screen for Y chromosome aneuploidies by noting supernumerary "male" sex chromatin bodies was not developed until 1970, a decade after the first reported sex chromosome aneuploidy.
In December 1969, Lore Zech at the Karolinska Institute in Stockholm first reported intense fluorescence of the AT-rich distal half of the long arm of the Y chromosome in the nuclei of metaphase cells treated with quinacrine mustard.
Four months later, in April 1970, Peter L. Pearson and Martin Bobrow at the MRC Population Genetics Unit in Oxford and Canino G. Vosa at the University of Oxford reported fluorescent "male" sex chromatin bodies in the nuclei of interphase cells in buccal smears treated with quinacrine dihdyrochloride.
# Physical traits
Most often, the extra Y chromosome causes no unusual physical features or medical problems. 47,XYY boys have an increased growth velocity during earliest childhood, with an average final height approximately 7 cm above expected final height. Severe acne was noted in a very few early case reports, but dermatologists specializing in acne now doubt the existence of a relationship with 47,XYY.
Testosterone levels (prenatally and postnatally) are normal in 47,XYY males. Most 47,XYY males have normal sexual development and usually have normal fertility. Since XYY is not characterized by distinct physical features, the condition is usually detected only during genetic analysis for another reason.
# Behavioral characteristics
47,XYY boys have an increased risk of learning difficulties (in up to 50%) and delayed speech and language skills. In contrast, a national survey of US children conducted in 2004 for the CDC found that 10% of 46,XY boys had a learning disability.
As with 47,XXY boys and 47,XXX girls, IQ scores of 47,XYY boys average 10–15 points below their siblings. It is important to realize that this amount of variation — an average difference of 12 IQ points — occurs naturally between children in the same family. In 14 prenatally diagnosed 47,XYY boys from high socioeconomic status families, IQ scores available for 6 boys ranged from 100–147 with a mean of 120. For 11 boys with siblings, in 9 instances their siblings were stronger academically, but in one case they were performing equal to and in another case superior to their brothers and sisters.
Developmental delays and behavioral problems are also possible, but these characteristics vary widely among affected boys and men, are not unique to 47,XYY and are managed no differently than in 46,XY males. Aggression is not seen more frequently in 47,XYY males.
|
XYY syndrome
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Template:Distinguish2
XYY syndrome is an aneuploidy of the sex chromosomes in which a human male receives an extra Y chromosome,producing a 47,XYY karyotype.
Some medical geneticists question whether the term "syndrome" is appropriate for this condition because its phenotype is normal and the vast majority (an estimated 97% in the UK) of 47,XYY males do not know their karyotype.[1][2]
# Etiology
47,XYY is not inherited, but usually occurs as a random event during the formation of sperm cells. An error in chromosome separation during metaphase II (of meiosis II) called nondisjunction can result in sperm cells with an extra copy of the Y chromosome. If one of these atypical sperm cells contributes to the genetic makeup of a child, the child will have an extra Y chromosome in each of the body's cells.[3][4]
In some cases, the addition of an extra Y chromosome results from nondisjunction during cell division during a post-zygotic mitosis in early embryonic development. This can produce 46,XY/47,XYY mosaics.[3][4]
# Incidence
About 1 in 1,000 boys are born with a 47,XYY karyotype. The incidence of 47,XYY is not affected by advanced paternal or maternal age.[1][5][6]
# First case
The first published report of a man with a 47,XYY karyotype was by Avery A. Sandberg and colleagues at Roswell Park Memorial Institute in Buffalo, New York in 1961. It was an incidental finding in a normal 44-year-old, 6 ft. [183 cm] tall man of average intelligence who was karyotyped because he had a daughter with Down syndrome.[7][8]
47,XYY was the last of the common sex chromosome aneuploidies to be discovered, two years after the discoveries of 47,XXY, 45,X, and 47,XXX in 1959. Even the much less common 48,XXYY had been discovered in 1960, a year before 47,XYY. Screening for these X chromosome aneuploidies was possible by noting the presence or absence of "female" sex chromatin bodies (Barr bodies) in the nuclei of interphase cells in buccal smears, a technique developed a decade before the first reported sex chromosome aneuploidy.[9]
An analogous technique to screen for Y chromosome aneuploidies by noting supernumerary "male" sex chromatin bodies was not developed until 1970, a decade after the first reported sex chromosome aneuploidy.[10][11]
In December 1969, Lore Zech at the Karolinska Institute in Stockholm first reported intense fluorescence of the AT-rich distal half of the long arm of the Y chromosome in the nuclei of metaphase cells treated with quinacrine mustard.[12]
Four months later, in April 1970, Peter L. Pearson and Martin Bobrow at the MRC Population Genetics Unit in Oxford and Canino G. Vosa at the University of Oxford reported fluorescent "male" sex chromatin bodies in the nuclei of interphase cells in buccal smears treated with quinacrine dihdyrochloride.[13]
# Physical traits
Most often, the extra Y chromosome causes no unusual physical features or medical problems. 47,XYY boys have an increased growth velocity during earliest childhood, with an average final height approximately 7 cm above expected final height.[14] Severe acne was noted in a very few early case reports, but dermatologists specializing in acne now doubt the existence of a relationship with 47,XYY.[15]
Testosterone levels (prenatally and postnatally) are normal in 47,XYY males.[16] Most 47,XYY males have normal sexual development and usually have normal fertility. Since XYY is not characterized by distinct physical features, the condition is usually detected only during genetic analysis for another reason.
# Behavioral characteristics
47,XYY boys have an increased risk of learning difficulties (in up to 50%) and delayed speech and language skills.[1][17][18][5][19][20][6][3] In contrast, a national survey of US children conducted in 2004 for the CDC found that 10% of 46,XY boys had a learning disability.[21]
As with 47,XXY boys and 47,XXX girls, IQ scores of 47,XYY boys average 10–15 points below their siblings.[17][5][19][6] It is important to realize that this amount of variation — an average difference of 12 IQ points — occurs naturally between children in the same family.[17] In 14 prenatally diagnosed 47,XYY boys from high socioeconomic status families, IQ scores available for 6 boys ranged from 100–147 with a mean of 120. For 11 boys with siblings, in 9 instances their siblings were stronger academically, but in one case they were performing equal to and in another case superior to their brothers and sisters.[22]
Developmental delays and behavioral problems are also possible, but these characteristics vary widely among affected boys and men, are not unique to 47,XYY and are managed no differently than in 46,XY males.[5][3] Aggression is not seen more frequently in 47,XYY males.[1][17][5][19][20]
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https://www.wikidoc.org/index.php/47,XYY
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f6e79c9df68d7a6ccf4d9eef2ad59c831f5ed438
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510K Pathway
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510K Pathway
# Introduction
Each person who wants to market in the U.S., a Class I, II, and III device intended for human use, for which a Premarket Approval application (PMA) is not required, must submit a 510(k) to FDA unless the device is exempt from 510(k) requirements of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) and does not exceed the limitations of exemptions in .9 of the device classification regulation chapters (e.g., 21 CFR 862.9, 21 CFR 864.9). There is no 510(k) form; however, 21 CFR 807 Subpart E describes requirements for a 510(k) submission. Before marketing a device, each submitter must receive an order, in the form of a letter, from FDA which finds the device to be substantially equivalent (SE) and states that the device can be marketed in the U.S. This order "clears" the device for commercial distribution.
A 510(k) is a premarket submission made to FDA to demonstrate that the device to be marketed is at least as safe and effective, that is, substantially equivalent, to a legally marketed device (21 CFR 807.92(a)(3)) that is not subject to PMA. Submitters must compare their device to one or more similar legally marketed devices and make and support their substantial equivalence claims. A legally marketed device is a device that was legally marketed prior to May 28, 1976 (preamendments device), or a device which has been reclassified from Class III to Class II or I, a device which has been found SE through the 510(k) process, or a device that was granted marketing authorization via the De Novo classification process under section 513(f)(2) of the FD&C Act that is not exempt from premarket notification requirements. The legally marketed device(s) to which equivalence is drawn is commonly known as the "predicate." Although devices recently cleared under 510(k) are often selected as the predicate to which equivalence is claimed, any legally marketed device may be used as a predicate. Legally marketed also means that the predicate cannot be one that is in violation of the Act.
Until the submitter receives an order declaring a device SE, the submitter may not proceed to market the device. Once the device is determined to be SE, it can then be marketed in the U.S. The SE determination is usually made within 90 days and is made based on the information submitted by the submitter.
The FDA does not perform 510(k) pre-clearance facility inspections. The submitter may market the device immediately after 510(k) clearance is granted. The manufacturer should be prepared for an FDA quality system (21 CFR 820) inspection at any time after 510(k) clearance.
# What is Substantial Equivalence
A 510(k) requires demonstration of substantial equivalence to another legally U.S. marketed device. Substantial equivalence means that the new device is at least as safe and effective as the predicate.
A device is substantially equivalent if, in comparison to a predicate it:
has the same intended use as the predicate; and
has the same technological characteristics as the predicate;
-r
has the same intended use as the predicate; and
has different technological characteristics and does not raise different questions of safety and effectiveness; and
the information submitted to FDA demonstrates that the device is at least as safe and effective as the legally marketed device.
A claim of substantial equivalence does not mean the new and predicate devices must be identical. Substantial equivalence is established with respect to intended use, design, energy used or delivered, materials, chemical composition, manufacturing process, performance, safety, effectiveness, labeling, biocompatibility, standards, and other characteristics, as applicable.
A device may not be marketed in the U.S. until the submitter receives a letter declaring the device substantially equivalent. If FDA determines that a device is not substantially equivalent, the applicant may:
resubmit another 510(k) with new data,
request a Class I or II designation through the De Novo Classification process
file a reclassification petition, or
submit a premarket approval application (PMA).
# Who is Required to Submit a 510(k)
The FD&C Act and the 510(k) regulation (21 CFR 807) do not specify who must submit a 510(k). Instead, they specify which actions, such as introducing a device to the U.S. market, require a 510(k) submission.
The following four categories of parties must submit a 510(k) to the FDA:
Domestic manufacturers introducing a device to the U.S. market;
Finished device manufacturers must submit a 510(k) if they manufacture a device according to their own specifications and market it in the U.S. Accessories to finished devices that are sold to the end user are also considered finished devices. However, manufacturers of device components are not required to submit a 510(k) unless such components are promoted for sale to an end user as replacement parts. Contract manufacturers, those firms that manufacture devices under contract according to someone else’s specifications, are not required to submit a 510(k).
Specification developers introducing a device to the U.S. market;
A specification developer develops the specifications for a finished device, but has the device manufactured under contract by another firm or entity. The specification developer submits the 510(k), not the contract manufacturer.
Repackers or relabelers who make labeling changes or whose operations significantly affect the device.
Repackagers or relabelers may be required to submit a 510(k) if they significantly change the labeling or otherwise affect any condition of the device. Significant labeling changes may include modification of manuals, such as adding a new intended use, deleting or adding warnings, contraindications, etc. Operations, such as sterilization, could alter the condition of the device. However, most repackagers or relabelers are not required to submit a 510(k).
Foreign manufacturers/exporters or U.S. representatives of foreign manufacturers/exporters introducing a device to the U.S. market.
Please note that all manufacturers (including specification developers) of Class II and III devices and select Class I devices are required to follow design controls (21 CFR 820.30) during the development of their device. The holder of a 510(k) must have design control documentation available for FDA review during a site inspection. In addition, any changes to the device specifications or manufacturing processes must be made in accordance with the Quality System regulation (21 CFR 820) and may be subject to a new 510(k). Additional information is found on the webpage "Is a new 510(k) required for a modification to the device?"
# When a 510(k) is Required
A 510(k) is required when:
Unless exempt, introducing a device into commercial distribution (marketing) for the first time. After May 28, 1976 (effective date of the Medical Device Amendments to the Act), anyone who wants to sell a device in the U.S. is required to make a 510(k) submission at least 90 days prior to offering the device for sale, even though it may have been under development or clinical investigation before that date. If your device was not marketed by your firm before May 28, 1976, a 510(k) is required.
There is a change or modification to a legally marketed device and that change could significantly affect its safety or effectiveness. The burden is on the 510(k) holder to decide whether or not a modification could significantly affect safety or effectiveness of the device. Any modifications must be made in accordance with the Quality System regulation, 21 CFR 820, and recorded in the device master record and change control records. It is recommended that the justification for submitting or not submitting a new 510(k) be recorded in the change control records.
A new 510(k) submission is required for changes or modifications to an existing device, where the modifications could significantly affect the safety or effectiveness of the device or the device is to be marketed for a new or different intended use. See Is a new 510(k) required for a modification to the device? for additional information.
Back to Top Arrow
# When a 510(k) is Not Required
The following are examples of when a 510(k) is not required.
You sell unfinished devices to another firm for further processing or sell components to be used in the assembling of devices by other firms. However, if your components are to be sold directly to end users as replacement parts, a 510(k) is required.
Your device is not being marketed or commercially distributed. You do not need a 510(k) to develop, evaluate, or test a device. This includes clinical evaluation. Please note that if you perform clinical trials with your device, you are subject to the Investigational Device Exemption (IDE) regulation (21 CFR 812).
You distribute another firm's domestically manufactured device. You may place a label on the device, "Distributed by ABC Firm" or "Manufactured for ABC Firm," (21 CFR 801.1) and sell it to end users without submission of a 510(k).
In most cases, if you are a repackager or a relabeler and the existing labeling or condition of the device is not significantly changed. The labeling should be consistent with the labeling submitted in the 510(k) with the same indications for use and warnings and contraindications.
Your device was legally in commercial distribution before May 28, 1976 and has not been significantly changed or modified in design, components, method of manufacture, or intended use. These devices are "grandfathered" and you have Preamendment Status documentation to prove this.
The device is made outside the U.S. and you are an importer of the foreign made medical device. A 510(k) is not required if a 510(k) has been submitted by the foreign manufacturer and received marketing clearance. Once the foreign manufacturer has received 510(k) clearance for the device, the foreign manufacturer may export his device to any U.S. importer.
Your device is exempted from 510(k) by regulation (21 CFR 862-892). That is, certain Class I or II devices can be marketed for the first time without having to submit a 510(k). A list of the Class I and II exempted devices can be found on Medical Device Exemptions 510(k) and GMP Requirements. However, if the device exceeds the limitations of exemptions in .9 of the device classification regulation chapters (e.g., 21 CFR 862.9, 21 CFR 864.9), such as the device has a different intended use or operates using a different fundamental scientific technology than a legally marketed device in that generic type of device, or the device is a reprocessed single-use device, then a 510(k) must be submitted to market the new device.
# Preamendment Devices
The term "preamendments device" refers to devices legally marketed in the U.S. by a firm before May 28, 1976 and which have not been:
significantly changed or modified since then; and
for which a regulation requiring a PMA application has not been published by FDA.
Devices meeting the above criteria are "grandfathered" devices and do not require a 510(k). The device must have the same intended use as that marketed before May 28, 1976. If the device is labeled for a different intended use, then the device is considered a new device and a 510(k) must be submitted to FDA for marketing clearance.
Please note that you must be the owner of the device on the market before May 28, 1976, for the device to be grandfathered. If your device is similar to a grandfathered device and marketed after May 28, 1976, then your device does NOT meet the requirements of being grandfathered and you must submit a 510(k). In order for a firm to claim that it has a preamendments device, it must demonstrate that its device was labeled, promoted, and distributed in interstate commerce for a specific intended use and that intended use has not changed. See Preamendment Status for information on documentation requirements.
# Third Party Review Program
The Center for Devices and Radiological Health (CDRH) has implemented a Third Party Review Program. This program provides an option to manufacturers of certain devices of submitting their 510(k) to private parties (Recognized Third Parties) identified by FDA for review instead of submitting directly to CDRH.
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510K Pathway
# Introduction
Each person who wants to market in the U.S., a Class I, II, and III device intended for human use, for which a Premarket Approval application (PMA) is not required, must submit a 510(k) to FDA unless the device is exempt from 510(k) requirements of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) and does not exceed the limitations of exemptions in .9 of the device classification regulation chapters (e.g., 21 CFR 862.9, 21 CFR 864.9). There is no 510(k) form; however, 21 CFR 807 Subpart E describes requirements for a 510(k) submission. Before marketing a device, each submitter must receive an order, in the form of a letter, from FDA which finds the device to be substantially equivalent (SE) and states that the device can be marketed in the U.S. This order "clears" the device for commercial distribution.
A 510(k) is a premarket submission made to FDA to demonstrate that the device to be marketed is at least as safe and effective, that is, substantially equivalent, to a legally marketed device (21 CFR 807.92(a)(3)) that is not subject to PMA. Submitters must compare their device to one or more similar legally marketed devices and make and support their substantial equivalence claims. A legally marketed device is a device that was legally marketed prior to May 28, 1976 (preamendments device), or a device which has been reclassified from Class III to Class II or I, a device which has been found SE through the 510(k) process, or a device that was granted marketing authorization via the De Novo classification process under section 513(f)(2) of the FD&C Act that is not exempt from premarket notification requirements. The legally marketed device(s) to which equivalence is drawn is commonly known as the "predicate." Although devices recently cleared under 510(k) are often selected as the predicate to which equivalence is claimed, any legally marketed device may be used as a predicate. Legally marketed also means that the predicate cannot be one that is in violation of the Act.
Until the submitter receives an order declaring a device SE, the submitter may not proceed to market the device. Once the device is determined to be SE, it can then be marketed in the U.S. The SE determination is usually made within 90 days and is made based on the information submitted by the submitter.
The FDA does not perform 510(k) pre-clearance facility inspections. The submitter may market the device immediately after 510(k) clearance is granted. The manufacturer should be prepared for an FDA quality system (21 CFR 820) inspection at any time after 510(k) clearance.
# What is Substantial Equivalence
A 510(k) requires demonstration of substantial equivalence to another legally U.S. marketed device. Substantial equivalence means that the new device is at least as safe and effective as the predicate.
A device is substantially equivalent if, in comparison to a predicate it:
has the same intended use as the predicate; and
has the same technological characteristics as the predicate;
or
has the same intended use as the predicate; and
has different technological characteristics and does not raise different questions of safety and effectiveness; and
the information submitted to FDA demonstrates that the device is at least as safe and effective as the legally marketed device.
A claim of substantial equivalence does not mean the new and predicate devices must be identical. Substantial equivalence is established with respect to intended use, design, energy used or delivered, materials, chemical composition, manufacturing process, performance, safety, effectiveness, labeling, biocompatibility, standards, and other characteristics, as applicable.
A device may not be marketed in the U.S. until the submitter receives a letter declaring the device substantially equivalent. If FDA determines that a device is not substantially equivalent, the applicant may:
resubmit another 510(k) with new data,
request a Class I or II designation through the De Novo Classification process
file a reclassification petition, or
submit a premarket approval application (PMA).
# Who is Required to Submit a 510(k)
The FD&C Act and the 510(k) regulation (21 CFR 807) do not specify who must submit a 510(k). Instead, they specify which actions, such as introducing a device to the U.S. market, require a 510(k) submission.
The following four categories of parties must submit a 510(k) to the FDA:
Domestic manufacturers introducing a device to the U.S. market;
Finished device manufacturers must submit a 510(k) if they manufacture a device according to their own specifications and market it in the U.S. Accessories to finished devices that are sold to the end user are also considered finished devices. However, manufacturers of device components are not required to submit a 510(k) unless such components are promoted for sale to an end user as replacement parts. Contract manufacturers, those firms that manufacture devices under contract according to someone else’s specifications, are not required to submit a 510(k).
Specification developers introducing a device to the U.S. market;
A specification developer develops the specifications for a finished device, but has the device manufactured under contract by another firm or entity. The specification developer submits the 510(k), not the contract manufacturer.
Repackers or relabelers who make labeling changes or whose operations significantly affect the device.
Repackagers or relabelers may be required to submit a 510(k) if they significantly change the labeling or otherwise affect any condition of the device. Significant labeling changes may include modification of manuals, such as adding a new intended use, deleting or adding warnings, contraindications, etc. Operations, such as sterilization, could alter the condition of the device. However, most repackagers or relabelers are not required to submit a 510(k).
Foreign manufacturers/exporters or U.S. representatives of foreign manufacturers/exporters introducing a device to the U.S. market.
Please note that all manufacturers (including specification developers) of Class II and III devices and select Class I devices are required to follow design controls (21 CFR 820.30) during the development of their device. The holder of a 510(k) must have design control documentation available for FDA review during a site inspection. In addition, any changes to the device specifications or manufacturing processes must be made in accordance with the Quality System regulation (21 CFR 820) and may be subject to a new 510(k). Additional information is found on the webpage "Is a new 510(k) required for a modification to the device?"
# When a 510(k) is Required
A 510(k) is required when:
Unless exempt, introducing a device into commercial distribution (marketing) for the first time. After May 28, 1976 (effective date of the Medical Device Amendments to the Act), anyone who wants to sell a device in the U.S. is required to make a 510(k) submission at least 90 days prior to offering the device for sale, even though it may have been under development or clinical investigation before that date. If your device was not marketed by your firm before May 28, 1976, a 510(k) is required.
There is a change or modification to a legally marketed device and that change could significantly affect its safety or effectiveness. The burden is on the 510(k) holder to decide whether or not a modification could significantly affect safety or effectiveness of the device. Any modifications must be made in accordance with the Quality System regulation, 21 CFR 820, and recorded in the device master record and change control records. It is recommended that the justification for submitting or not submitting a new 510(k) be recorded in the change control records.
A new 510(k) submission is required for changes or modifications to an existing device, where the modifications could significantly affect the safety or effectiveness of the device or the device is to be marketed for a new or different intended use. See Is a new 510(k) required for a modification to the device? for additional information.
Back to Top Arrow
# When a 510(k) is Not Required
The following are examples of when a 510(k) is not required.
You sell unfinished devices to another firm for further processing or sell components to be used in the assembling of devices by other firms. However, if your components are to be sold directly to end users as replacement parts, a 510(k) is required.
Your device is not being marketed or commercially distributed. You do not need a 510(k) to develop, evaluate, or test a device. This includes clinical evaluation. Please note that if you perform clinical trials with your device, you are subject to the Investigational Device Exemption (IDE) regulation (21 CFR 812).
You distribute another firm's domestically manufactured device. You may place a label on the device, "Distributed by ABC Firm" or "Manufactured for ABC Firm," (21 CFR 801.1) and sell it to end users without submission of a 510(k).
In most cases, if you are a repackager or a relabeler and the existing labeling or condition of the device is not significantly changed. The labeling should be consistent with the labeling submitted in the 510(k) with the same indications for use and warnings and contraindications.
Your device was legally in commercial distribution before May 28, 1976 and has not been significantly changed or modified in design, components, method of manufacture, or intended use. These devices are "grandfathered" and you have Preamendment Status documentation to prove this.
The device is made outside the U.S. and you are an importer of the foreign made medical device. A 510(k) is not required if a 510(k) has been submitted by the foreign manufacturer and received marketing clearance. Once the foreign manufacturer has received 510(k) clearance for the device, the foreign manufacturer may export his device to any U.S. importer.
Your device is exempted from 510(k) by regulation (21 CFR 862-892). That is, certain Class I or II devices can be marketed for the first time without having to submit a 510(k). A list of the Class I and II exempted devices can be found on Medical Device Exemptions 510(k) and GMP Requirements. However, if the device exceeds the limitations of exemptions in .9 of the device classification regulation chapters (e.g., 21 CFR 862.9, 21 CFR 864.9), such as the device has a different intended use or operates using a different fundamental scientific technology than a legally marketed device in that generic type of device, or the device is a reprocessed single-use device, then a 510(k) must be submitted to market the new device.
# Preamendment Devices
The term "preamendments device" refers to devices legally marketed in the U.S. by a firm before May 28, 1976 and which have not been:
significantly changed or modified since then; and
for which a regulation requiring a PMA application has not been published by FDA.
Devices meeting the above criteria are "grandfathered" devices and do not require a 510(k). The device must have the same intended use as that marketed before May 28, 1976. If the device is labeled for a different intended use, then the device is considered a new device and a 510(k) must be submitted to FDA for marketing clearance.
Please note that you must be the owner of the device on the market before May 28, 1976, for the device to be grandfathered. If your device is similar to a grandfathered device and marketed after May 28, 1976, then your device does NOT meet the requirements of being grandfathered and you must submit a 510(k). In order for a firm to claim that it has a preamendments device, it must demonstrate that its device was labeled, promoted, and distributed in interstate commerce for a specific intended use and that intended use has not changed. See Preamendment Status for information on documentation requirements.
# Third Party Review Program
The Center for Devices and Radiological Health (CDRH) has implemented a Third Party Review Program. This program provides an option to manufacturers of certain devices of submitting their 510(k) to private parties (Recognized Third Parties) identified by FDA for review instead of submitting directly to CDRH.
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https://www.wikidoc.org/index.php/510K_Pathway
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4cb9e38cfe5bdd9bc79e727571284c450607f41b
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wikidoc
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5α-Reductase
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5α-Reductase
5α-reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in 3 metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism. There are three isoenzymes of 5α-reductase, SRD5A1, SRD5A2, and SRD5A3, which vary in different tissues with age.
5α-Reductases catalyze the following chemical reaction:
Thus, the two substrates of these enzymes are a 3-oxo-5α-steroid and acceptor, whereas its two products are 3-oxo-Δ4-steroid and a reduced acceptor.
For example:
# Production and activity
The enzyme is produced in many tissues in both males and females, in the reproductive tract, testes and ovaries, skin, seminal vesicles, prostate, epididymis and many organs, including the Nervous System. There are three isoenzymes of 5α-reductase: steroid 5α-reductase 1, 2, and 3 (SRD5A1, SRD5A2 and SRD5A3).
5α-Reductases act on 3-oxo (3-keto), Δ4,5 C19/C21 steroids as its substrates. “3-keto” refers to the double bond of the third carbon to oxygen. Carbons 4 and 5 also have a double bond, represented by 'Δ4,5'. The reaction involves a stereospecific and permanent break of the Δ4,5 with the help of NADPH as a cofactor. A hydride anion (H−) is also placed on the α face at the fifth carbon, and a proton on the β face at carbon 4.
# Distribution with age
5α-R1 is expressed in fetal scalp and nongenital skin of the back, anywhere from 5 to 50 times less than in the adult. 5α-R2 is expressed in fetal prostates similar to adults. 5α-R1 is expressed mainly in the epithelium and 5α-R2 the stroma of the fetal prostate. Scientists looked for 5α-R2 expression in fetal liver, adrenal, testis, ovary, brain, scalp, chest, and genital skin, using immunoblotting, and were only able to find it in genital skin.
After birth, the 5α-R1 is expressed in more locations, including the liver, skin, scalp and prostate. 5α-R2 is expressed in prostate, seminal vesicles, epididymis, liver, and to a lesser extent the scalp and skin. Hepatic expression of both 5α-R1 and 2 is immediate, but disappears in the skin and scalp at month 18. Then, at puberty, only 5α-R1 is reexpressed in the skin and scalp.
5α-R1 and 5α-R2 appear to be expressed in the prostate in male fetuses and throughout postnatal life. In adulthood, 5α-R1-3 is ubiquitously expressed. 5α-R1 and 5α-R2 are also expressed, although to different degrees in liver, genital and nongenital skin, prostate, epididymis, seminal vesicle, testis, ovary, uterus, kidney, exocrine pancreas, and the brain.
# Substrates
Specific substrates include testosterone, progesterone, androstenedione, epitestosterone, cortisol, aldosterone, and deoxycorticosterone. Outside of dihydrotestosterone, much of the physiological role of 5α-reduced steroids is unknown. Beyond reducing testosterone to dihydrotestosterone, 5alpha-reductase enzyme isoforms I and II reduce progesterone to dihydroprogesterone (DHP) and deoxycorticosterone to dihydrodeoxycorticosterone (DHDOC). In vitro and animal models suggest subsequent 3alpha-reduction of DHT, DHP and DHDOC lead to steroid metabolites with effects on cerebral function achieved by enhancing GABAergic inhibition. These neuroactive steroid derivatives enhance GABA via allosteric modulation at GABA(A) receptors and have anticonvulsant, antidepressant and anxiolytic effects, and also alter sexual and alcohol related behavior. 5α-dihydrocortisol is present in the aqueous humor of the eye, is synthesized in the lens, and might help make the aqueous humor itself. Allopregnanolone and THDOC are neurosteroids, with the latter having effects on the susceptibility of animals to seizures. In socially isolated mice, 5α-R1 is specifically down-regulated in glutamatergic pyramidal neurons that converge on the amygdala from cortical and hippocampal regions. This down-regulation may account for the appearance of behavioral disorders such as anxiety, aggression, and cognitive dysfunction. 5α-dihydroaldosterone is a potent antinatriuretic agent, although different from aldosterone. Its formation in the kidney is enhanced by restriction of dietary salt, suggesting it may help retain sodium as follows:
5α-DHP is a major hormone in circulation of normal cycling and pregnant women.
## Testosterone
5α-Reductase is most known for converting testosterone, the male sex hormone, into the more potent dihydrotestosterone:
- Testosterone.
Testosterone.
- Dihydrotestosterone
The major difference is the Δ4,5 double-bond on the A (leftmost) ring. The other differences between the diagrams are unrelated to structure.
## List of conversions
The following reactions are known to be catalyzed by 5α-reductase:
- Cholestenone → 5α-Cholestanone
- Progesterone → 5α-Dihydroprogesterone
- 3α-Dihydroprogesterone → Allopregnanolone
- 3β-Dihydroprogesterone → Isopregnanolone
- Deoxycorticosterone → 5α-Dihydrodeoxycorticosterone
- Corticosterone → 5α-Dihydrocorticosterone
- Cortisol → 5α-Dihydrocortisol
- Aldosterone → 5α-Dihydroaldosterone
- Androstenedione → 5α-Androstanedione
- Testosterone → 5α-Dihydrotestosterone
# Inhibition
The mechanism of 5α reductase inhibition is complex, but involves the binding of NADPH to the enzyme followed by the substrate. 5α-reductase inhibitor drugs are used in benign prostatic hyperplasia, prostate cancer, pattern hair loss (androgenetic alopecia), and hormone replacement therapy for transgender women.
Inhibition of the enzyme can be classified into two categories: steroidal, which are irreversible, and nonsteroidal. There are more steroidal inhibitors, with examples including finasteride (MK-906), dutasteride (GG745), 4-MA, turosteride, MK-386, MK-434, and MK-963. Researchers have pursued synthesis of nonsteroidals to inhibit 5α-reductase due to the undesired side effects of steroidals. The most potent and selective inhibitors of 5α-R1 are found in this class, and include benzoquinolones, nonsteroidal aryl acids, butanoid acid derivatives, and more recognizably, polyunsaturated fatty acids (especially linolenic acid), zinc, and green tea. Riboflavin was also identified as a 5α-reductase inhibitor .
Additionally, it has been claimed that alfatradiol works through this mechanism of activity (5α-reductase), as well as the Ganoderic acids in lingzhi mushroom, and the Saw Palmetto.
Inhibition of 5α-reductase results in decreased conversion of testosterone to DHT, leading to increased testosterone and estradiol. Other enzymes compensate to a degree for the absent conversion, specifically with local expression at the skin of reductive 17β-hydroxysteroid dehydrogenase, oxidative 3α-hydroxysteroid dehydrogenase, and 3β-hydroxysteroid dehydrogenase enzymes.
Gynecomastia, erectile dysfunction, impaired cognitive function, fatigue, hypoglycemia, impaired liver function, constipation, and depression, are only a few of the possible side-effects of 5α-reductase inhibition. Long term side effects, that continued even after discontinuation of the drug have been reported.
## Finasteride
Finasteride inhibits two 5α-reductase isoenzymes (II and III), while dutasteride inhibits all three. Finasteride potently inhibits 5α-R2 at a mean inhibitory concentration IC50 of 69 nM, but is less effective with 5α-R1 till an IC50 of 360 nM. Finasteride decreases mean serum level of DHT by 71% after 6 months, and was shown in vitro to inhibit 5α-R3 at a similar potency to 5α-R2 in transfected cell lines.
## Dutasteride
Dutasteride inhibits 5α-reductase isoenzymes type 1 and 2 better than finasteride, leading to a more complete reduction in DHT at 24 weeks (94.7% versus 70.8%). It also reduces intraprostatic DHT 97% in men with prostate cancer at 5 mg/day over three months. A second study with 3.5 mg/day for 4 months decreased intraprostatic DHT even further by 99%. The suppression of DHT in vivo, and the report that dutasteride inhibits 5α-R3 in vitro suggest that dutasteride may be a triple 5α reductase inhibitor.
# Congenital deficiencies
## 5α-Reductase 1
5α-Reductase type 1 inactivated male mice have reduced bone mass and forelimb muscle grip strength, which has been proposed to be due to lack of 5α-reductase type 1 expression in bone and muscle. In 5 alpha reductase type 2 deficient males, the type 1 isoenzyme is thought to be responsible for their virilization at puberty.
## 5α-Reductase 2
The second isoenzyme of 5α reductase is deficient in the classic intersex condition (pseudovaginal perineoscrotal hypospadias), or 5α-reductase deficiency. It was first discovered in indigenous cultures of Papua, New Guinea, where children were born with feminine genitalia in the absence of endogenous DHT during pregnancy, but with the surge of testosterone during adolescence, changed to males at puberty. Because of this change at puberty, the condition is also sometimes called "guevedoche." There is a range of external appearance that has been described of external genitalia at birth, with varying degrees of virilization.
## 5α-Reductase 3
When small interfering RNA is used to knock down the expression of 5α-R3 isozyme in cell lines, there is decreased cell growth, viability, and a decrease in DHT/T ratios. It has also shown the ability to reduce testosterone, androstenedione, and progesterone in androgen stimulated prostate cell lines by adenovirus vectors.
Congenital deficiency of 5α-R3 at the gene SRD53A has been linked to a rare, autosomal recessive condition in which patients are born with severe intellectual dysfunction and cerebellar and ocular defects. The presumed deficiency is reduction of the terminal bond of polyprenol to dolichol, an important step in N-glycosylation of proteins, which in turn is important for proper folding of asparagine residues on nascent protein in the endoplasmic reticulum.
# Nomenclature
This enzyme belongs to the family of oxidoreductases, to be specific, those acting on the CH-CH group of donor with other acceptors. The systematic name of this enzyme class is 3-oxo-5α-steroid:acceptor Δ4-oxidoreductase. Other names in common use include:
- 5α-Reductase
- 3-Oxosteroid Δ4-dehydrogenase
- 3-Oxo-5α-steroid Δ4-dehydrogenase
- Steroid Δ4-5α-reductase
- Δ4-3-Keto steroid 5α-reductase
- Δ4-3-Oxo steroid reductase
- Δ4-3-Ketosteroid-5α-oxidoreductase
- Δ4-3-Oxosteroid-5α-reductase
- 3-Keto-Δ4-steroid-5α-reductase
- Testosterone 5α-reductase
- 4-Ene-3-ketosteroid-5α-oxidoreductase
- Δ4-5α-Dehydrogenase
- 3-Oxo-5α-steroid:(acceptor) Δ4-oxidoreductase
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5α-Reductase
5α-reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in 3 metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism. There are three isoenzymes of 5α-reductase, SRD5A1, SRD5A2, and SRD5A3, which vary in different tissues with age.
5α-Reductases catalyze the following chemical reaction:
Thus, the two substrates of these enzymes are a 3-oxo-5α-steroid and acceptor, whereas its two products are 3-oxo-Δ4-steroid and a reduced acceptor.
For example:
# Production and activity
The enzyme is produced in many tissues in both males and females, in the reproductive tract, testes and ovaries,[1] skin, seminal vesicles, prostate, epididymis and many organs,[2] including the Nervous System.[3][4] There are three isoenzymes of 5α-reductase: steroid 5α-reductase 1, 2, and 3 (SRD5A1, SRD5A2 and SRD5A3).[2][5][6][7]
5α-Reductases act on 3-oxo (3-keto), Δ4,5 C19/C21 steroids as its substrates. “3-keto” refers to the double bond of the third carbon to oxygen. Carbons 4 and 5 also have a double bond, represented by 'Δ4,5'. The reaction involves a stereospecific and permanent break of the Δ4,5 with the help of NADPH as a cofactor. A hydride anion (H−) is also placed on the α face at the fifth carbon, and a proton on the β face at carbon 4.[8]
# Distribution with age
5α-R1 is expressed in fetal scalp and nongenital skin of the back, anywhere from 5 to 50 times less than in the adult. 5α-R2 is expressed in fetal prostates similar to adults. 5α-R1 is expressed mainly in the epithelium and 5α-R2 the stroma of the fetal prostate. Scientists looked for 5α-R2 expression in fetal liver, adrenal, testis, ovary, brain, scalp, chest, and genital skin, using immunoblotting, and were only able to find it in genital skin.[8]
After birth, the 5α-R1 is expressed in more locations, including the liver, skin, scalp and prostate. 5α-R2 is expressed in prostate, seminal vesicles, epididymis, liver, and to a lesser extent the scalp and skin. Hepatic expression of both 5α-R1 and 2 is immediate, but disappears in the skin and scalp at month 18. Then, at puberty, only 5α-R1 is reexpressed in the skin and scalp.
5α-R1 and 5α-R2 appear to be expressed in the prostate in male fetuses and throughout postnatal life. In adulthood, 5α-R1-3 is ubiquitously expressed. 5α-R1 and 5α-R2 are also expressed, although to different degrees in liver, genital and nongenital skin, prostate, epididymis, seminal vesicle, testis, ovary, uterus, kidney, exocrine pancreas, and the brain.[3][8]
# Substrates
Specific substrates include testosterone, progesterone, androstenedione,[9] epitestosterone, cortisol, aldosterone, and deoxycorticosterone. Outside of dihydrotestosterone, much of the physiological role of 5α-reduced steroids is unknown.[8] Beyond reducing testosterone to dihydrotestosterone, 5alpha-reductase enzyme isoforms I and II reduce progesterone to dihydroprogesterone (DHP) and deoxycorticosterone to dihydrodeoxycorticosterone (DHDOC). In vitro and animal models suggest subsequent 3alpha-reduction of DHT, DHP and DHDOC lead to steroid metabolites with effects on cerebral function achieved by enhancing GABAergic inhibition. These neuroactive steroid derivatives enhance GABA via allosteric modulation at GABA(A) receptors and have anticonvulsant, antidepressant and anxiolytic effects, and also alter sexual and alcohol related behavior.[10] 5α-dihydrocortisol is present in the aqueous humor of the eye, is synthesized in the lens, and might help make the aqueous humor itself.[11] Allopregnanolone and THDOC are neurosteroids, with the latter having effects on the susceptibility of animals to seizures. In socially isolated mice, 5α-R1 is specifically down-regulated in glutamatergic pyramidal neurons that converge on the amygdala from cortical and hippocampal regions. This down-regulation may account for the appearance of behavioral disorders such as anxiety, aggression, and cognitive dysfunction.[3][4] 5α-dihydroaldosterone is a potent antinatriuretic agent, although different from aldosterone. Its formation in the kidney is enhanced by restriction of dietary salt, suggesting it may help retain sodium as follows:[12]
5α-DHP is a major hormone in circulation of normal cycling and pregnant women.[13]
## Testosterone
5α-Reductase is most known for converting testosterone, the male sex hormone, into the more potent dihydrotestosterone:
- Testosterone.
Testosterone.
- Dihydrotestosterone
The major difference is the Δ4,5 double-bond on the A (leftmost) ring. The other differences between the diagrams are unrelated to structure.
## List of conversions
The following reactions are known to be catalyzed by 5α-reductase:[9]
- Cholestenone → 5α-Cholestanone
- Progesterone → 5α-Dihydroprogesterone
- 3α-Dihydroprogesterone → Allopregnanolone
- 3β-Dihydroprogesterone → Isopregnanolone
- Deoxycorticosterone → 5α-Dihydrodeoxycorticosterone
- Corticosterone → 5α-Dihydrocorticosterone
- Cortisol → 5α-Dihydrocortisol
- Aldosterone → 5α-Dihydroaldosterone
- Androstenedione → 5α-Androstanedione
- Testosterone → 5α-Dihydrotestosterone
# Inhibition
The mechanism of 5α reductase inhibition is complex, but involves the binding of NADPH to the enzyme followed by the substrate. 5α-reductase inhibitor drugs are used in benign prostatic hyperplasia, prostate cancer, pattern hair loss (androgenetic alopecia), and hormone replacement therapy for transgender women.
Inhibition of the enzyme can be classified into two categories: steroidal, which are irreversible, and nonsteroidal. There are more steroidal inhibitors, with examples including finasteride (MK-906), dutasteride (GG745), 4-MA, turosteride, MK-386, MK-434, and MK-963. Researchers have pursued synthesis of nonsteroidals to inhibit 5α-reductase due to the undesired side effects of steroidals. The most potent and selective inhibitors of 5α-R1 are found in this class, and include benzoquinolones, nonsteroidal aryl acids, butanoid acid derivatives, and more recognizably, polyunsaturated fatty acids (especially linolenic acid), zinc, and green tea.[8] Riboflavin was also identified as a 5α-reductase inhibitor .[14]
Additionally, it has been claimed that alfatradiol works through this mechanism of activity (5α-reductase), as well as the Ganoderic acids in lingzhi mushroom, and the Saw Palmetto.
Inhibition of 5α-reductase results in decreased conversion of testosterone to DHT, leading to increased testosterone and estradiol. Other enzymes compensate to a degree for the absent conversion, specifically with local expression at the skin of reductive 17β-hydroxysteroid dehydrogenase, oxidative 3α-hydroxysteroid dehydrogenase, and 3β-hydroxysteroid dehydrogenase enzymes.[15]
Gynecomastia, erectile dysfunction, impaired cognitive function, fatigue, hypoglycemia, impaired liver function, constipation, and depression, are only a few of the possible side-effects of 5α-reductase inhibition. Long term side effects, that continued even after discontinuation of the drug have been reported.[16]
## Finasteride
Finasteride inhibits two 5α-reductase isoenzymes (II and III), while dutasteride inhibits all three.[2] Finasteride potently inhibits 5α-R2 at a mean inhibitory concentration IC50 of 69 nM, but is less effective with 5α-R1 till an IC50 of 360 nM.[17] Finasteride decreases mean serum level of DHT by 71% after 6 months,[18] and was shown in vitro to inhibit 5α-R3 at a similar potency to 5α-R2 in transfected cell lines.[2]
## Dutasteride
Dutasteride inhibits 5α-reductase isoenzymes type 1 and 2 better than finasteride, leading to a more complete reduction in DHT at 24 weeks (94.7% versus 70.8%).[19] It also reduces intraprostatic DHT 97% in men with prostate cancer at 5 mg/day over three months.[20] A second study with 3.5 mg/day for 4 months decreased intraprostatic DHT even further by 99%.[21] The suppression of DHT in vivo, and the report that dutasteride inhibits 5α-R3 in vitro[22] suggest that dutasteride may be a triple 5α reductase inhibitor.[8]
# Congenital deficiencies
## 5α-Reductase 1
5α-Reductase type 1 inactivated male mice have reduced bone mass and forelimb muscle grip strength, which has been proposed to be due to lack of 5α-reductase type 1 expression in bone and muscle.[23] In 5 alpha reductase type 2 deficient males, the type 1 isoenzyme is thought to be responsible for their virilization at puberty.[6]
## 5α-Reductase 2
The second isoenzyme of 5α reductase is deficient in the classic intersex condition (pseudovaginal perineoscrotal hypospadias), or 5α-reductase deficiency. It was first discovered in indigenous cultures of Papua, New Guinea, where children were born with feminine genitalia in the absence of endogenous DHT during pregnancy, but with the surge of testosterone during adolescence, changed to males at puberty. Because of this change at puberty, the condition is also sometimes called "guevedoche."[24] There is a range of external appearance that has been described of external genitalia at birth, with varying degrees of virilization.
## 5α-Reductase 3
When small interfering RNA is used to knock down the expression of 5α-R3 isozyme in cell lines, there is decreased cell growth, viability, and a decrease in DHT/T ratios.[25] It has also shown the ability to reduce testosterone, androstenedione, and progesterone in androgen stimulated prostate cell lines by adenovirus vectors.[8]
Congenital deficiency of 5α-R3 at the gene SRD53A has been linked to a rare, autosomal recessive condition in which patients are born with severe intellectual dysfunction and cerebellar and ocular defects. The presumed deficiency is reduction of the terminal bond of polyprenol to dolichol, an important step in N-glycosylation of proteins, which in turn is important for proper folding of asparagine residues on nascent protein in the endoplasmic reticulum.[26]
# Nomenclature
This enzyme belongs to the family of oxidoreductases, to be specific, those acting on the CH-CH group of donor with other acceptors. The systematic name of this enzyme class is 3-oxo-5α-steroid:acceptor Δ4-oxidoreductase. Other names in common use include:
- 5α-Reductase
- 3-Oxosteroid Δ4-dehydrogenase
- 3-Oxo-5α-steroid Δ4-dehydrogenase
- Steroid Δ4-5α-reductase
- Δ4-3-Keto steroid 5α-reductase
- Δ4-3-Oxo steroid reductase
- Δ4-3-Ketosteroid-5α-oxidoreductase
- Δ4-3-Oxosteroid-5α-reductase
- 3-Keto-Δ4-steroid-5α-reductase
- Testosterone 5α-reductase
- 4-Ene-3-ketosteroid-5α-oxidoreductase
- Δ4-5α-Dehydrogenase
- 3-Oxo-5α-steroid:(acceptor) Δ4-oxidoreductase
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https://www.wikidoc.org/index.php/5%CE%B1-Reductase
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2b8c8afd62cf6c00cfdf3e005da5ac301a0f6976
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A-a gradient
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A-a gradient
# Overview
The Alveolar-arterial gradient (A-a gradient), is used to compare the causes of hypoxemia.
## A-a Gradient Equation
A - a gradient = PAO2 - PaO2
Where:
PAO2 = alveolar PO2 (calculated from the alveolar gas equation)
PaO2 = arterial PO2 (measured in arterial blood)
## The Alveolar Gas Equation
PAO2 = PIO2 - PACO2/R
Where:
PIO2 = FIO2 x (760 mmHg - 47mmHg) = inspired O2
- FIO2 = 21% at sea level atmospheric pressure = 0.21
- 760 mmHg = atmospheric pressure at sea level
- 47 mmHg = H2O pressure
PACO2 = arterial PCO2 measured in plasma
R = respiratory exchange ratio or respiratory quotient = 0.8 under normal conditions
## Values and Meaning
The normal A-a gradient is < 10 mmHg, but can range from 5-20 mmHg in a normal individual. An increased A-a gradient suggests a diffusion defect, V/Q (ventilation/perfusion) defect, or right-to-left shunt.
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A-a gradient
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The Alveolar-arterial gradient (A-a gradient), is used to compare the causes of hypoxemia.
## A-a Gradient Equation
A - a gradient = PAO2 - PaO2
Where:
PAO2 = alveolar PO2 (calculated from the alveolar gas equation)
PaO2 = arterial PO2 (measured in arterial blood)
## The Alveolar Gas Equation
PAO2 = PIO2 - PACO2/R
Where:
PIO2 = FIO2 x (760 mmHg - 47mmHg) = inspired O2
- FIO2 = 21% at sea level atmospheric pressure = 0.21
- 760 mmHg = atmospheric pressure at sea level
- 47 mmHg = H2O pressure
PACO2 = arterial PCO2 measured in plasma
R = respiratory exchange ratio or respiratory quotient = 0.8 under normal conditions
## Values and Meaning
The normal A-a gradient is < 10 mmHg, but can range from 5-20 mmHg in a normal individual. An increased A-a gradient suggests a diffusion defect, V/Q (ventilation/perfusion) defect, or right-to-left shunt. [1]
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https://www.wikidoc.org/index.php/A-a_gradient
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AANAT (gene)
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AANAT (gene)
AANAT is a gene that encodes an enzyme aralkylamine N-acetyltransferase. It is the key regulator of day-night cycle (circadian rhythm). It is found in all animals. In humans it is present on chromosome 17, in chimpanzees chromosome 17, in mouse and sheep chromosome 11, in rat chromosome 10, and in chicken chromosome 18.
# Function
The protein encoded by this gene belongs to the acetyltransferase superfamily. It is the penultimate enzyme in melatonin synthesis and controls the night/day rhythm in melatonin production in the vertebrate pineal gland. Melatonin is essential for the function of the circadian clock that influences activity and sleep. This enzyme is regulated by cAMP-dependent phosphorylation that promotes its interaction with 14-3-3 proteins and thus protects the enzyme against proteasomal degradation.
# Clinical significance
This gene may contribute to numerous genetic diseases such as delayed sleep phase syndrome.
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AANAT (gene)
AANAT is a gene that encodes an enzyme aralkylamine N-acetyltransferase.[1] It is the key regulator of day-night cycle (circadian rhythm). It is found in all animals. In humans it is present on chromosome 17, in chimpanzees chromosome 17, in mouse and sheep chromosome 11, in rat chromosome 10, and in chicken chromosome 18.[2]
# Function
The protein encoded by this gene belongs to the acetyltransferase superfamily. It is the penultimate enzyme in melatonin synthesis and controls the night/day rhythm in melatonin production in the vertebrate pineal gland. Melatonin is essential for the function of the circadian clock that influences activity and sleep. This enzyme is regulated by cAMP-dependent phosphorylation that promotes its interaction with 14-3-3 proteins and thus protects the enzyme against proteasomal degradation.[1]
# Clinical significance
This gene may contribute to numerous genetic diseases such as delayed sleep phase syndrome.[1]
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https://www.wikidoc.org/index.php/AANAT_(gene)
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9e1263e4560a886c219fd73a5b99a991831e2ea2
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Multivitamin
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Multivitamin
Synonyms and keywords: MVI
# Overview
A multivitamin is a preparation intended to supplement a human diet with vitamins, dietary minerals and other nutritional elements. Such preparations are available in the form of tablets, capsules, pastilles, powders, liquids and injectable formulations. Other than injectable formulations, which are only available and administered under medical supervision, multivitamins are recognized by the Codex Alimentarius Commission (the United Nations' highest authority on food standards) as a category of food.
# Multivitamin products and components
Many multivitamins are formulated and/or labelled to differentiate consumer sectors e.g. prenatal, children, mature or 50+, men's , women's, diabetic, stress or megavitamin. Consumer multivitamin formulas are available as tablets, capsules, bulk powder, or liquid. Once and twice per day multivitamin formulas dominate common usage, although some formulas are designed for consumption 3 - 7 times per day or even allow hourly use.
Compositional variation amongst brands and lines allows substantial consumer choices. Modern multivitamin products roughly classify into RDA centric multivitamins with or without iron, RDA centric multivitamin/multimineral formulas with or without iron, higher potency formulas with mostly above RDA components with or without iron, and more specialized formulas by condition, such as for diabetics or by less common components, such as diversified antioxidants, herbal extracts or premium vitamin and mineral forms. Legally, the US FDA allows a multivitamin to be called "high potency" if at least two-thirds of its nutrients have at least 100 percent of the DV. In practice, "high potency" usually means substantially increased vitamin C and Bs with some other enhanced vitamin and mineral levels, but some minerals may still be much less than DV.
Some components are typically much lower than RDA amounts, often for cost reasons, e.g. biotin, usually the most expensive vitamin component, at over $4000 per active pound, is typically added in at only 5%-30% of RDA in many one per day formulations. Sometimes low content composition is for population subgroups, where the RDA would be inappropriate, such often occurs with iron, where the original population intake calculation was ca 12-13 mg iron per day by including menstruating females but some percentage of HFE gene bearing males, and others, may only need as little as ~1 mg iron per day including the normal dietary contribution.
Basic commercial multivitamin supplement products often contain the following ingredients:
vitamin C, B1, B2, B3, B6, folic acid (B9),B12, B5(pantothenate), H (biotin), A, E, D3, K1, potassium iodide, cupric (sulfate anhydrous, picolinate, sulfate monohydrate, trioxide), selenomethionine, borax, zinc, calcium, magnesium, chromium, manganese, molybdenum, betacarotene, and iron. Other formulas may include additional ingredients such as other carotenes (e.g. lutein, lycopene), higher than RDA amounts of B, C or E vitamins including gamma-tocopherol, "near" B vitamins (inositol, choline, PABA), trimethylglycine (anhydrous betaine), betaine hydrochloride, vitamin K2 as menaquinone-7, lecithin, citrus bioflavinoids or nutrient forms variously described as more easily absorbable.
# Uses
By supplementing the diet with additional vitamins and minerals, multivitamins can be a valuable tool for those with dietary imbalances or different nutritional needs. People with dietary imbalances may include those on restrictive diets and those who can't or won't eat a nutritious diet. Pregnant women and elderly adults have different nutritional needs than other adults, and a multivitamin may be indicated by their physicians.
Classified as a food, RDA centric multivitamins are not to be confused with the basic orthomolecular medicine daily recommendations. The proponents of that also generally recommend individually optimized, often higher, vitamin intakes. They also recommend more absorbable forms of vitamins and minerals, in inexpensive but higher potency formulas, spread across the day. Often iron-free, fluoride-free formulas, and sometimes copper-free formulas, are preferred.
# Precautions
While multivitamins can be a valuable tool to correct dietary imbalances, it is worth exercising basic caution before taking them, especially if any medical conditions exist. In particular, pregnant women should generally consult their doctors before taking any multivitamins. Because high doses of vitamin A are believed to cause birth defects, for example, special multivitamin formulations exist for pregnant women that do not contain this nutrient.
Severe vitamin and mineral deficiencies require medical treatment and can be very difficult to treat with common over-the-counter multivitamins. In such situations, special vitamin or mineral forms with much higher potencies are available, either as individual components or as specialized formulations, sometimes requiring a prescription.
Multivitamins in bottle related quantites may risk acute overdosage if taken in large amounts, due to the slight toxicity of certain components, principally iron. In particular, other components at extraordinary levels in high potency forms include (but are not limited to) vitamin A, vitamin D, vitamin B6, time release niacin, and potassium. Total iron content of the whole bottle is the primary concern for child safety. There also are strict limits on the retinol content for vitamin A during pregnancies that are specifically addressed by prenatal formulas. Additionally, various medical conditions and medications may adversely interact with multivitamins.
For normal adults taking a multivitamin for general health purposes, conventional medicine and government authorities recommend that a multivitamin should contain 100% DRI/RDA or less for each ingredient. However, many common brand supplements in the United States contain above-DRI amounts for some vitamins or minerals. Many brands offer low iron or iron-free versions of their multivitamin supplements.
Some analyses have suggested that high potency synthetic beta-carotene, vitamin A, and vitamin E supplements, without adequate other redox antioxidants such as vitamin C, may shorten life rather than extend it in cases of oxidative stress (e.g. smokers), liver disease and liver stressing chemicals (e.g. statins). Other analyses, however, suggest that there appears to be little risk to supplement users of experiencing adverse side effects due to excessive intakes of micronutrients.
# Scientific assessment
## Evidence in favor
In 2002, the Journal of the American Medical Association stated that "it appears prudent for all adults to take vitamin supplements." In this article, which examined the clinical applications of vitamins for the prevention of chronic diseases in adults, the authors, Robert H. Fletcher and Kathleen M. Fairfield from the Harvard School of Medicine, examined English-language articles about vitamins in relation to chronic diseases published between 1966 and 2002, and concluded that inadequate intake of several vitamins has been linked to the development of diseases including coronary heart disease, cancer, and osteoporosis. Similarly, the April 9, 1998 issue of the New England Journal of Medicine featured an editorial entitled "Eat Right and Take a Multivitamin" that was based on studies that showed health benefits resulting from the consumption of nutritional supplements. Bruce Ames, professor of Biochemistry and Molecular Biology at the University of California, Berkeley, and a senior scientist at Children's Hospital Oakland Research Institute (CHORI), suggests that "to maximize human health and lifespan, scientists must abandon outdated models of micronutrients" and that "a metabolic tune-up through an improved supply of micronutrients is likely to have great health benefits."
## Evidence against
In 2006 the National Institutes of Health convened an expert panel to examine the available evidence on nutrient supplements. This review concluded that "Most of the studies we examined do not provide strong evidence for beneficial health-related effects of supplements taken singly, in pairs, or in combinations of three or more." They noted that multivitamins could provide health benefits to some groups of people, such as postmenopausal women, but that there was "disturbing evidence of risk" in other groups, such as smokers. The panel's report concluded that the "present evidence is insufficient to recommend either for or against the use of Multivitamin/Mineral Supplements by the American public to prevent chronic disease."
Similarly, a 2006 report for the United States Department of Health and Human Services concluded that "regular supplementation with a single nutrient or a mixture of nutrients for years has no significant benefits in the primary prevention of cancer, cardiovascular disease, cataract, age-related macular degeneration or cognitive decline." However, the report noted that multivitamins have beneficial effects in people with poor nutritional status, vitamin D and calcium can help prevent fractures in older people, and that zinc and antioxidants can help prevent age-related macular degeneration in people at a high risk of developing this disease.
In 2007 the United Kingdom Food Standards Agency published an updated set of recommendations for eating a healthy diet. The recommendations stated that pregnant women should take extra folic acid and iron and that older people might need extra vitamin D and iron. However, the report advised that "Vitamin and mineral supplements are not a replacement for good eating habits" and stated that supplements are unnecessary for healthy adults who eat a balanced diet.
# Regulations by governmental agencies
## The United States of America
Because of their categorization as a dietary supplement by the Food and Drug Administration (FDA), most multivitamins sold in the U.S. are not required to undergo the rigorous testing procedures typical of pharmaceutical drugs.
However, some multivitamins contain very high doses of one or several vitamins or minerals, or are specifically intended to treat, cure, or prevent disease, and therefore require a prescription or medicinal license in the U.S. Since such drugs contain no new substances, they do not require the same testing as would be required by a New Drug Application, but were allowed on the market as drugs due to Drug Efficacy Study Implementation program.
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Multivitamin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: MVI
# Overview
A multivitamin is a preparation intended to supplement a human diet with vitamins, dietary minerals and other nutritional elements. Such preparations are available in the form of tablets, capsules, pastilles, powders, liquids and injectable formulations. Other than injectable formulations, which are only available and administered under medical supervision, multivitamins are recognized by the Codex Alimentarius Commission (the United Nations' highest authority on food standards) as a category of food. [1]
# Multivitamin products and components
Many multivitamins are formulated and/or labelled to differentiate consumer sectors e.g. prenatal, children, mature or 50+, men's , women's, diabetic, stress or megavitamin. Consumer multivitamin formulas are available as tablets, capsules, bulk powder, or liquid. Once and twice per day multivitamin formulas dominate common usage, although some formulas are designed for consumption 3 - 7 times per day or even allow hourly use.
Compositional variation amongst brands and lines allows substantial consumer choices. Modern multivitamin products roughly classify into RDA centric multivitamins with or without iron, RDA centric multivitamin/multimineral formulas with or without iron, higher potency formulas with mostly above RDA components with or without iron, and more specialized formulas by condition, such as for diabetics or by less common components, such as diversified antioxidants, herbal extracts or premium vitamin and mineral forms. Legally, the US FDA allows a multivitamin to be called "high potency" if at least two-thirds of its nutrients have at least 100 percent of the DV. In practice, "high potency" usually means substantially increased vitamin C and Bs with some other enhanced vitamin and mineral levels, but some minerals may still be much less than DV.
Some components are typically much lower than RDA amounts, often for cost reasons, e.g. biotin, usually the most expensive vitamin component, at over $4000 per active pound, is typically added in at only 5%-30% of RDA in many one per day formulations. Sometimes low content composition is for population subgroups, where the RDA would be inappropriate, such often occurs with iron, where the original population intake calculation was ca 12-13 mg iron per day by including menstruating females but some percentage of HFE gene bearing males, and others, may only need as little as ~1 mg iron per day including the normal dietary contribution.
Basic commercial multivitamin supplement products often contain the following ingredients:
vitamin C, B1, B2, B3, B6, folic acid (B9),B12, B5(pantothenate), H (biotin), A, E, D3, K1, potassium iodide, cupric (sulfate anhydrous, picolinate, sulfate monohydrate, trioxide), selenomethionine, borax, zinc, calcium, magnesium, chromium, manganese, molybdenum, betacarotene, and iron. Other formulas may include additional ingredients such as other carotenes (e.g. lutein, lycopene), higher than RDA amounts of B, C or E vitamins including gamma-tocopherol, "near" B vitamins (inositol, choline, PABA), trimethylglycine (anhydrous betaine), betaine hydrochloride, vitamin K2 as menaquinone-7, lecithin, citrus bioflavinoids or nutrient forms variously described as more easily absorbable.
# Uses
By supplementing the diet with additional vitamins and minerals, multivitamins can be a valuable tool for those with dietary imbalances or different nutritional needs.[2] People with dietary imbalances may include those on restrictive diets and those who can't or won't eat a nutritious diet. Pregnant women and elderly adults have different nutritional needs than other adults, and a multivitamin may be indicated by their physicians.
Classified as a food, RDA centric multivitamins are not to be confused with the basic orthomolecular medicine daily recommendations.[3] The proponents of that also generally recommend individually optimized, often higher, vitamin intakes. They also recommend more absorbable forms of vitamins and minerals, in inexpensive but higher potency formulas, spread across the day. Often iron-free, fluoride-free formulas, and sometimes copper-free formulas, are preferred.
# Precautions
While multivitamins can be a valuable tool to correct dietary imbalances, it is worth exercising basic caution before taking them, especially if any medical conditions exist. In particular, pregnant women should generally consult their doctors before taking any multivitamins. Because high doses of vitamin A are believed to cause birth defects, for example, special multivitamin formulations exist for pregnant women that do not contain this nutrient.
Severe vitamin and mineral deficiencies require medical treatment and can be very difficult to treat with common over-the-counter multivitamins. In such situations, special vitamin or mineral forms with much higher potencies are available, either as individual components or as specialized formulations, sometimes requiring a prescription.
Multivitamins in bottle related quantites may risk acute overdosage if taken in large amounts, due to the slight toxicity of certain components, principally iron. In particular, other components at extraordinary levels in high potency forms include (but are not limited to) vitamin A, vitamin D, vitamin B6, time release niacin, and potassium. Total iron content of the whole bottle is the primary concern for child safety. There also are strict limits on the retinol content for vitamin A during pregnancies that are specifically addressed by prenatal formulas. Additionally, various medical conditions and medications may adversely interact with multivitamins.
For normal adults taking a multivitamin for general health purposes, conventional medicine and government authorities recommend that a multivitamin should contain 100% DRI/RDA or less for each ingredient. However, many common brand supplements in the United States contain above-DRI amounts for some vitamins or minerals. Many brands offer low iron or iron-free versions of their multivitamin supplements.
Some analyses have suggested that high potency synthetic beta-carotene, vitamin A, and vitamin E supplements, without adequate other redox antioxidants such as vitamin C, may shorten life rather than extend it[4] in cases of oxidative stress (e.g. smokers), liver disease and liver stressing chemicals (e.g. statins). Other analyses, however, suggest that there appears to be little risk to supplement users of experiencing adverse side effects due to excessive intakes of micronutrients. [5]
# Scientific assessment
## Evidence in favor
In 2002, the Journal of the American Medical Association stated that "it appears prudent for all adults to take vitamin supplements." In this article, which examined the clinical applications of vitamins for the prevention of chronic diseases in adults, the authors, Robert H. Fletcher and Kathleen M. Fairfield from the Harvard School of Medicine, examined English-language articles about vitamins in relation to chronic diseases published between 1966 and 2002, and concluded that inadequate intake of several vitamins has been linked to the development of diseases including coronary heart disease, cancer, and osteoporosis. [6] Similarly, the April 9, 1998 issue of the New England Journal of Medicine featured an editorial entitled "Eat Right and Take a Multivitamin" that was based on studies that showed health benefits resulting from the consumption of nutritional supplements. [7] Bruce Ames, professor of Biochemistry and Molecular Biology at the University of California, Berkeley, and a senior scientist at Children's Hospital Oakland Research Institute (CHORI), suggests that "to maximize human health and lifespan, scientists must abandon outdated models of micronutrients" and that "a metabolic tune-up through an improved supply of micronutrients is likely to have great health benefits."[8]
## Evidence against
In 2006 the National Institutes of Health convened an expert panel to examine the available evidence on nutrient supplements.[9][10] This review concluded that "Most of the studies we examined do not provide strong evidence for beneficial health-related effects of supplements taken singly, in pairs, or in combinations of three or more." They noted that multivitamins could provide health benefits to some groups of people, such as postmenopausal women, but that there was "disturbing evidence of risk" in other groups, such as smokers. The panel's report concluded that the "present evidence is insufficient to recommend either for or against the use of Multivitamin/Mineral Supplements by the American public to prevent chronic disease."
Similarly, a 2006 report for the United States Department of Health and Human Services concluded that "regular supplementation with a single nutrient or a mixture of nutrients for years has no significant benefits in the primary prevention of cancer, cardiovascular disease, cataract, age-related macular degeneration or cognitive decline."[11] However, the report noted that multivitamins have beneficial effects in people with poor nutritional status, vitamin D and calcium can help prevent fractures in older people, and that zinc and antioxidants can help prevent age-related macular degeneration in people at a high risk of developing this disease.
In 2007 the United Kingdom Food Standards Agency published an updated set of recommendations for eating a healthy diet.[12] The recommendations stated that pregnant women should take extra folic acid and iron and that older people might need extra vitamin D and iron. However, the report advised that "Vitamin and mineral supplements are not a replacement for good eating habits" and stated that supplements are unnecessary for healthy adults who eat a balanced diet.
# Regulations by governmental agencies
## The United States of America
Because of their categorization as a dietary supplement by the Food and Drug Administration (FDA), most multivitamins sold in the U.S. are not required to undergo the rigorous testing procedures typical of pharmaceutical drugs.
However, some multivitamins contain very high doses of one or several vitamins or minerals, or are specifically intended to treat, cure, or prevent disease, and therefore require a prescription or medicinal license in the U.S. Since such drugs contain no new substances, they do not require the same testing as would be required by a New Drug Application, but were allowed on the market as drugs due to Drug Efficacy Study Implementation program.[13]
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https://www.wikidoc.org/index.php/ABC_Plus_Senior
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a5cf14f3380682d02798fa16f08204692b122ab1
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wikidoc
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AFREGS Trial
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AFREGS Trial
# Objective
To study the angiographic and clinical effects of increasing HDL levels with pharmacologic treatment.
# Methods
The Air Force Regression Study (AFREGS) was a randomized, double- blinded, placebo controlled trial with 143 patients younger than 76 years of age with low HDL levels and angiographically evident coronary artery disease. These patients were randomly allocated to the gemfibrozil, niacin, cholestyramineand corresponding placebo, with aggressive dietary and lifestyle intervention at baseline. They were then followed up for a period of 30 months for clinical events which includes hospitalization for angina, myocardial infarction, transient ischemic attack and stroke, death and other cardiovascular procedures.
# Results
- The pharmacologically treated group had a 20% decrease in total cholesterol, 36% increase in HDL cholesterol, 26% decrease in LDL cholesterol and a 50% reduction in triglyceride levels compared to the placebo group.
- Focal coronary stenosis showed an increase of 1.4% in the placebo and a decrease of 0.8% in the drug group.
- 26% of patients in the placebo group reached a composite cardiovascular event end point whereas the same was seen in 13% of patients in the drug group.
# Conclusion
Pharmacologic regimens aimed at raising HDL cholesterol levels improved the cholesterol levels, slowed the progression of stenosis, and prevents cardiovascular events in some who exercise regularly and are on a low-fat diet.
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AFREGS Trial
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Objective
To study the angiographic and clinical effects of increasing HDL levels with pharmacologic treatment.
# Methods
The Air Force Regression Study (AFREGS) was a randomized, double- blinded, placebo controlled trial with 143 patients younger than 76 years of age with low HDL levels and angiographically evident coronary artery disease. These patients were randomly allocated to the gemfibrozil, niacin, cholestyramineand corresponding placebo, with aggressive dietary and lifestyle intervention at baseline. They were then followed up for a period of 30 months for clinical events which includes hospitalization for angina, myocardial infarction, transient ischemic attack and stroke, death and other cardiovascular procedures.
# Results
- The pharmacologically treated group had a 20% decrease in total cholesterol, 36% increase in HDL cholesterol, 26% decrease in LDL cholesterol and a 50% reduction in triglyceride levels compared to the placebo group.
- Focal coronary stenosis showed an increase of 1.4% in the placebo and a decrease of 0.8% in the drug group.
- 26% of patients in the placebo group reached a composite cardiovascular event end point whereas the same was seen in 13% of patients in the drug group.
# Conclusion
Pharmacologic regimens aimed at raising HDL cholesterol levels improved the cholesterol levels, slowed the progression of stenosis, and prevents cardiovascular events in some who exercise regularly and are on a low-fat diet.[1]
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https://www.wikidoc.org/index.php/AFREGS_Trial
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d2c4b9bb6fabbdc8a7aa564216689ca60879165b
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wikidoc
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Alkaptonuria
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Alkaptonuria
# Overview
Alkaptonuria (black urine disease, alcaptonuria or ochronosis) is a rare inherited genetic disorder of tyrosine metabolism. This is an autosomal recessive trait that is caused by a defect in the enzyme homogentisic acid oxidase (EC 1.13.11.5). The enzyme normally breaks down a toxic tyrosine byproduct, homogentisic acid (also called alkapton), which is harmful to bones and cartilage and is excreted in urine.
# Symptoms
A distinctive characteristic of alkaptonuria is that ear wax exposed to air turns red or black (depending on diet) after several hours because of the accumulation of homogentisic acid. Similarly, urine exposed to air can become dark; this is useful for diagnosising young children using diapers. It is also possible to develop a black discoloration of the nails. In adulthood, but usually not before age forty, persons suffering from alkaptonuria develop progressive arthritis (especially of the spine), due to the long-term buildup of homogentisate in bones and cartilage. The urine is malodorous.
# Diagnosis
Presumptive diagnosis can be made by adding sodium or potassium hydroxide to urine and observing the formation of a dark brown to black pigment on the surface layer of urine within 30 minutes to 1 hour. Diagnosis can be confirmed by demonstrating the presence of homogentisic acid in the urine. This may be done by paper chromatography and thin-layer chromatography.
# Treatment
Prevention is not possible and the treatment is aimed at ameliorating symptoms. Reducing intake of the amino acids phenylalanine and tyrosine to the minimum required to sustain health (phenylalanine is an essential amino acid) can help slow the progression of the disease.
# History
Alkaptonuria was one of the four diseases described by Sir Archibald Edward Garrod, as being the result of the accumulation of intermediates due to metabolic deficiencies. He linked ochronosis with the accumulation of alkaptans in 1902, and his views on the subject were summarised in a 1908 Croonian lecture at the Royal College of Physicians. While Garrod identified it as a recessive condition, its genetic basis was not elucidated until 1996, when it was linked to HGO mutations.
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Alkaptonuria
For patient information click here
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Alkaptonuria (black urine disease, alcaptonuria or ochronosis) is a rare inherited genetic disorder of tyrosine metabolism. This is an autosomal recessive trait that is caused by a defect in the enzyme homogentisic acid oxidase (EC 1.13.11.5). The enzyme normally breaks down a toxic tyrosine byproduct, homogentisic acid (also called alkapton), which is harmful to bones and cartilage and is excreted in urine.
# Symptoms
A distinctive characteristic of alkaptonuria is that ear wax exposed to air turns red or black (depending on diet) after several hours because of the accumulation of homogentisic acid. Similarly, urine exposed to air can become dark; this is useful for diagnosising young children using diapers. It is also possible to develop a black discoloration of the nails. In adulthood, but usually not before age forty, persons suffering from alkaptonuria develop progressive arthritis (especially of the spine), due to the long-term buildup of homogentisate in bones and cartilage. The urine is malodorous.
# Diagnosis
Presumptive diagnosis can be made by adding sodium or potassium hydroxide to urine and observing the formation of a dark brown to black pigment on the surface layer of urine within 30 minutes to 1 hour. Diagnosis can be confirmed by demonstrating the presence of homogentisic acid in the urine. This may be done by paper chromatography and thin-layer chromatography.
# Treatment
Prevention is not possible and the treatment is aimed at ameliorating symptoms. Reducing intake of the amino acids phenylalanine and tyrosine to the minimum required to sustain health (phenylalanine is an essential amino acid) can help slow the progression of the disease.
# History
Alkaptonuria was one of the four diseases described by Sir Archibald Edward Garrod, as being the result of the accumulation of intermediates due to metabolic deficiencies. He linked ochronosis with the accumulation of alkaptans in 1902,[1] and his views on the subject were summarised in a 1908 Croonian lecture at the Royal College of Physicians.[2] While Garrod identified it as a recessive condition, its genetic basis was not elucidated until 1996, when it was linked to HGO mutations.[3]
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https://www.wikidoc.org/index.php/AKU
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4ff7439946e408dcaa8c814acfd15ac430311757
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wikidoc
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ATP synthase
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ATP synthase
# Overview
An ATP synthase (EC 3.6.3.14) is a general term for an enzyme that can synthesize adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and inorganic phosphate by using some form of energy. This energy is often in the form of protons moving down a electrochemical gradient, such as from the lumen into the stroma of chloroplasts or from the inter-membrane space into the matrix in mitochondria. The overall reaction sequence is:
These enzymes are of crucial importance in almost all organisms, because ATP is the common "energy currency" of cells.
The antibiotic oligomycin inhibits the FO unit of ATP synthase.
# Structure and nomenclature
In mitochondria, the F1FO ATP synthase has a long history of scientific study.
- the FO portion is within the membrane.
- The F1 portion of the ATP synthase is above the membrane.
It's easy to visualize the FOF1 particle as resembling the fruiting body of a common mushroom, with the head being the F1 particle, the stalk being the gamma subunit of F1, and the base and "roots" being the FO particle embedded in the membrane.
The nomenclature of the enzyme suffers from a long history. The F1 fraction derives it name from the term "Fraction 1" and FO (written as a subscript "O", not "zero") derives its name from being the oligomycin binding fraction.
Taking as an example the nomenclature of subunits in the bovine enzyme, many subunits have alphabet names:
- Greek letters: alpha, beta, gamma, delta, epsilon
- Roman letters: a, b, c, d, e, f, g, h
Others have more complex names:
- F6 (from "Fraction 6")
- OSCP (the oligomycin sensitivity conferral protein), ATP5O
- A6L (named for the gene that codes for it in the mitochondrial genome)
- IF1 (inhibitory factor 1), ATPIF1
The F1 particle is large and can be seen in the transmission electron microscope by negative staining. These are particles of 9 nm diameter that pepper the inner mitochondrial membrane. They were originally called elementary particles and were thought to contain the entire respiratory apparatus of the mitochondrion, but through a long series of experiments, Ephraim Racker and his colleagues (who first isolated the F1 particle in 1961) were able to show that this particle is correlated with ATPase activity in uncoupled mitochondria and with the ATPase activity in submitochondrial particles created by exposing mitochondria to ultrasound. This ATPase activity was further associated with the creation of ATP by a long series of experiments in many laboratories.
# Binding change mechanism
In the 1960s through the 1970s, Paul Boyer developed his binding change, or flip-flop, mechanism, which postulated that ATP synthesis is coupled with a conformational change in the ATP synthase generated by rotation of the gamma subunit. The research group of John E. Walker, then at the MRC Laboratory of Molecular Biology in Cambridge but now at the MRC Dunn Human Nutrition Unit (also in Cambridge) crystallized the F1 catalytic-domain of ATP synthase. The structure, at the time the largest asymmetric protein structure known, indicated that Boyer's rotary-catalysis model was essentially correct. For elucidating this Boyer and Walker shared half of the 1997 Nobel Prize in Chemistry. Jens Christian Skou received the other half of the Chemistry prize that year "for the first discovery of an ion-transporting enzyme, Na+, K+ -ATPase"
The crystal structure of the F1 showed alternating alpha and beta subunits (3 of each), arranged like segments of an orange around an asymmetrical gamma subunit. According to the current model of ATP synthesis (known as the alternating catalytic model), the proton-motive force across the inner mitochondrial membrane, generated by the electron transport chain, drives the passage of protons through the membrane via the FO region of ATP synthase. A portion of the FO (the ring of c-subunits) rotates as the protons pass through the membrane. The c-ring is tightly attached to the asymmetric central stalk (consisting primarily of the gamma subunit) which rotates within the alpha3beta3 of F1 causing the 3 catalytic nucleotide binding sites to go through a series of conformational changes that leads to ATP synthesis. The major F1 subunits are prevented from rotating in sympathy with the central stalk rotor by a peripheral stalk that joins the alpha3beta3 to the non-rotating portion of FO. The structure of the intact ATP synthase is currently known at low-resolution from electron cryo-microscopy (cryo-EM) studies of the complex. The cryo-EM model of ATP synthase shows that the peripheral stalk is a flexible rope-like structure that wraps around the complex as it joins F1 to FO. Under the right conditions, the enzyme reaction can also be carried out in reverse, with ATP hydrolysis driving proton pumping across the membrane.
The binding change mechanism involves the active site of a β subunit cycling between three states. In the "open" state, ADP and phosphate enter the active site, in the diagram to the right this is shown in brown. The protein then closes up around the molecules and binds them loosely - the "loose" state (shown in red). The enzyme then undergoes another change in shape and forces these molecules together, with the active site in the resulting "tight" state (shown in pink) binding the newly-produced ATP molecule with very high affinity. Finally, the active site cycles back to the open state, releasing ATP and binding more ADP and phosphate, ready for the next cycle of ATP production.
# Physiological role
Like other enzymes, the activity of F1FO ATP synthase is reversible. Large enough quantities of ATP cause it to create a transmembrane proton gradient, this is used by fermenting bacteria which do not have an electron transport chain, and hydrolyze ATP to make a proton gradient, which they use for flagella and transport of nutrients into the cell.
In respiring bacteria under physiological conditions, ATP synthase generally runs in the opposite direction, creating ATP while using the protonmotive force created by the electron transport chain as a source of energy. The overall process of creating energy in this fashion is termed oxidative phosphorylation.
The same process takes place in mitochondria, where ATP synthase is located in the inner mitochondrial membrane (so that F1-part sticks into mitochondrial matrix, where ATP synthesis takes place).
# ATP synthase in different organisms
## Plant ATP synthase
In plants ATP synthase is also present in chloroplasts (CF1FO-ATP synthase). The enzyme is integrated into thylakoid membrane; the CF1-part sticks into stroma, where dark reactions of photosynthesis (Also called the light-independent reactions or the Calvin cycle) and ATP synthesis take place. The overall structure and the catalytic mechanism of the chloroplast ATP synthase are almost the same as those of the mitochondrial enzyme. However, in chloroplasts the proton motive force is generated not by respiratory electron transport chain, but by primary photosynthetic proteins.
## E. coli ATP synthase
E. coli ATP synthase is the simplest known form of ATP synthase, with 8 different subunit types.
## Yeast ATP synthase
Yeast ATP synthase is the most complex known and is made of 20 different types of subunits.
# Evolution of ATP synthase
The evolution of ATP synthase is thought to be an example of modular evolution, where two subunits with their own functions have become associated and gained new functionality. The F1 particle shows significant similarity to hexameric DNA helicases and the FO particle shows some similarity to H+ powered flagellar motor complexes.
The α3β3 hexamer of the F1 particle shows significant structural similarity to hexameric DNA helicases; both form a ring with 3 fold rotational symmetry with a central pore. Both also have roles dependent on the relative rotation of a macromolecule within the pore; the DNA helicases use the helical shape of DNA to drive their motion along the DNA molecule and to detect supercoiling whilst the α3β3 hexamer uses the conformational changes due rotation of the γ subunit to drive an enzymatic reaction.
The H+ motor of the FO particle shows great functional similarity to the H+ motors seen in flagellar motors. Both feature a ring of many small alpha helical proteins which rotate relative to nearby stationary proteins using a H+ potential gradient as an energy source. This is, however, a fairly tenuous link - the overall structure of flagellar motors is far more complex than the FO particle and the ring of rotating proteins is far larger, with around 30 compared to the 10, 11 or 14 known in the FO complex.
The modular evolution theory for the origin of ATP synthase suggests that two subunits with independent function, a DNA helicase with ATPase activity and a H+ motor, were able to bind, and the rotation of the motor drive the ATPase activity of the helicase in reverse. This would then evolve to become more efficient, and eventually develop into the complex ATP synthases seen today. Alternatively the DNA helicase/H+ motor complex may have had H+ pump activity, the ATPase activity of the helicase driving the H+ motor in reverse. This could later evolve to carry out the reverse reaction and act as an ATP synthase.
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ATP synthase
# Overview
An ATP synthase (EC 3.6.3.14) is a general term for an enzyme that can synthesize adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and inorganic phosphate by using some form of energy. This energy is often in the form of protons moving down a electrochemical gradient, such as from the lumen into the stroma of chloroplasts or from the inter-membrane space into the matrix in mitochondria. The overall reaction sequence is:
These enzymes are of crucial importance in almost all organisms, because ATP is the common "energy currency" of cells.
The antibiotic oligomycin inhibits the FO unit of ATP synthase.
# Structure and nomenclature
In mitochondria, the F1FO ATP synthase has a long history of scientific study.
- the FO portion is within the membrane.
- The F1 portion of the ATP synthase is above the membrane.
It's easy to visualize the FOF1 particle as resembling the fruiting body of a common mushroom, with the head being the F1 particle, the stalk being the gamma subunit of F1, and the base and "roots" being the FO particle embedded in the membrane.
The nomenclature of the enzyme suffers from a long history. The F1 fraction derives it name from the term "Fraction 1" and FO (written as a subscript "O", not "zero") derives its name from being the oligomycin binding fraction.
Taking as an example the nomenclature of subunits in the bovine enzyme, many subunits have alphabet names:
- Greek letters: alpha, beta, gamma, delta, epsilon
- Roman letters: a, b, c, d, e, f, g, h
Others have more complex names:
- F6 (from "Fraction 6")
- OSCP (the oligomycin sensitivity conferral protein), ATP5O
- A6L (named for the gene that codes for it in the mitochondrial genome)
- IF1 (inhibitory factor 1), ATPIF1
The F1 particle is large and can be seen in the transmission electron microscope by negative staining.[1] These are particles of 9 nm diameter that pepper the inner mitochondrial membrane. They were originally called elementary particles and were thought to contain the entire respiratory apparatus of the mitochondrion, but through a long series of experiments, Ephraim Racker and his colleagues (who first isolated the F1 particle in 1961) were able to show that this particle is correlated with ATPase activity in uncoupled mitochondria and with the ATPase activity in submitochondrial particles created by exposing mitochondria to ultrasound. This ATPase activity was further associated with the creation of ATP by a long series of experiments in many laboratories.
# Binding change mechanism
In the 1960s through the 1970s, Paul Boyer developed his binding change, or flip-flop, mechanism, which postulated that ATP synthesis is coupled with a conformational change in the ATP synthase generated by rotation of the gamma subunit. The research group of John E. Walker, then at the MRC Laboratory of Molecular Biology in Cambridge but now at the MRC Dunn Human Nutrition Unit (also in Cambridge) crystallized the F1 catalytic-domain of ATP synthase. The structure, at the time the largest asymmetric protein structure known, indicated that Boyer's rotary-catalysis model was essentially correct. For elucidating this Boyer and Walker shared half of the 1997 Nobel Prize in Chemistry. Jens Christian Skou received the other half of the Chemistry prize that year "for the first discovery of an ion-transporting enzyme, Na+, K+ -ATPase"
The crystal structure of the F1 showed alternating alpha and beta subunits (3 of each), arranged like segments of an orange around an asymmetrical gamma subunit. According to the current model of ATP synthesis (known as the alternating catalytic model), the proton-motive force across the inner mitochondrial membrane, generated by the electron transport chain, drives the passage of protons through the membrane via the FO region of ATP synthase. A portion of the FO (the ring of c-subunits) rotates as the protons pass through the membrane. The c-ring is tightly attached to the asymmetric central stalk (consisting primarily of the gamma subunit) which rotates within the alpha3beta3 of F1 causing the 3 catalytic nucleotide binding sites to go through a series of conformational changes that leads to ATP synthesis. The major F1 subunits are prevented from rotating in sympathy with the central stalk rotor by a peripheral stalk that joins the alpha3beta3 to the non-rotating portion of FO. The structure of the intact ATP synthase is currently known at low-resolution from electron cryo-microscopy (cryo-EM) studies of the complex. The cryo-EM model of ATP synthase shows that the peripheral stalk is a flexible rope-like structure that wraps around the complex as it joins F1 to FO. Under the right conditions, the enzyme reaction can also be carried out in reverse, with ATP hydrolysis driving proton pumping across the membrane.
The binding change mechanism involves the active site of a β subunit cycling between three states.[2] In the "open" state, ADP and phosphate enter the active site, in the diagram to the right this is shown in brown. The protein then closes up around the molecules and binds them loosely - the "loose" state (shown in red). The enzyme then undergoes another change in shape and forces these molecules together, with the active site in the resulting "tight" state (shown in pink) binding the newly-produced ATP molecule with very high affinity. Finally, the active site cycles back to the open state, releasing ATP and binding more ADP and phosphate, ready for the next cycle of ATP production.
# Physiological role
Like other enzymes, the activity of F1FO ATP synthase is reversible. Large enough quantities of ATP cause it to create a transmembrane proton gradient, this is used by fermenting bacteria which do not have an electron transport chain, and hydrolyze ATP to make a proton gradient, which they use for flagella and transport of nutrients into the cell.
In respiring bacteria under physiological conditions, ATP synthase generally runs in the opposite direction, creating ATP while using the protonmotive force created by the electron transport chain as a source of energy. The overall process of creating energy in this fashion is termed oxidative phosphorylation.
The same process takes place in mitochondria, where ATP synthase is located in the inner mitochondrial membrane (so that F1-part sticks into mitochondrial matrix, where ATP synthesis takes place).
# ATP synthase in different organisms
## Plant ATP synthase
In plants ATP synthase is also present in chloroplasts (CF1FO-ATP synthase). The enzyme is integrated into thylakoid membrane; the CF1-part sticks into stroma, where dark reactions of photosynthesis (Also called the light-independent reactions or the Calvin cycle) and ATP synthesis take place. The overall structure and the catalytic mechanism of the chloroplast ATP synthase are almost the same as those of the mitochondrial enzyme. However, in chloroplasts the proton motive force is generated not by respiratory electron transport chain, but by primary photosynthetic proteins.
## E. coli ATP synthase
E. coli ATP synthase is the simplest known form of ATP synthase, with 8 different subunit types.
## Yeast ATP synthase
Yeast ATP synthase is the most complex known and is made of 20 different types of subunits.
# Evolution of ATP synthase
The evolution of ATP synthase is thought to be an example of modular evolution, where two subunits with their own functions have become associated and gained new functionality. The F1 particle shows significant similarity to hexameric DNA helicases and the FO particle shows some similarity to H+ powered flagellar motor complexes.
The α3β3 hexamer of the F1 particle shows significant structural similarity to hexameric DNA helicases; both form a ring with 3 fold rotational symmetry with a central pore. Both also have roles dependent on the relative rotation of a macromolecule within the pore; the DNA helicases use the helical shape of DNA to drive their motion along the DNA molecule and to detect supercoiling whilst the α3β3 hexamer uses the conformational changes due rotation of the γ subunit to drive an enzymatic reaction.
The H+ motor of the FO particle shows great functional similarity to the H+ motors seen in flagellar motors. Both feature a ring of many small alpha helical proteins which rotate relative to nearby stationary proteins using a H+ potential gradient as an energy source. This is, however, a fairly tenuous link - the overall structure of flagellar motors is far more complex than the FO particle and the ring of rotating proteins is far larger, with around 30 compared to the 10, 11 or 14 known in the FO complex.
The modular evolution theory for the origin of ATP synthase suggests that two subunits with independent function, a DNA helicase with ATPase activity and a H+ motor, were able to bind, and the rotation of the motor drive the ATPase activity of the helicase in reverse. This would then evolve to become more efficient, and eventually develop into the complex ATP synthases seen today. Alternatively the DNA helicase/H+ motor complex may have had H+ pump activity, the ATPase activity of the helicase driving the H+ motor in reverse. This could later evolve to carry out the reverse reaction and act as an ATP synthase.
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https://www.wikidoc.org/index.php/ATP_Synthase
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5392c221561067fe29db9f56421eef94e30ee7f9
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wikidoc
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Paracentesis
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Paracentesis
# Overview
# Paracentesis
For detailed approaching on performing paracentesis watch the video below;
# Overview
Paracentesis is a medical procedure used for a number of reasons:
- to relieve abdominal pressure from ascites
- to diagnose spontaneous bacterial peritonitis and other infections (e.g. abdominal TB)
- to diagnose metastatic cancer
- to diagnose blood in peritoneal space in trauma
- to puncture tympanic membrane for eg. to take bacterial swab from middle ear
# Paracentesis for Ascites
The procedure is often done in doctors office or an out-patient clinic. In an expert's hands, it is very safe, although there is a very small risk of introducing an infection, causing excessive bleeding or perforating a loop of bowel.
During the procedure, patients are asked to lie down and expose their abdomen. After cleaning the side of abdomen with an antiseptic solution, physicians will numb a small area of skin and then insert a fairly large-bore needle (along with a plastic sheath) 2 to 5 cm to reach the peritoneal (ascitic) fluid. The needle is then removed, leaving the plastic sheath behind to allow drainage of the fluid. The fluid can be drained by gravity or by connection to a vacuum bottle. Up to 10 litres of fluid may be drained during the procedure. If fluid drainage is more than 5 litres, patients may receive intravenous serum albumin (25% albumin, 8g/L) to prevent hypotension (low blood pressure).
The procedure generally is not painful; patients require no sedation. As long as they are not very dizzy and maintain their blood pressure after the procedure, they can go home afterwards.
# Ascitic fluid analysis
The serum-ascities albumin gradient can help determine the cause of the ascites.
The ascitic white blood cell count can help determine if the ascites is infected.
# Contraindications
Mild hematologic abnormalities do not increase the risk of bleeding. The risk of bleeding may be increased if:
- prothrombin time > 21 seconds
- international normalized ratio > 1.6
- platelet count < 50,000 per cubic millimeter.
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Paracentesis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Prince Tano Djan, BSc, MBChB [2]
# Overview
# Paracentesis
For detailed approaching on performing paracentesis watch the video below;
Template:Interventions infobox
# Overview
Paracentesis is a medical procedure used for a number of reasons:
- to relieve abdominal pressure from ascites
- to diagnose spontaneous bacterial peritonitis and other infections (e.g. abdominal TB)
- to diagnose metastatic cancer
- to diagnose blood in peritoneal space in trauma
- to puncture tympanic membrane for eg. to take bacterial swab from middle ear
# Paracentesis for Ascites
The procedure is often done in doctors office or an out-patient clinic. In an expert's hands, it is very safe, although there is a very small risk of introducing an infection, causing excessive bleeding or perforating a loop of bowel.
During the procedure, patients are asked to lie down and expose their abdomen. After cleaning the side of abdomen with an antiseptic solution, physicians will numb a small area of skin and then insert a fairly large-bore needle (along with a plastic sheath) 2 to 5 cm to reach the peritoneal (ascitic) fluid. The needle is then removed, leaving the plastic sheath behind to allow drainage of the fluid. The fluid can be drained by gravity or by connection to a vacuum bottle. Up to 10 litres of fluid may be drained during the procedure. If fluid drainage is more than 5 litres, patients may receive intravenous serum albumin (25% albumin, 8g/L) to prevent hypotension (low blood pressure).
The procedure generally is not painful; patients require no sedation. As long as they are not very dizzy and maintain their blood pressure after the procedure, they can go home afterwards.
# Ascitic fluid analysis
The serum-ascities albumin gradient can help determine the cause of the ascites.
The ascitic white blood cell count can help determine if the ascites is infected.
# Contraindications
Mild hematologic abnormalities do not increase the risk of bleeding.[1] The risk of bleeding may be increased if:[2]
- prothrombin time > 21 seconds
- international normalized ratio > 1.6
- platelet count < 50,000 per cubic millimeter.
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https://www.wikidoc.org/index.php/Abdominal_paracentesis
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Acanthamoeba
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Acanthamoeba
# Overview
Acanthamoeba is a genus of amoebae, one of the most common protozoa in soil, and also frequently found in fresh water and other habitats. The cells are small, usually 15 to 35 μm in length and oval to triangular in shape when moving. The pseudopods form a clear hemispherical lobe at the anterior, and there are various short filose extensions from the margins of the body. These give it a spiny appearance, which is what the name Acanthamoeba refers to. Cysts are common. Most species are free-living bacterivores, but some are opportunists that can cause infections in humans and other animals.
# Acanthamoeba as a human pathogen
Diseases caused by Acanthamoeba include amoebic keratitis and encephalitis. The latter is caused by Acanthamoeba entering cuts and spreading to the central nervous system. The former is a rare disease where amoebae invade the cornea of the eye. In the United States, it is nearly always associated with contact lens use, as Acanthamoeba can survive in the space between the lens and the eye. However, elsewhere in the world, many cases of Acanthamoeba present in non-contact lens wearers.
For this reason, contact lenses must be properly disinfected before wearing, and should be removed when swimming or surfing.
To detect Acanthamoeba on a contact lens in a laboratory, a sheep blood agar plate with a layer (a lawn) of E. coli is made. Part of the contact lens is placed on the agar plate. If Acanthamoeba are present, they will ingest the bacteria, leaving a clear patch on the plate around the area of the lens. Polymerase chain reaction can also be used to confirm a diagnosis of Acanthamoeba keratitis, especially when contact lenses are not involved.
## Acanthamoeba and MRSA
Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen in the hospital setting due to its resistance to many antibiotics. Recent findings demonstrate that MRSA can infect and replicate inside of Acanthamoeba polyphaga; this Acanthamoeba species is widespread throughout the environment. Since A. polyphaga can form cysts, cysts infected with MRSA can act as a mode of airborne dispersal for MRSA. Additionally, it is noted that "evidence with other pathogens suggests that pathogens that emerge from amoeba are more resistant to antibiotics and more virulent." It has been observed that Acanthamoeba can increase MRSA numbers by 1000-fold.
# Importance of Acanthamoeba in soil ecology
A. castellanii can be found at high densities in various soil ecosystems. It preys on bacteria, but also fungi and other protozoa.
This species is able to lyse bacteria and produce a wide range of enzymes such as cellulases or chitinases and probably contributes to the break down of organic matter in soil, contributing to the microbial loop.
# Acanthamoeba species
Species of Acanthamoeba are distinguished mainly on the form of cysts, and include the following; those marked with an asterisk are known to cause infections.
A. astronyxis*
A. castellanii*
A. comandoni
A. culbertsoni*
A. divionensis
A. griffini
A. hatchetti*
A. healyi
A. jacobsi
A. lenticulata
A. lugdunensis*
A. mauritaniensis
A. palestinensis*
A. pearcei
A. polyphaga*
A. pustulosa
A. quina*
A. rhysodes*
A. royreba
A. terricola
A. triangularis
A. tubiashi
# Endosymbiontes of Acanthamoeba
Acanthamoeba sp. contain diverse bacterial endosymbionts which are similar to human pathogens. Because of this they are considered to be potential emerging human pathogens. The exact nature of these symbionts and the benefit they represent for the amoebal host still have to be clarified.
# Life Cycle
Acanthamoeba spp. have been found in soil; fresh, brackish, and sea water; sewage; swimming pools; contact lens equipment; medicinal pools; dental treatment units; dialysis machines; heating, ventilating, and air conditioning systems; mammalian cell cultures; vegetables; human nostrils and throats; and human and animal brain, skin, and lung tissues. Unlike N. fowleri, Acanthamoeba has only two stages, cysts and trophozoites, in its life cycle. No flagellated stage exists as part of the life cycle. The trophozoites replicate by mitosis (nuclear membrane does not remain intact). The trophozoites are the infective forms, although both cysts and trophozoites gain entry into the body through various means. Entry can occur through the eye, the nasal passages to the lower respiratory tract, or ulcerated or broken skin. When Acanthamoeba spp. enters the eye it can cause severe keratitis in otherwise healthy individuals, particularly contact lens users. When it enters the respiratory system or through the skin, it can invade the central nervous system by hematogenous dissemination causing granulomatous amebic encephalitis (GAE) or disseminated disease, or skin lesions in individuals with compromised immune systems. Acanthamoeba spp. cysts and trophozoites are found in tissue.
- Acanthamoeba Life Cycle Adapted from CDC
## Medical Therapy
## Antimicrobial Regimen
- 1. Granulomatous amoebic encephalitis, meningitis, and disseminated Acanthamoeba disease
- Preferred regimen (1): Pentamidine AND Itraconazole AND Sulfadiazine AND Flucytosine
- Preferred regimen (2): Sulfadiazine AND Fluconazole AND Pyrimethamine
- Preferred regimen (3): Sulfadiazine AND Flucytosine AND TMP-SMX
- Preferred regimen (4): TMP-SMX AND Rifampin AND Ketoconazole
- Preferred regimen (5): Miltefosine AND Amikacin
- Preferred regimen (6): Miltefosine AND Voriconazole
- Preferred regimen (7): Pentamidine AND Itraconazole AND Flucytosine AND Levofloxacin AND Amphotericin B AND Rifampin
- Preferred regimen (8): Pentamidine AND Fluconazole AND Miltefosine
- Note: The mainstay of successful treatment includes early diagnosis and combination therapy with pentamidine, azole, sulfonamide, miltefosine, and possibly flucytosine.
- 2. Cutaneous acanthamoebiasis
- Preferred regimen: Pentamidine AND Sulfadiazine AND Flucytosine AND (Itraconazole OR Fluconazole) AND Chlorhexidine topical AND Ketoconazole topical
- 3. Acanthamoeba keratitis
- Preferred regimen: (Polyhexamethylene biguanide topical OR Chlorhexidine topical) ± (Propamidine topical OR Hexamidine topical)
- Note (1): Azole antifungal drugs (Ketoconazole, Itraconazole, Voriconazole) may be considered as oral or topical adjuncts.
- Note (2): The duration of therapy for Acanthamoeba keratitis may last six months to a year.
- Note (3): Pain control can be helped by topical cyclopegic solutions and oral nonsteroidal medications.
- Note (4): The use of corticosteroids to control inflammation is controversial.
- Note (5): Penetrating keratoplasty may help restore visual acuity.
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Acanthamoeba
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tamar Sifri [2]
# Overview
Acanthamoeba is a genus of amoebae, one of the most common protozoa in soil, and also frequently found in fresh water and other habitats. The cells are small, usually 15 to 35 μm in length and oval to triangular in shape when moving. The pseudopods form a clear hemispherical lobe at the anterior, and there are various short filose extensions from the margins of the body. These give it a spiny appearance, which is what the name Acanthamoeba refers to. Cysts are common. Most species are free-living bacterivores, but some are opportunists that can cause infections in humans and other animals.
# Acanthamoeba as a human pathogen
Diseases caused by Acanthamoeba include amoebic keratitis and encephalitis[1]. The latter is caused by Acanthamoeba entering cuts and spreading to the central nervous system. The former is a rare disease where amoebae invade the cornea of the eye. In the United States, it is nearly always associated with contact lens use, as Acanthamoeba can survive in the space between the lens and the eye.[2][3][4][5] However, elsewhere in the world, many cases of Acanthamoeba present in non-contact lens wearers.[6]
For this reason, contact lenses must be properly disinfected before wearing, and should be removed when swimming or surfing.
To detect Acanthamoeba on a contact lens in a laboratory, a sheep blood agar plate with a layer (a lawn) of E. coli is made. Part of the contact lens is placed on the agar plate. If Acanthamoeba are present, they will ingest the bacteria, leaving a clear patch on the plate around the area of the lens. Polymerase chain reaction can also be used to confirm a diagnosis of Acanthamoeba keratitis, especially when contact lenses are not involved.[7]
## Acanthamoeba and MRSA
Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen in the hospital setting due to its resistance to many antibiotics. Recent findings demonstrate that MRSA can infect and replicate inside of Acanthamoeba polyphaga; this Acanthamoeba species is widespread throughout the environment. Since A. polyphaga can form cysts, cysts infected with MRSA can act as a mode of airborne dispersal for MRSA. Additionally, it is noted that "evidence with other pathogens suggests that pathogens that emerge from amoeba are more resistant to antibiotics and more virulent."[8] It has been observed that Acanthamoeba can increase MRSA numbers by 1000-fold.[9]
# Importance of Acanthamoeba in soil ecology
A. castellanii can be found at high densities in various soil ecosystems. It preys on bacteria, but also fungi and other protozoa.
This species is able to lyse bacteria and produce a wide range of enzymes such as cellulases or chitinases[10] and probably contributes to the break down of organic matter in soil, contributing to the microbial loop.
# Acanthamoeba species
Species of Acanthamoeba are distinguished mainly on the form of cysts, and include the following; those marked with an asterisk are known to cause infections.
A. astronyxis*
A. castellanii*
A. comandoni
A. culbertsoni*
A. divionensis
A. griffini
A. hatchetti*
A. healyi
A. jacobsi
A. lenticulata
A. lugdunensis*
A. mauritaniensis
A. palestinensis*
A. pearcei
A. polyphaga*
A. pustulosa
A. quina*
A. rhysodes*
A. royreba
A. terricola
A. triangularis
A. tubiashi
# Endosymbiontes of Acanthamoeba
Acanthamoeba sp. contain diverse bacterial endosymbionts which are similar to human pathogens. Because of this they are considered to be potential emerging human pathogens.[11] The exact nature of these symbionts and the benefit they represent for the amoebal host still have to be clarified.
# Life Cycle
Acanthamoeba spp. have been found in soil; fresh, brackish, and sea water; sewage; swimming pools; contact lens equipment; medicinal pools; dental treatment units; dialysis machines; heating, ventilating, and air conditioning systems; mammalian cell cultures; vegetables; human nostrils and throats; and human and animal brain, skin, and lung tissues. Unlike N. fowleri, Acanthamoeba has only two stages, cysts and trophozoites, in its life cycle. No flagellated stage exists as part of the life cycle. The trophozoites replicate by mitosis (nuclear membrane does not remain intact). The trophozoites are the infective forms, although both cysts and trophozoites gain entry into the body through various means. Entry can occur through the eye, the nasal passages to the lower respiratory tract, or ulcerated or broken skin. When Acanthamoeba spp. enters the eye it can cause severe keratitis in otherwise healthy individuals, particularly contact lens users. When it enters the respiratory system or through the skin, it can invade the central nervous system by hematogenous dissemination causing granulomatous amebic encephalitis (GAE) or disseminated disease, or skin lesions in individuals with compromised immune systems. Acanthamoeba spp. cysts and trophozoites are found in tissue.
- Acanthamoeba Life Cycle Adapted from CDC
## Medical Therapy
## Antimicrobial Regimen
- 1. Granulomatous amoebic encephalitis, meningitis, and disseminated Acanthamoeba disease[12][13]
- Preferred regimen (1): Pentamidine AND Itraconazole AND Sulfadiazine AND Flucytosine
- Preferred regimen (2): Sulfadiazine AND Fluconazole AND Pyrimethamine
- Preferred regimen (3): Sulfadiazine AND Flucytosine AND TMP-SMX
- Preferred regimen (4): TMP-SMX AND Rifampin AND Ketoconazole
- Preferred regimen (5): Miltefosine AND Amikacin
- Preferred regimen (6): Miltefosine AND Voriconazole
- Preferred regimen (7): Pentamidine AND Itraconazole AND Flucytosine AND Levofloxacin AND Amphotericin B AND Rifampin
- Preferred regimen (8): Pentamidine AND Fluconazole AND Miltefosine
- Note: The mainstay of successful treatment includes early diagnosis and combination therapy with pentamidine, azole, sulfonamide, miltefosine, and possibly flucytosine.
- 2. Cutaneous acanthamoebiasis[14][15][16]
- Preferred regimen: Pentamidine AND Sulfadiazine AND Flucytosine AND (Itraconazole OR Fluconazole) AND Chlorhexidine topical AND Ketoconazole topical
- 3. Acanthamoeba keratitis[17]
- Preferred regimen: (Polyhexamethylene biguanide topical OR Chlorhexidine topical) ± (Propamidine topical OR Hexamidine topical)
- Note (1): Azole antifungal drugs (Ketoconazole, Itraconazole, Voriconazole) may be considered as oral or topical adjuncts.
- Note (2): The duration of therapy for Acanthamoeba keratitis may last six months to a year.
- Note (3): Pain control can be helped by topical cyclopegic solutions and oral nonsteroidal medications.
- Note (4): The use of corticosteroids to control inflammation is controversial.
- Note (5): Penetrating keratoplasty may help restore visual acuity.
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Olivary body
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Olivary body
# Overview
In anatomy, the olivary bodies or simply olives (Latin oliva and olivae, singular and plural, respectively) are a pair of prominent oval structures in the medulla oblongata, the lower portion of the brainstem. They contain the olivary nuclei.
# External anatomy
The olivary body is located on the anterior surface of the medulla lateral to the pyramid, from which it is separated by the antero-lateral sulcus and the fibers of the hypoglossal nerve.
Behind, it is separated from the postero-lateral sulcus by the ventral spinocerebellar fasciculus. In the depression between the upper end of the olive and the pons lies the vestibulocochlear nerve.
In humans, it measures about 1.25 cm. in length, and between its upper end and the pons there is a slight depression to which the roots of the facial nerve are attached.
The external arcuate fibers wind across the lower part of the pyramid and olive and enter the inferior peduncle.
# Olivary nuclei
The olivary nuclei consist of the following nuclei:
- The inferior olivary nucleus.
- The medial accessory olivary nucleus lies between the inferior olivary nucleus and the pyramid, and forms a curved lamina, the concavity of which is directed laterally. The fibers of the hypoglossal nerve, as they traverse the medulla, pass between the medial accessory and the inferior olivary nuclei.
- The dorsal accessory olivary nucleus is the smallest, and appears on transverse section as a curved lamina behind the inferior olivary nucleus.
- The superior olivary nucleus is considered part of the pons.
# Additional images
- Schematic representation of the chief ganglionic categories (I to V).
- Superficial dissection of brain-stem. Lateral view.
- Deep dissection of brain-stem. Lateral view.
- Deep dissection of brain-stem. Lateral view.
- Deep dissection of brain-stem. Ventral view.
- Section of the medulla oblongata at about the middle of the olive.
- Diagram showing the course of the arcuate fibers.
- The formatio reticularis of the medulla oblongata, shown by a transverse section passing through the middle of the olive.
- Dissection showing the projection fibers of the cerebellum.
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Olivary body
Template:Infobox Brain
# Overview
In anatomy, the olivary bodies or simply olives (Latin oliva and olivae, singular and plural, respectively) are a pair of prominent oval structures in the medulla oblongata, the lower portion of the brainstem. They contain the olivary nuclei.
# External anatomy
The olivary body is located on the anterior surface of the medulla lateral to the pyramid, from which it is separated by the antero-lateral sulcus and the fibers of the hypoglossal nerve.
Behind, it is separated from the postero-lateral sulcus by the ventral spinocerebellar fasciculus. In the depression between the upper end of the olive and the pons lies the vestibulocochlear nerve.
In humans, it measures about 1.25 cm. in length, and between its upper end and the pons there is a slight depression to which the roots of the facial nerve are attached.
The external arcuate fibers wind across the lower part of the pyramid and olive and enter the inferior peduncle.
# Olivary nuclei
The olivary nuclei consist of the following nuclei:
- The inferior olivary nucleus.
- The medial accessory olivary nucleus lies between the inferior olivary nucleus and the pyramid, and forms a curved lamina, the concavity of which is directed laterally. The fibers of the hypoglossal nerve, as they traverse the medulla, pass between the medial accessory and the inferior olivary nuclei.
- The dorsal accessory olivary nucleus is the smallest, and appears on transverse section as a curved lamina behind the inferior olivary nucleus.
- The superior olivary nucleus is considered part of the pons.
# Additional images
- Schematic representation of the chief ganglionic categories (I to V).
- Superficial dissection of brain-stem. Lateral view.
- Deep dissection of brain-stem. Lateral view.
- Deep dissection of brain-stem. Lateral view.
- Deep dissection of brain-stem. Ventral view.
- Section of the medulla oblongata at about the middle of the olive.
- Diagram showing the course of the arcuate fibers.
- The formatio reticularis of the medulla oblongata, shown by a transverse section passing through the middle of the olive.
- Dissection showing the projection fibers of the cerebellum.
# External links
- Template:GraySubject (primary source for article)
- Template:BrainMaps
Template:Gray's
Template:Rhombencephalon
Template:WikiDoc Sources
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Acepromazine
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Acepromazine
Acepromazine or acetylpromazine (more commonly known as ACP, Ace, or by the trade names Atravet or Acezine 2, number depending on mg/ml dose) is a phenothiazine derivative antipsychotic drug. It was first used in humans in the 1950s, but is now little used in humans (the closely related analogue, chlorpromazine, is still used as an antipsychotic in humans). Acepromazine is frequently used in animals as a sedative and antiemetic. Its principal value is in quietening and calming anxious animals.
The standard pharmaceutical preparation, acepromazine maleate, is used in veterinary medicine in dogs, and cats. It is used widely in horses as a pre-anaesthetic sedative and has been shown to reduce anaesthesia related death. However, it should be used with caution (but is not absolutely contraindicated) in stallions due to the risk of paraphimosis and persistent priapism. Its potential for cardiac effects, namely hypotension due to peripheral vasodilation, can be profound and as such is not recommended for use in geriatric or debilitated animals, especially dogs. In these cases it is most often substituted with midazolam or diazepam and left out of the preanesthetic medication altogether.
# Administration
## Canine
When used as a premedication it is commonly administered via the subcutaneous or intramuscular route within the clinic and as single or di-scored unflavoured tablets for oral administration. It is also administered orally prior to travel, veterinary exams, and other predictable situations in which the animal is expected to be exceptionally excited, anxious, uncooperative, or even hostile.
### Potential adverse effects in dogs
Literature from the 1950s raised concerns about phenothiazine-induced seizures in human patients. A family of Boxers in the UK were implicated for an increased seizure risk when given acepromazine and it was previously recommended to avoid this medication in this breed. For this reason, caution has typically been advised when contemplating acepromazine use in epileptic canine patients although no veterinary studies have been published until quite recently. The two published veterinary studies have failed to show a positive association between use of acepromazine and seizure activity and show a possible role for acepromazine in seizure control: in a retrospective study at University of Tennessee, acepromazine was administered for tranquilization to 36 dogs with a prior history of seizures and to decrease seizure activity in 11 dogs. No seizures were seen within 16 hours of acepromazine administration in the 36 dogs that received the drug for tranquilization during hospitalization. After acepromazine administration, seizures abated for 1.5 to 8 hours (n=6) or did not recur (n=2) in eight of 10 dogs that were actively seizing. Excitement-induced seizure frequency was reduced for 2 months in one dog. A second retrospective study also concluded that administration of acepromazine to dogs with prior or acute seizure history did not potentiate seizures and there was some trend toward seizure reduction. It should be noted that the original seizure cautions reported in the 1950s were in human patients on relatively high anti-psychotic doses of chlorpromazine while the doses of acepromazine used in the only two published veterinary studies cited above are much lower.
Recently a multi-drug resistance gene (MDR1) has been isolated by researchers at Washington State University College of Veterinary Medicine. Mutations in the gene are more common in certain herding breeds and whippets (although Border Collies are underrepresented) as well as many mixed breeds. The mutation causes increased sensitivity to ivermectin and related avermectins, acepromazine, certain opioids and opioid derivatives, as well as vincristine and certain other chemotherapeutics. It is recommended that acepromazine dose be reduced by 25% in heterozyogtes and by 30-50% in dogs homozygous for the mutation. Owners may test their dogs via a kit available from WSU and are strongly encouraged to share those results with their veterinarian.
The Boxer is reported to have a breed-related sensitivity to acepromazine. In 1996 a warning was placed in the cardiology section of the Veterinary Information Network (VIN), a US-based network for practicing veterinarians, entitled "Acepromazine and Boxers." It described several adverse reactions to acepromazine in three Boxers at the University of California at Davis veterinary teaching hospital. The reactions included collapse, respiratory arrest, and profound bradycardia (slow heart rate, less than 60 beats per minute). While there is disagreement among some veterinarians on this point, a number of veterinary publications recommend the drug be avoided in the breed. Individual dogs of any breed can have a profound reaction characterized by hypotension (low blood pressure), especially if there is an underlying heart problem.
Acepromazine should be used with caution in sighthounds.
## Equine
Acepromazine can be administered by the intramuscular route, taking effect within 30–45 minutes, or may be given intravenously, taking effect within 15 minutes. Sedation usually lasts for 1–4 hours, although some horses may feel the effects for up to 24 hours. The standard dose is highly variable, depending upon the desired effect following administration. An oral gel formulation is also available (Sedalin gel). The dosage by this route is also highly variable, but it is generally accepted that the recommended dose will give moderate sedation in most horses.
In the UK, acepromazine is not authorised for use in horses intended for human consumption.
In equine surgery, premedication with acepromazine has been shown to reduce the perianaesthetic mortality rate, although the reasons for this are unclear.
Additionally, acepromazine is used as a vasodilator in the treatment of laminitis, where an oral dose equivalent to "mild sedation" is commonly used, although the dose used is highly dependent on the treating veterinarian. While it is shown to elicit vasodilation in the distal limb, evidence showing its efficacy at increasing perfusion in the laminae is lacking. It is also sometimes used to treat a horse experiencing Equine Exertional Rhabdomyolysis.
### Precautions when using in horses
Acepromazine is a prohibited class A drug under FEI rules, and its use is prohibited or restricted by many other equestrian organizations. It can be detected in the blood for 72–120 hours, although repeated doses may make it remain present for several months.
Side effects are not common, but the use of acepromazine in stallions should be used with caution (but is not absolutely contraindicated) due to the risk of paraphimosis and priapism.
Acepromazine should not be used in horses dewormed with piperazine. It lowers blood pressure, and should therefore be used with caution in horses that are experiencing anemia, dehydration, shock, or colic.
## Feline
Acepromazine is sometimes recommended or prescribed in tiny oral doses to the pet cats of allergy sufferers.
# Drug reaction: MDR1 gene deletion
For over 20 years herding dogs have died from negative reactions to acepromazine that were rooted in genetic mutations. This reveals a lack of understanding about acepromazine, and other drugs with potentially toxic side effects. Scientists isolated the problem: the Multi Drug Resistant 1 (MDR1) gene. In addition, more than 30 potentially toxic drugs have been identified, and a lab test has been developed to identify dogs with the abnormal MDR1 gene. Three different factors are now recognized that contribute to drug toxicity especially common in herding dogs: a genetic mutation, drugs that inactivate normal cell pumps, and substances that inactivate cell enzymes so they cannot break down drugs.
In addition to having proteins on the membrane that remove drugs from the cell, most cells have enzymes that break down drugs and inactivate them. Cytochrome P 450 is a family of enzymes that inactivates about 60% of drugs used in pets. One of the CYP 450 family—CYP3A—can be blocked or inactivated by ketoconazole and by grapefruit juice. With CYP3A inactivated, drugs reach toxic concentrations within cells.
Dogs can have both the defective MDR1 gene and have inactivated CYP3A enzymes. These dogs are very likely to develop toxicity with certain drugs.
Dogs at risk: Australian Shepherd, Border Collie, Collie, English Shepherd, German Shepherd, Old English Sheepdog, and Sighthounds. Other dogs including mixed breeds, shelties, long haired greyhound may also lack P-glycoprotein transporters.
## Drugs that become toxic if not pumped out by P-glycoproteins
Many different drugs are normally pumped from cells by P-glycoproteins: anticancer drugs, antiparasitics, antibiotics, cardiac drugs, immunosuppressants, opioids, steroid hormones, and miscellaneous drugs. Acepromazine can become toxic in dogs with the MDR1 mutation. The commonly used veterinary antihelmintic ivermectin is another example of a drug which is peripherally acting due to p-glycoprotein.
Drugs like acepromazine can lead to hearing loss and other serious side effects.
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Acepromazine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Acepromazine or acetylpromazine (more commonly known as ACP, Ace, or by the trade names Atravet or Acezine 2, number depending on mg/ml dose) is a phenothiazine derivative antipsychotic drug. It was first used in humans in the 1950s,[1] but is now little used in humans (the closely related analogue, chlorpromazine, is still used as an antipsychotic in humans). Acepromazine is frequently used in animals as a sedative and antiemetic. Its principal value is in quietening and calming anxious animals.[citation needed]
The standard pharmaceutical preparation, acepromazine maleate, is used in veterinary medicine in dogs, and cats. It is used widely in horses as a pre-anaesthetic sedative and has been shown to reduce anaesthesia related death.[citation needed] However, it should be used with caution (but is not absolutely contraindicated) in stallions due to the risk of paraphimosis and persistent priapism.[citation needed] Its potential for cardiac effects, namely hypotension due to peripheral vasodilation, can be profound and as such is not recommended for use in geriatric or debilitated animals, especially dogs.[citation needed] In these cases it is most often substituted with midazolam or diazepam and left out of the preanesthetic medication altogether.[citation needed]
# Administration
## Canine
When used as a premedication it is commonly administered via the subcutaneous or intramuscular route within the clinic and as single or di-scored unflavoured tablets for oral administration.[citation needed] It is also administered orally prior to travel, veterinary exams, and other predictable situations in which the animal is expected to be exceptionally excited, anxious, uncooperative, or even hostile.
### Potential adverse effects in dogs
Literature from the 1950s raised concerns about phenothiazine-induced seizures in human patients. A family of Boxers in the UK were implicated for an increased seizure risk when given acepromazine and it was previously recommended to avoid this medication in this breed. For this reason, caution has typically been advised when contemplating acepromazine use in epileptic canine patients although no veterinary studies have been published until quite recently. The two published veterinary studies have failed to show a positive association between use of acepromazine and seizure activity and show a possible role for acepromazine in seizure control: in a retrospective study at University of Tennessee, acepromazine was administered for tranquilization to 36 dogs with a prior history of seizures and to decrease seizure activity in 11 dogs. No seizures were seen within 16 hours of acepromazine administration in the 36 dogs that received the drug for tranquilization during hospitalization. After acepromazine administration, seizures abated for 1.5 to 8 hours (n=6) or did not recur (n=2) in eight of 10 dogs that were actively seizing. Excitement-induced seizure frequency was reduced for 2 months in one dog.[2] A second retrospective study also concluded that administration of acepromazine to dogs with prior or acute seizure history did not potentiate seizures and there was some trend toward seizure reduction.[3] It should be noted that the original seizure cautions reported in the 1950s were in human patients on relatively high anti-psychotic doses of chlorpromazine while the doses of acepromazine used in the only two published veterinary studies cited above are much lower.
Recently a multi-drug resistance gene (MDR1) has been isolated by researchers at Washington State University College of Veterinary Medicine. Mutations in the gene are more common in certain herding breeds and whippets (although Border Collies are underrepresented) as well as many mixed breeds. The mutation causes increased sensitivity to ivermectin and related avermectins, acepromazine, certain opioids and opioid derivatives, as well as vincristine and certain other chemotherapeutics. It is recommended that acepromazine dose be reduced by 25% in heterozyogtes and by 30-50% in dogs homozygous for the mutation. Owners may test their dogs via a kit available from WSU and are strongly encouraged to share those results with their veterinarian.[4]
The Boxer is reported to have a breed-related sensitivity to acepromazine. In 1996 a warning was placed in the cardiology section of the Veterinary Information Network (VIN), a US-based network for practicing veterinarians, entitled "Acepromazine and Boxers." It described several adverse reactions to acepromazine in three Boxers at the University of California at Davis veterinary teaching hospital. The reactions included collapse, respiratory arrest, and profound bradycardia (slow heart rate, less than 60 beats per minute). While there is disagreement among some veterinarians on this point, a number of veterinary publications recommend the drug be avoided in the breed.[5] Individual dogs of any breed can have a profound reaction characterized by hypotension (low blood pressure), especially if there is an underlying heart problem.
Acepromazine should be used with caution in sighthounds.[5][citation needed]
## Equine
Acepromazine can be administered by the intramuscular route, taking effect within 30–45 minutes, or may be given intravenously, taking effect within 15 minutes. Sedation usually lasts for 1–4 hours, although some horses may feel the effects for up to 24 hours. The standard dose is highly variable, depending upon the desired effect following administration. An oral gel formulation is also available (Sedalin gel). The dosage by this route is also highly variable, but it is generally accepted that the recommended dose will give moderate sedation in most horses.[citation needed]
In the UK, acepromazine is not authorised for use in horses intended for human consumption.[6]
In equine surgery, premedication with acepromazine has been shown to reduce the perianaesthetic mortality rate,[7] although the reasons for this are unclear.
Additionally, acepromazine is used as a vasodilator in the treatment of laminitis, where an oral dose equivalent to "mild sedation" is commonly used, although the dose used is highly dependent on the treating veterinarian. While it is shown to elicit vasodilation in the distal limb, evidence showing its efficacy at increasing perfusion in the laminae is lacking. It is also sometimes used to treat a horse experiencing Equine Exertional Rhabdomyolysis.[citation needed]
### Precautions when using in horses
Acepromazine is a prohibited class A drug under FEI rules, and its use is prohibited or restricted by many other equestrian organizations. It can be detected in the blood for 72–120 hours, although repeated doses may make it remain present for several months.
Side effects are not common, but the use of acepromazine in stallions should be used with caution (but is not absolutely contraindicated) due to the risk of paraphimosis and priapism.[8]
Acepromazine should not be used in horses dewormed with piperazine. It lowers blood pressure, and should therefore be used with caution in horses that are experiencing anemia, dehydration, shock, or colic.
## Feline
Acepromazine is sometimes recommended or prescribed in tiny oral doses to the pet cats of allergy sufferers. [9]
# Drug reaction: MDR1 gene deletion
For over 20 years herding dogs have died from negative reactions to acepromazine that were rooted in genetic mutations.[citation needed] This reveals a lack of understanding about acepromazine, and other drugs with potentially toxic side effects. Scientists isolated the problem: the Multi Drug Resistant 1 (MDR1) gene. In addition, more than 30 potentially toxic drugs have been identified, and a lab test has been developed to identify dogs with the abnormal MDR1 gene. Three different factors are now recognized that contribute to drug toxicity especially common in herding dogs: a genetic mutation, drugs that inactivate normal cell pumps, and substances that inactivate cell enzymes so they cannot break down drugs.
In addition to having proteins on the membrane that remove drugs from the cell, most cells have enzymes that break down drugs and inactivate them. Cytochrome P 450 is a family of enzymes that inactivates about 60% of drugs used in pets. One of the CYP 450 family—CYP3A—can be blocked or inactivated by ketoconazole and by grapefruit juice. With CYP3A inactivated, drugs reach toxic concentrations within cells.
Dogs can have both the defective MDR1 gene and have inactivated CYP3A enzymes. These dogs are very likely to develop toxicity with certain drugs.
Dogs at risk: Australian Shepherd, Border Collie, Collie, English Shepherd, German Shepherd, Old English Sheepdog, and Sighthounds. Other dogs including mixed breeds, shelties, long haired greyhound may also lack P-glycoprotein transporters.
## Drugs that become toxic if not pumped out by P-glycoproteins
Many different drugs are normally pumped from cells by P-glycoproteins: anticancer drugs, antiparasitics, antibiotics, cardiac drugs, immunosuppressants, opioids, steroid hormones, and miscellaneous drugs. Acepromazine can become toxic in dogs with the MDR1 mutation. The commonly used veterinary antihelmintic ivermectin is another example of a drug which is peripherally acting due to p-glycoprotein.
Drugs like acepromazine can lead to hearing loss and other serious side effects.
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Acetaldehyde
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Acetaldehyde
# Overview
Acetaldehyde, sometimes known as ethanal, is an organic chemical compound with the formula CH3CHO or MeCHO. It is a flammable liquid with a fruity smell. Acetaldehyde occurs naturally in ripe fruit, coffee, and fresh bread and is produced by plants as part of their normal metabolism. It is popularly known as the chemical that causes hangovers.
In the chemical industry, acetaldehyde is used as an intermediate in the production of acetic acid, certain esters, and a number of other chemicals. In 1989, US production stood at 740 million pounds (336,000 t). An important production method for acetaldehyde is the Wacker process.
# Ethenol
Only a trace of acetaldehyde exists as the enol form, ethenol, with Keq = 6 x 10-5. Ethenol has been detected in the interstellar medium, specifically in between our Milky Way Galaxy and the Galaxy N-ID9
# Applications in organic synthesis
Acetaldehyde is a common 2-carbon building block in organic synthesis. Because of its small size and its availability as the anhydrous monomer (unlike formaldehyde), it is a common electrophile. With respect to its condensation reactions, acetaldehyde is prochiral. It is mainly used as a source of the CH3C+H(OH) synthon in aldol and related condensation reactions. Grignard reagents and organolithium compounds react with MeCHO to give hydroxyethyl derivatives. In one of the more spectacular condensation reactions, three equivalents of formaldehyde add to MeCHO to give pentaerythritol, C(CH2OH)4.
In a Strecker reaction, acetaldehyde condenses with cyanide and ammonia to give, after hydrolysis, the amino acid alanine. Acetaldehyde can condense with amines to yield imines, such as the condensation with cyclohexylamine to give N-ethylidenecyclohexylamine. These imines can be used to direct subsequent reactions like an aldol condensation.
It is also an important building block for the synthesis of heterocyclic compounds. A remarkable example is its conversion upon treatment with ammonia to 5-ethyl-2-methylpyridine ("aldehyde-collidine”).
## Acetal derivatives
Three molecules of acetaldehyde condense to form “paraldehyde,” a cyclic trimer containing C-O single bonds; four condense to form the cyclic molecule called metaldehyde.
Acetaldehyde forms a stable acetal upon reaction with ethanol under conditions that favor dehydration. The product, CH3CH(OCH2CH3)2, is in fact called "acetal," although acetal is used more widely to describe other compounds with the formula RCH(OR')2.
# Biological aspects
In the liver, the enzyme alcohol dehydrogenase converts ethanol into acetaldehyde, which is then further converted into harmless acetic acid by acetaldehyde dehydrogenase. The last steps of alcoholic fermentation in bacteria, plants and yeast involve the conversion of pyruvate into acetaldehyde by the enzyme pyruvate decarboxylase, followed by the conversion of acetaldehyde into ethanol. The latter reaction is again catalyzed by an alcohol dehydrogenase, now operating in the opposite direction.
## Acetaldehyde and hangovers
Most people of East Asian descent have a mutation in their alcohol dehydrogenase gene that makes this enzyme unusually effective at converting ethanol to acetaldehyde, and about half of such people also have a form of acetaldehyde dehydrogenase which is less effective at converting acetaldehyde to acetic acid. This combination causes them to suffer from the alcohol flush reaction, in which acetaldehyde accumulates after drinking, leading to severe and immediate hangover symptoms. These people are therefore less likely to become alcoholics. The drug Antabuse (disulfiram) also prevents the oxidation of acetaldehyde to acetic acid, with the same unpleasant effects for drinkers. It has been used in the treatment of alcoholism.
# Other occurrences
Acetaldehyde is an air pollutant resulting from combustion, such as automotive exhaust and tobacco smoke, contributing to the addictive properties of tobacco.
# Safety
Acetaldehyde is toxic, an irritant, and a probable carcinogen.
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Acetaldehyde
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Acetaldehyde, sometimes known as ethanal, is an organic chemical compound with the formula CH3CHO or MeCHO. It is a flammable liquid with a fruity smell. Acetaldehyde occurs naturally in ripe fruit, coffee, and fresh bread and is produced by plants as part of their normal metabolism. It is popularly known as the chemical that causes hangovers.
In the chemical industry, acetaldehyde is used as an intermediate in the production of acetic acid, certain esters, and a number of other chemicals. In 1989, US production stood at 740 million pounds (336,000 t). An important production method for acetaldehyde is the Wacker process.
# Ethenol
Only a trace of acetaldehyde exists as the enol form, ethenol, with Keq = 6 x 10-5.[1] Ethenol has been detected in the interstellar medium, specifically in between our Milky Way Galaxy and the Galaxy N-ID9[2]
# Applications in organic synthesis
Acetaldehyde is a common 2-carbon building block in organic synthesis.[3] Because of its small size and its availability as the anhydrous monomer (unlike formaldehyde), it is a common electrophile. With respect to its condensation reactions, acetaldehyde is prochiral. It is mainly used as a source of the CH3C+H(OH) synthon in aldol and related condensation reactions.[4] Grignard reagents and organolithium compounds react with MeCHO to give hydroxyethyl derivatives.[5] In one of the more spectacular condensation reactions, three equivalents of formaldehyde add to MeCHO to give pentaerythritol, C(CH2OH)4.[6]
In a Strecker reaction, acetaldehyde condenses with cyanide and ammonia to give, after hydrolysis, the amino acid alanine.[7] Acetaldehyde can condense with amines to yield imines, such as the condensation with cyclohexylamine to give N-ethylidenecyclohexylamine. These imines can be used to direct subsequent reactions like an aldol condensation.[8]
It is also an important building block for the synthesis of heterocyclic compounds. A remarkable example is its conversion upon treatment with ammonia to 5-ethyl-2-methylpyridine ("aldehyde-collidine”).[9]
## Acetal derivatives
Three molecules of acetaldehyde condense to form “paraldehyde,” a cyclic trimer containing C-O single bonds; four condense to form the cyclic molecule called metaldehyde.
Acetaldehyde forms a stable acetal upon reaction with ethanol under conditions that favor dehydration. The product, CH3CH(OCH2CH3)2, is in fact called "acetal,"[10] although acetal is used more widely to describe other compounds with the formula RCH(OR')2.
# Biological aspects
In the liver, the enzyme alcohol dehydrogenase converts ethanol into acetaldehyde, which is then further converted into harmless acetic acid by acetaldehyde dehydrogenase. The last steps of alcoholic fermentation in bacteria, plants and yeast involve the conversion of pyruvate into acetaldehyde by the enzyme pyruvate decarboxylase, followed by the conversion of acetaldehyde into ethanol. The latter reaction is again catalyzed by an alcohol dehydrogenase, now operating in the opposite direction.
## Acetaldehyde and hangovers
Most people of East Asian descent have a mutation in their alcohol dehydrogenase gene that makes this enzyme unusually effective at converting ethanol to acetaldehyde, and about half of such people also have a form of acetaldehyde dehydrogenase which is less effective at converting acetaldehyde to acetic acid[11]. This combination causes them to suffer from the alcohol flush reaction, in which acetaldehyde accumulates after drinking, leading to severe and immediate hangover symptoms. These people are therefore less likely to become alcoholics. The drug Antabuse (disulfiram) also prevents the oxidation of acetaldehyde to acetic acid, with the same unpleasant effects for drinkers. It has been used in the treatment of alcoholism.
# Other occurrences
Acetaldehyde is an air pollutant resulting from combustion, such as automotive exhaust and tobacco smoke, contributing to the addictive properties of tobacco.[12]
# Safety
Acetaldehyde is toxic, an irritant, and a probable carcinogen.[13]
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Acheiropodia
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Acheiropodia
# Overview
Acheiropodia, also known as Horn Kolb Syndrome, Acheiropody and Aleijadinhos (Brazilian type), is an autosomal recessive disorder that results in hemimelia, a lack of formation of the distal extremities.
This is a congenital defect which consists of bilateral amputations of the distal upper and lower extremities, as well as aplasia of the hands and feet. It was first discovered and is prevalent almost exclusively in Brazil.
# Genetics
It has been associated with a mutation in the LMBR1 gene.
File:Autorecessive.svg
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Acheiropodia
# Overview
Acheiropodia, also known as Horn Kolb Syndrome, Acheiropody and Aleijadinhos (Brazilian type), is an autosomal recessive[1] disorder that results in hemimelia, a lack of formation of the distal extremities.
This is a congenital defect which consists of bilateral amputations of the distal upper and lower extremities, as well as aplasia of the hands and feet. It was first discovered and is prevalent almost exclusively in Brazil.[2]
# Genetics
It has been associated with a mutation in the LMBR1 gene.[3]
File:Autorecessive.svg
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https://www.wikidoc.org/index.php/Acheiropodia
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993bf53df1f747a19d1a6356493ea3ad9a4045bc
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Acidogenesis
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Acidogenesis
Acidogenesis represents the second stage in the four stages of anaerobic digestion:
- Hydrolysis: A chemical reaction where particulates are solubilized and large polymers, converted into simpler monomers;
- Acidogenesis: A biological reaction where simple monomers are converted into volatile fatty acids;
- Acetogenesis: A biological reaction where volatile fatty acids are converted into acetic acid, carbon dioxide, and hydrogen; and
- Methanogenesis: A biological reaction where acetate are converted into methane and carbon dioxide, while hydrogen is consumed.
Anaerobic digestion is a complex biochemical process of biologically-mediated reactions by a consortia of microorganisms to convert organic compounds into methane and carbon dioxide. It is a stabilization process, producing odor, pathogens, and mass reduction.
Hydrolytic bacteria form a variety of reduced end-products from the fermentation of a given substrate. One fundamental question which arises, concerns the metabolic features which control carbon and electron flow to a given reduced end-product during pure culture, and mixed methanogenic cultures of hydrolytic bacteria. Thermoanaerobium brockii is a representative thermophilic, hydrolytic bacterium, which ferments glucose, via the Embden-Meyerhof Parnas Pathway. T. brockii is an atypical hetero-lactic acid bacterium because it forms molecular hydrogen (H2), in addition to lactic acid and ethanol. The reduced end-products of glucose fermentation are enzymatically-formed from pyruvate, via the following mechanisms: lactate by fructose 1-6 all-phosphate (F6P) activated lactate dehydrogenase; H2 by pyruvate ferredoxin oxidoreductase and hydrogenase; and ethanol via NADH- and NADPH-linked alcohol dehydrogenase .
By its side, the acidogenic activity was found in the early 20th century, but it was not until mid-'60s that the engineering of phases separation was assumed in order to improve the stability and waste digesters treatment . In this phase, complex molecules (carbohydrates, lipids, proteins) are depolymerized into soluble compounds by hydrolytic enzymes (cellulases, hemicelulases, amylases, lipases and proteases). The hydrolyzed compounds are fermented into volatile fatty acids (acetate, propionate, butyrate, and lactate), neutral compounds (ethanol, methanol), ammonia, hydrogen and carbon dioxide
Acetogenesis is one of the main reactions of this stage, in this, the intermediary metabolites produced are metabolized to acetate, hydrogen and carbonic gas by the three main groups of bacteria:
- homoacetogens;
- syntrophes; and
- sulphoreductors.
For the acetic acid production are considered three kind of bacteria:
- Clostridium aceticum;
- Acetobacter woodii; and
- Clostridium termoautotrophicum.
Winter y Wolfe, in 1979, demonstrated that A. wodii in syntrophic association with Methanosarcina produce methane and carbon dioxide from fructose, instead of three molecules of acetate . C. thermoaceticum and C. formiaceticum are able to reduce the carbonic gas to acetate, but they do not have hydrogenases which inhabilite the hydrogen use, so they can produce three molecules of acetate from fructose. Acetic acid is equally a co-metabolite of the organic substrates fermentation (sugars, glycerol, lactic acid, etc.) by diverse groups of microorganisms which produce different acids: *propionic bacteria (propionate + acetate);
- Clostridium (butyrate + acetate);
- Enterobacteria (acetate + lactate); and
- Hetero-fermentative bacteria (acetate, propionate, butyrate, valerate, etc.).
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Acidogenesis
Acidogenesis represents the second stage in the four stages of anaerobic digestion:
- Hydrolysis: A chemical reaction where particulates are solubilized and large polymers, converted into simpler monomers;
- Acidogenesis: A biological reaction where simple monomers are converted into volatile fatty acids;
- Acetogenesis: A biological reaction where volatile fatty acids are converted into acetic acid, carbon dioxide, and hydrogen; and
- Methanogenesis: A biological reaction where acetate are converted into methane and carbon dioxide, while hydrogen is consumed.
Anaerobic digestion is a complex biochemical process of biologically-mediated reactions by a consortia of microorganisms to convert organic compounds into methane and carbon dioxide. It is a stabilization process, producing odor, pathogens, and mass reduction.
Hydrolytic bacteria form a variety of reduced end-products from the fermentation of a given substrate. One fundamental question which arises, concerns the metabolic features which control carbon and electron flow to a given reduced end-product during pure culture, and mixed methanogenic cultures of hydrolytic bacteria. Thermoanaerobium brockii is a representative thermophilic, hydrolytic bacterium, which ferments glucose, via the Embden-Meyerhof Parnas Pathway. T. brockii is an atypical hetero-lactic acid bacterium because it forms molecular hydrogen (H2), in addition to lactic acid and ethanol. The reduced end-products of glucose fermentation are enzymatically-formed from pyruvate, via the following mechanisms: lactate by fructose 1-6 all-phosphate (F6P) activated lactate dehydrogenase; H2 by pyruvate ferredoxin oxidoreductase and hydrogenase; and ethanol via NADH- and NADPH-linked alcohol dehydrogenase [1] .
By its side, the acidogenic activity was found in the early 20th century, but it was not until mid-'60s that the engineering of phases separation was assumed in order to improve the stability and waste digesters treatment [2]. In this phase, complex molecules (carbohydrates, lipids, proteins) are depolymerized into soluble compounds by hydrolytic enzymes (cellulases, hemicelulases, amylases, lipases and proteases). The hydrolyzed compounds are fermented into volatile fatty acids (acetate, propionate, butyrate, and lactate), neutral compounds (ethanol, methanol), ammonia, hydrogen and carbon dioxide [3] [4] [5]
Acetogenesis is one of the main reactions of this stage, in this, the intermediary metabolites produced are metabolized to acetate, hydrogen and carbonic gas by the three main groups of bacteria:
- homoacetogens;
- syntrophes; and
- sulphoreductors.
For the acetic acid production are considered three kind of bacteria:
- Clostridium aceticum;
- Acetobacter woodii; and
- Clostridium termoautotrophicum.
Winter y Wolfe, in 1979, demonstrated that A. wodii in syntrophic association with Methanosarcina produce methane and carbon dioxide from fructose, instead of three molecules of acetate [6]. C. thermoaceticum and C. formiaceticum are able to reduce the carbonic gas to acetate, but they do not have hydrogenases which inhabilite the hydrogen use, so they can produce three molecules of acetate from fructose. Acetic acid is equally a co-metabolite of the organic substrates fermentation (sugars, glycerol, lactic acid, etc.) by diverse groups of microorganisms which produce different acids: *propionic bacteria (propionate + acetate);
- Clostridium (butyrate + acetate);
- Enterobacteria (acetate + lactate); and
- Hetero-fermentative bacteria (acetate, propionate, butyrate, valerate, etc.).
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https://www.wikidoc.org/index.php/Acidogenesis
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534bc07421f9e62747adbdaee1a2d83060b01af6
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Palygorskite
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Palygorskite
Palygorskite (also known as attapulgite) is a magnesium aluminium phyllosilicate with formula (Mg,Al)2Si4O10(OH)·4(H2O) which occurs in a type of clay soil common to the Southeastern United States. It is one of the types of fuller's earth. When used in medicine, it physically binds to acids and toxic substances in the stomach and digestive tract. For that reason, it has often been used in antidiarrheal medications. Until 2003, it was the active ingredient used in Kaopectate, before that product was reformulated with bismuth subsalicylate. Like bismuth, it is not absorbed into the body, however the two work differently.
Seven to ten percent attapulgite clay mixed with the eutectic salt, sodium sulfate decahydrate (Glaubers salt), will keep anhydrous crystals suspended in the solution where they will hydrate during phase change and hence contribute to the heat absorbed and released when Glaubers salt are used for heat storage.
## Name
The name attapulgite is derived from the U.S. town of Attapulgus, Georgia, in the extreme southwest corner of the state, where the mineral is abundant. It is surface-mined in the area, dry ground and air separated into precise particle sizes, and transported in covered hopper cars via the railroad and is also shipped in 50 pound paper bags and bulk bags by truck.
The name palygorskite is given after the place in the Ural Mountains where it was discovered.
## Social use
Palygorskite is known to have been a key constituent of the pigment called "Maya Blue", which was used notably by the pre-Columbian Maya civilization of Mesoamerica on ceramics, sculptures, murals and (most probably) Maya textiles. The clay mineral was also used by the Maya as a curative for certain illnesses, and there is evidence to show it was also added to pottery temper. A Maya region source for palygorskite was unknown until the 1960s, when one was found at a cenote on the Yucatán Peninsula near the modern township of Sacalum, Yucatán. A second possible site was more recently (2005) identified, near Ticul, Yucatán.
The Maya Blue pigment synthetic was also manufactured in other Mesoamerican regions and used by other Mesoamerican cultures, such as the Aztecs of central Mexico. The blue coloration seen on Maya and Aztec codices, and early colonial-era manuscripts and maps, is largely produced by the organic-inorganic mixture of añil leaves and palygorskite, with smaller amounts of other mineral additives. Human sacrificial victims in Postclassic Mesoamerica were frequently daubed with this blue pigmentation.
## Extraction
Three companies are involved in the industrial extraction and processing of attapulgite clay on the same Attapulgus deposit: Active Minerals International, LLC, Engelhard/BASF, and Zemex Corp. Active Minerals and Engelhard/BASF are the largest producers. Active Minerals operates a dedicated factory to produce the patented product Actigel 208.
## Properties
Attapulgite clays are swellable clays like bentonites, although more acicular (or needle like). Attapulgite,unlike bentonite, will swell in salt water and is used in special salt water drilling mud for off shore oil drilling. Like many clays, they can be considered as charged particles with zones of + and - charges. Standard attapulgite clays are agglomorated bundles of clay particles between 20 and 100 microns long and below 1 micron in diameter. Most grades contain up to 25% non-attapulgite material in the form of carbonates and other inclusions. Despite this, they are a beneficial ingredient of cementitious tile adhesives in competition with polyacrylates and starch ethers. The advantage of attapulgites is that their performance is not temperature sensitive and they have lower water demand. They must have free ions in an aquous system to work.
Actigel 208 is a patented exfoliated attapulgite where the clay has been chemically and mechanically purified into discrete particles 20 angstroms diameter. This material has special viscosity modification properties with high solid aqueous systems that cannot be matched with any other ingredients
# Notes
- ↑ See abstract of Arnold (2005).
- ↑ Haude (1997).
- ↑ Arnold and Bohor (1975), as cited in Haude (1997).
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Palygorskite
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Palygorskite (also known as attapulgite) is a magnesium aluminium phyllosilicate with formula (Mg,Al)2Si4O10(OH)·4(H2O) which occurs in a type of clay soil common to the Southeastern United States. It is one of the types of fuller's earth. When used in medicine, it physically binds to acids and toxic substances in the stomach and digestive tract. For that reason, it has often been used in antidiarrheal medications. Until 2003, it was the active ingredient used in Kaopectate, before that product was reformulated with bismuth subsalicylate. Like bismuth, it is not absorbed into the body, however the two work differently.
Seven to ten percent attapulgite clay mixed with the eutectic salt, sodium sulfate decahydrate (Glaubers salt), will keep anhydrous crystals suspended in the solution where they will hydrate during phase change and hence contribute to the heat absorbed and released when Glaubers salt are used for heat storage.
## Name
The name attapulgite is derived from the U.S. town of Attapulgus, Georgia, in the extreme southwest corner of the state, where the mineral is abundant. It is surface-mined in the area, dry ground and air separated into precise particle sizes, and transported in covered hopper cars via the railroad and is also shipped in 50 pound paper bags and bulk bags by truck.
The name palygorskite is given after the place in the Ural Mountains where it was discovered.
## Social use
Palygorskite is known to have been a key constituent of the pigment called "Maya Blue", which was used notably by the pre-Columbian Maya civilization of Mesoamerica on ceramics, sculptures, murals and (most probably) Maya textiles. The clay mineral was also used by the Maya as a curative for certain illnesses, and there is evidence to show it was also added to pottery temper. A Maya region source for palygorskite was unknown until the 1960s, when one was found at a cenote on the Yucatán Peninsula near the modern township of Sacalum, Yucatán. A second possible site was more recently (2005) identified, near Ticul, Yucatán.[1]
The Maya Blue pigment synthetic was also manufactured in other Mesoamerican regions and used by other Mesoamerican cultures, such as the Aztecs of central Mexico. The blue coloration seen on Maya and Aztec codices, and early colonial-era manuscripts and maps, is largely produced by the organic-inorganic mixture of añil leaves and palygorskite, with smaller amounts of other mineral additives.[2] Human sacrificial victims in Postclassic Mesoamerica were frequently daubed with this blue pigmentation.[3]
## Extraction
Three companies are involved in the industrial extraction and processing of attapulgite clay on the same Attapulgus deposit: Active Minerals International, LLC, Engelhard/BASF, and Zemex Corp. Active Minerals and Engelhard/BASF are the largest producers. Active Minerals operates a dedicated factory to produce the patented product Actigel 208.
## Properties
Attapulgite clays are swellable clays like bentonites, although more acicular (or needle like). Attapulgite,unlike bentonite, will swell in salt water and is used in special salt water drilling mud for off shore oil drilling. Like many clays, they can be considered as charged particles with zones of + and - charges. Standard attapulgite clays are agglomorated bundles of clay particles between 20 and 100 microns long and below 1 micron in diameter. Most grades contain up to 25% non-attapulgite material in the form of carbonates and other inclusions. Despite this, they are a beneficial ingredient of cementitious tile adhesives in competition with polyacrylates and starch ethers. The advantage of attapulgites is that their performance is not temperature sensitive and they have lower water demand. They must have free ions in an aquous system to work.
Actigel 208 is a patented exfoliated attapulgite where the clay has been chemically and mechanically purified into discrete particles 20 angstroms diameter. This material has special viscosity modification properties with high solid aqueous systems that cannot be matched with any other ingredients
# Notes
- ↑ See abstract of Arnold (2005).
- ↑ Haude (1997).
- ↑ Arnold and Bohor (1975), as cited in Haude (1997).
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7250f3f21ece078f06f9c695cd3ebd520bc03651
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wikidoc
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Pioglitazone
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Pioglitazone
# 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
Pioglitazone is a thiazolidinedione and an agonist for peroxisome proliferator-activated receptor (PPAR) gamma that is FDA approved for the {{{indicationType}}} of type 2 diabetes mellitus. There is a Black Box Warning for this drug as shown here. Common adverse reactions include upper respiratory tract infection, headache, sinusitis, myalgia, and pharyngitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Monotherapy and Combination Therapy
- ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings.
- Important Limitations of Use
- ACTOS exerts its antihyperglycemic effect only in the presence of endogenous insulin. ACTOS should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings.
- Use caution in patients with liver disease.
- Recommendations for All Patients
- ACTOS should be taken once daily and can be taken without regard to meals.
- The recommended starting dose for patients without congestive heart failure is 15 mg or 30 mg once daily.
- The recommended starting dose for patients with congestive heart failure (NYHA Class I or II) is 15 mg once daily.
- The dose can be titrated in increments of 15 mg up to a maximum of 45 mg once daily based on glycemic response as determined by HbA1c.
- After initiation of ACTOS or with dose increase, monitor patients carefully for adverse reactions related to fluid retention such as weight gain, edema, and signs and symptoms of congestive heart failure.
- Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be obtained prior to initiating ACTOS. Routine periodic monitoring of liver tests during treatment with ACTOS is not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of ACTOS or who are found to have abnormal liver tests while taking ACTOS should be managed as described under Warnings and Precautions.
- Concomitant Use with an Insulin Secretagogue or Insulin
- If hypoglycemia occurs in a patient co-administered ACTOS and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.
- If hypoglycemia occurs in a patient co-administered ACTOS and insulin, the dose of insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose should be individualized based on glycemic response.
- Concomitant Use with Strong CYP2C8 Inhibitors
- Coadministration of ACTOS and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of ACTOS is 15 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pioglitazone in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Pioglitazone 15 mg/day was increased to 30 mg/day after 2 weeks and to 45 mg/day after another 2 weeks.
- Dosing Information
- Pioglitazone (45 mg/day).
- Dosing Information
- Pioglitazone 15 mg.
- Dosing Information
- Pioglitazone 45 mg/day.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Pioglitazone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pioglitazone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pioglitazone in pediatric patients.
# Contraindications
- Initiation in patients with established NYHA Class III or IV heart failure.
- Use in patients with known hypersensitivity to pioglitazone or any other component of ACTOS.
# Warnings
### Precautions
- Congestive Heart Failure
- ACTOS, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when ACTOS is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Patients should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of ACTOS must be considered.
- Hypoglycemia
- Patients receiving ACTOS in combination with insulin or other antidiabetic medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for hypoglycemia. A reduction in the dose of the concomitant antidiabetic medication may be necessary to reduce the risk of hypoglycemia.
- Hepatic Effects
- There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking ACTOS, although the reports contain insufficient information necessary to establish the probable cause. There has been no evidence of drug-induced hepatotoxicity in the ACTOS controlled clinical trial database to date.
- Patients with type 2 diabetes may have fatty liver disease or cardiac disease with episodic congestive heart failure, both of which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel (serum alanine aminotransferase , aspartate aminotransferase , alkaline phosphatase, and total bilirubin) and assessing the patient is recommended before initiating ACTOS therapy. In patients with abnormal liver tests, ACTOS should be initiated with caution.
- Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (ALT greater than 3 times the upper limit of the reference range), ACTOS treatment should be interrupted and investigation done to establish the probable cause. ACTOS should not be restarted in these patients without another explanation for the liver test abnormalities.
- Patients who have serum ALT greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies are at risk for severe drug-induced liver injury, and should not be restarted on ACTOS. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with ACTOS can be used with caution.
- Urinary Bladder Tumors
- Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study. In two 3-year trials in which ACTOS was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking ACTOS compared to 5/3679 (0.14%) in patients not taking ACTOS. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on ACTOS and two (0.05%) cases on placebo.
- A five-year interim report of an ongoing 10-year observational cohort study found a non-significant increase in the risk for bladder cancer in subjects ever exposed to ACTOS, compared to subjects never exposed to ACTOS (HR 1.2 ). Compared to never exposure, a duration of ACTOS therapy longer than 12 months was associated with an increase in risk (HR 1.4 ), which reached statistical significance after more than 24 months of ACTOS use (HR 1.4 ). Interim results from this study suggested that taking ACTOS longer than 12 months increased the relative risk of developing bladder cancer in any given year by 40% which equates to an absolute increase of three cases in 10,000 (from approximately seven in 10,000 to approximately 10 in 10,000 ).
- There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. Consequently, ACTOS should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with ACTOS should be considered in patients with a prior history of bladder cancer.
- Edema
- In controlled clinical trials, edema was reported more frequently in patients treated with ACTOS than in placebo-treated patients and is dose-related. In postmarketing experience, reports of new onset or worsening edema have been received.
- ACTOS should be used with caution in patients with edema. Because thiazolidinediones, including ACTOS, can cause fluid retention, which can exacerbate or lead to congestive heart failure, ACTOS should be used with caution in patients at risk for congestive heart failure. Patients treated with ACTOS should be monitored for signs and symptoms of congestive heart failure.
- Fractures
- In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to ACTOS (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for ACTOS versus 2.5% (23/905) for placebo. This difference was noted after the first year of treatment and persisted during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. No increase in the incidence of fracture was observed in men treated with ACTOS (1.7%) versus placebo (2.1%). The risk of fracture should be considered in the care of patients, especially female patients, treated with ACTOS and attention should be given to assessing and maintaining bone health according to current standards of care.
- Macular Edema
- Macular edema has been reported in postmarketing experience in diabetic patients who were taking ACTOS or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but others were diagnosed on routine ophthalmologic examination.
- Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of the thiazolidinedione.
- Patients with diabetes should have regular eye exams by an ophthalmologist according to current standards of care. Patients with diabetes who report any visual symptoms should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings.
- Ovulation
- Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. This effect has not been investigated in clinical trials, so the frequency of this occurrence is not known. Adequate contraception in all premenopausal women treated with ACTOS is recommended.
- Macrovascular Outcomes
- There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ACTOS or any other antidiabetic drug.
# 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.
- Over 8500 patients with type 2 diabetes have been treated with ACTOS in randomized, double-blind, controlled clinical trials, including 2605 patients with type 2 diabetes and macrovascular disease treated with ACTOS in the PROactive clinical trial. In these trials, over 6000 patients have been treated with ACTOS for six months or longer, over 4500 patients have been treated with ACTOS for one year or longer, and over 3000 patients have been treated with ACTOS for at least two years.
- In six pooled 16- to 26-week placebo-controlled monotherapy and 16- to 24-week add-on combination therapy trials, the incidence of withdrawals due to adverse events was 4.5% for patients treated with ACTOS and 5.8% for comparator-treated patients. The most common adverse events leading to withdrawal were related to inadequate glycemic control, although the incidence of these events was lower (1.5%) with ACTOS than with placebo (3.0%).
- In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% for patients treated with ACTOS and 7.7% for placebo-treated patients. Congestive heart failure was the most common serious adverse event leading to withdrawal occurring in 1.3% of patients treated with ACTOS and 0.6% of patients treated with placebo.
- Common Adverse Events: 16- to 26-Week Monotherapy Trials
- A summary of the incidence and type of common adverse events reported in three pooled 16- to 26-week placebo-controlled monotherapy trials of ACTOS is provided in Table 1. Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with ACTOS than in patients who received placebo. None of these adverse events were related to ACTOS dose.
- Common Adverse Events: 16- to 24-Week Add-on Combination Therapy Trials
- A summary of the overall incidence and types of common adverse events reported in trials of ACTOS add-on to sulfonylurea is provided in Table 2. Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of ACTOS.
- A summary of the overall incidence and types of common adverse events reported in trials of ACTOS add-on to metformin is provided in Table 3. Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of ACTOS.
- Table 4 summarizes the incidence and types of common adverse events reported in trials of ACTOS add-on to insulin. Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of ACTOS.
- A summary of the overall incidence and types of common adverse events reported in the PROactive trial is provided in Table 5. Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with ACTOS than in patients who received placebo.
- Congestive Heart Failure
- A summary of the incidence of adverse events related to congestive heart failure is provided in Table 6 for the 16- to 24-week add-on to sulfonylurea trials, for the 16- to 24-week add-on to insulin trials, and for the 16- to 24-week add-on to metformin trials. None of the events were fatal.
- Patients with type 2 diabetes and NYHA class II or early class III congestive heart failure were randomized to receive 24 weeks of double-blind treatment with either ACTOS at daily doses of 30 mg to 45 mg (n=262) or glyburide at daily doses of 10 mg to 15 mg (n=256). A summary of the incidence of adverse events related to congestive heart failure reported in this study is provided in Table 7.
- Congestive heart failure events leading to hospitalization that occurred during the PROactive trial are summarized in Table 8.
- Cardiovascular Safety
- In the PROactive trial, 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to ACTOS (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. Almost all patients (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, nitrates, diuretics, aspirin, statins and fibrates). At baseline, patients had a mean age of 62 years, mean duration of diabetes of 9.5 years, and mean HbA1c of 8.1%. Mean duration of follow-up was 34.5 months.
- The primary objective of this trial was to examine the effect of ACTOS on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events. The primary efficacy variable was the time to the first occurrence of any event in a cardiovascular composite endpoint that included all-cause mortality, nonfatal myocardial infarction (MI) including silent MI, stroke, acute coronary syndrome, cardiac intervention including coronary artery bypass grafting or percutaneous intervention, major leg amputation above the ankle, and bypass surgery or revascularization in the leg. A total of 514 (19.7%) patients treated with ACTOS and 572 (21.7%) placebo-treated patients experienced at least one event from the primary composite endpoint (hazard ratio 0.90; 95% Confidence Interval: 0.80, 1.02; p=0.10).
- Although there was no statistically significant difference between ACTOS and placebo for the three-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with ACTOS. The number of first occurrences and total individual events contributing to the primary composite endpoint is shown in Table 9.
- Weight Gain
- Dose-related weight gain occurs when ACTOS is used alone or in combination with other antidiabetic medications. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.
- Tables 10 and 11 summarize the changes in body weight with ACTOS and placebo in the 16- to 26-week randomized, double-blind monotherapy and 16- to 24-week combination add-on therapy trials and in the PROactive trial.
- Edema
- Edema induced from taking ACTOS is reversible when ACTOS is discontinued. The edema usually does not require hospitalization unless there is coexisting congestive heart failure. A summary of the frequency and types of edema adverse events occurring in clinical investigations of ACTOS is provided in Table 12.
- Hepatic Effects
- There has been no evidence of induced hepatotoxicity with ACTOS in the ACTOS controlled clinical trial database to date. One randomized, double-blind 3-year trial comparing ACTOS to glyburide as add-on to metformin and insulin therapy was specifically designed to evaluate the incidence of serum ALT elevation to greater than three times the upper limit of the reference range, measured every eight weeks for the first 48 weeks of the trial then every 12 weeks thereafter. A total of 3/1051 (0.3%) patients treated with ACTOS and 9/1046 (0.9%) patients treated with glyburide developed ALT values greater than three times the upper limit of the reference range. None of the patients treated with ACTOS in the ACTOS controlled clinical trial database to date have had a serum ALT greater than three times the upper limit of the reference range and a corresponding total bilirubin greater than two times the upper limit of the reference range, a combination predictive of the potential for severe drug-induced liver injury.
- Hypoglycemia
- In the ACTOS clinical trials, adverse events of hypoglycemia were reported based on clinical judgment of the investigators and did not require confirmation with fingerstick glucose testing.
- In the 16-week add-on to sulfonylurea trial, the incidence of reported hypoglycemia was 3.7% with ACTOS 30 mg and 0.5% with placebo. In the 16-week add-on to insulin trial, the incidence of reported hypoglycemia was 7.9% with ACTOS 15 mg, 15.4% with ACTOS 30 mg, and 4.8% with placebo.
- The incidence of reported hypoglycemia was higher with ACTOS 45 mg compared to ACTOS 30 mg in both the 24-week add-on to sulfonylurea trial (15.7% vs. 13.4%) and in the 24-week add-on to insulin trial (47.8% vs. 43.5%).
- Three patients in these four trials were hospitalized due to hypoglycemia. All three patients were receiving ACTOS 30 mg (0.9%) in the 24-week add-on to insulin trial. An additional 14 patients reported severe hypoglycemia (defined as causing considerable interference with patient's usual activities) that did not require hospitalization. These patients were receiving ACTOS 45 mg in combination with sulfonylurea (n=2) or ACTOS 30 mg or 45 mg in combination with insulin (n=12).
- Urinary Bladder Tumors
- Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study. In two 3-year trials in which ACTOS was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking ACTOS compared to 5/3679 (0.14%) in patients not taking ACTOS. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on ACTOS and two (0.05%) cases on placebo. There are too few events of bladder cancer to establish causality.
- Laboratory Abnormalities
- Hematologic Effects
- ACTOS may cause decreases in hemoglobin and hematocrit. In placebo-controlled monotherapy trials, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS compared with a mean change in hemoglobin of -1% to +1% in placebo-treated patients. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume associated with ACTOS therapy and are not likely to be associated with any clinically significant hematologic effects.
- Creatine Phosphokinase
- During protocol-specified measurement of serum creatine phosphokinase (CPK) in ACTOS clinical trials, an isolated elevation in CPK to greater than 10 times the upper limit of the reference range was noted in nine (0.2%) patients treated with ACTOS (values of 2150 to 11400 IU/L) and in no comparator-treated patients. Six of these nine patients continued to receive ACTOS, two patients were noted to have the CPK elevation on the last day of dosing and one patient discontinued ACTOS due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to ACTOS therapy is unknown.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of ACTOS. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- New onset or worsening diabetic macular edema with decreased visual acuity.
- Fatal and nonfatal hepatic failure.
- Postmarketing reports of congestive heart failure have been reported in patients treated with ACTOS, both with and without previously known heart disease and both with and without concomitant insulin administration.
- In postmarketing experience, there have been reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure.
# Drug Interactions
- Strong CYP2C8 Inhibitors
- An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the serum concentration-time curve or AUC) and half-life (t1/2) of pioglitazone. Therefore, the maximum recommended dose of ACTOS is 15 mg daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors.
- CYP2C8 Inducers
- An inducer of CYP2C8 (e.g., rifampin) may significantly decrease the exposure (AUC) of pioglitazone. Therefore, if an inducer of CYP2C8 is started or stopped during treatment with ACTOS, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dose of 45 mg for ACTOS.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies of ACTOS in pregnant women. Animal studies show increased rates of post-implantation loss, delayed development, reduced fetal weights, and delayed parturition at doses 10 to 40 times the maximum recommended human dose. ACTOS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Clinical Considerations
- Abnormal blood glucose concentrations during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality. Most experts recommend the use of insulin during pregnancy to maintain blood glucose concentrations as close to normal as possible for patients with diabetes.
- Animal Data
- In animal reproductive studies, pregnant rats and rabbits received pioglitazone at doses up to approximately 17 (rat) and 40 (rabbit) times the maximum recommended human oral dose (MRHD) based on body surface area (mg/m2); no teratogenicity was observed. Increases in embryotoxicity (increased postimplantation losses, delayed development, reduced fetal weights, and delayed parturition) occurred in rats that received oral doses approximately 10 or more times the MRHD (mg/m2 basis). No functional or behavioral toxicity was observed in rat offspring. When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in rat offspring at oral maternal doses approximately two or more times the MRHD (mg/m2 basis). In rabbits, embryotoxicity occurred at oral doses approximately 40 times the MRHD (mg/m2 basis).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pioglitazone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pioglitazone during labor and delivery.
### Nursing Mothers
- It is not known whether ACTOS is secreted in human milk. Pioglitazone is secreted in the milk of lactating rats. Because many drugs are excreted in human milk, and because of the potential for ACTOS to cause serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or discontinue ACTOS, taking into account the importance of ACTOS to the mother.
### Pediatric Use
- Safety and effectiveness of ACTOS in pediatric patients have not been established.
- ACTOS is not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures, and urinary bladder tumors.
### Geriatic Use
- A total of 92 patients (15.2%) treated with ACTOS in the three pooled 16- to 26-week double-blind, placebo-controlled, monotherapy trials were ≥65 years old and two patients (0.3%) were ≥75 years old. In the two pooled 16- to 24-week add-on to sulfonylurea trials, 201 patients (18.7%) treated with ACTOS were ≥65 years old and 19 (1.8%) were ≥75 years old. In the two pooled 16- to 24-week add-on to metformin trials, 155 patients (15.5%) treated with ACTOS were ≥65 years old and 19 (1.9%) were ≥75 years old. In the two pooled 16- to 24-week add-on to insulin trials, 272 patients (25.4%) treated with ACTOS were ≥65 years old and 22 (2.1%) were ≥75 years old.
- In PROactive, 1068 patients (41.0%) treated with ACTOS were ≥65 years old and 42 (1.6%) were ≥75 years old.
- In pharmacokinetic studies with pioglitazone, no significant differences were observed in pharmacokinetic parameters between elderly and younger patients.
- Although clinical experiences have not identified differences in effectiveness and safety between the elderly (≥65 years) and younger patients, these conclusions are limited by small sample sizes for patients ≥75 years old.
### Gender
There is no FDA guidance on the use of Pioglitazone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pioglitazone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pioglitazone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pioglitazone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pioglitazone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pioglitazone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- After initiation of ACTOS, and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema). If heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of ACTOS must be considered.
# IV Compatibility
There is limited information regarding IV Compatibility of Pioglitazone in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- During controlled clinical trials, one case of overdose with ACTOS was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period.
### Management
- In the event of overdosage, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Pioglitazone in the drug label.
# Pharmacology
## Mechanism of Action
- ACTOS is a thiazolidinedione that depends on the presence of insulin for its mechanism of action. ACTOS decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.
- In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.
- Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.
## Structure
- ACTOS tablets are a thiazolidinedione and an agonist for peroxisome proliferator-activated receptor (PPAR) gamma that contains an oral antidiabetic medication: pioglitazone.
- Pioglitazone phenyl] methyl]-2,4-] thiazolidinedione monohydrochloride contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the pharmacologic activity between the two enantiomers. The structural formula is as shown:
- Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of C19H20N2O3SHCl and a molecular weight of 392.90 daltons. It is soluble in N,N-dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether.
- ACTOS is available as a tablet for oral administration containing 15 mg, 30 mg, or 45 mg of pioglitazone (as the base) formulated with the following excipients: lactose monohydrate NF, hydroxypropylcellulose NF, carboxymethylcellulose calcium NF, and magnesium stearate NF.
## Pharmacodynamics
- Clinical studies demonstrate that ACTOS improves insulin sensitivity in insulin-resistant patients. ACTOS enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal and improves hepatic sensitivity to insulin. In patients with type 2 diabetes, the decreased insulin resistance produced by ACTOS results in lower plasma glucose concentrations, lower plasma insulin concentrations, and lower HbA1c values. In controlled clinical trials, ACTOS had an additive effect on glycemic control when used in combination with a sulfonylurea, metformin, or insulin.
- Patients with lipid abnormalities were included in clinical trials with ACTOS. Overall, patients treated with ACTOS had mean decreases in serum triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. There is no conclusive evidence of macrovascular benefit with ACTOS or any other antidiabetic medication.
- In a 26-week, placebo-controlled, dose-ranging monotherapy study, mean serum triglycerides decreased in the 15 mg, 30 mg, and 45 mg ACTOS dose groups compared to a mean increase in the placebo group. Mean HDL cholesterol increased to a greater extent in patients treated with ACTOS than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with ACTOS compared to placebo (see Table 14).
- In the two other monotherapy studies (16 weeks and 24 weeks) and in combination therapy studies with sulfonylurea (16 weeks and 24 weeks), metformin (16 weeks and 24 weeks) or insulin (16 weeks and 24 weeks), the results were generally consistent with the data above.
## Pharmacokinetics
- Following once-daily administration of ACTOS, steady-state serum concentrations of both pioglitazone and its major active metabolites, M-III (keto derivative of pioglitazone) and M-IV (hydroxyl derivative of pioglitazone), are achieved within seven days. At steady-state, M-III and M-IV reach serum concentrations equal to or greater than that of pioglitazone. At steady-state, in both healthy volunteers and patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the peak total pioglitazone serum concentrations (pioglitazone plus active metabolites) and 20% to 25% of the total AUC.
- Cmax, AUC, and trough serum concentrations (Cmin) for pioglitazone and M-III and M-IV, increased proportionally with administered doses of 15 mg and 30 mg per day.
- Absorption
- Following oral administration of pioglitazone, Tmax of pioglitazone was within two hours. Food delays the Tmax to three to four hours but does not alter the extent of absorption (AUC).
- Distribution
- The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 ± 0.41 (mean ± SD) L/kg of body weight. Pioglitazone is extensively protein bound (>99%) in human serum, principally to serum albumin. Pioglitazone also binds to other serum proteins, but with lower affinity. M-III and M-IV are also extensively bound (>98%) to serum albumin.
- Metabolism
- Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-III and M-IV are the major circulating active metabolites in humans.
- In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone, which include CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo study of pioglitazone in combination with gemfibrozil, a strong CYP2C8 inhibitor, showed that pioglitazone is a CYP2C8 substrate. Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with ACTOS showed that pioglitazone is not a strong CYP3A4 enzyme inducer.
- Excretion and Elimination
- Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.
- The mean serum half-life (t1/2) of pioglitazone and its metabolites (M-III and M-IV) range from three to seven hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be five to seven L/hr.
- Renal Impairment
- The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 50 mL/min) and severe (CLcr <30 mL/min) renal impairment when compared to subjects with normal renal function. Therefore, no dose adjustment in patients with renal impairment is required.
- Hepatic Impairment
- Compared with healthy controls, subjects with impaired hepatic function (Child-Turcotte-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone (pioglitazone, M-III, and M-IV) mean Cmax but no change in the mean AUC values. Therefore, no dose adjustment in patients with hepatic impairment is required.
- There are postmarketing reports of liver failure with ACTOS and clinical trials have generally excluded patients with serum ALT >2.5 times the upper limit of the reference range. Use caution in patients with liver disease.
- Geriatric Patients
- In healthy elderly subjects, Cmax of pioglitazone was not significantly different, but AUC values were approximately 21% higher than those achieved in younger subjects. The mean t1/2 of pioglitazone was also prolonged in elderly subjects (about ten hours) as compared to younger subjects (about seven hours). These changes were not of a magnitude that would be considered clinically relevant.
- Pediatric Patients
- Safety and efficacy of pioglitazone in pediatric patients have not been established. ACTOS is not recommended for use in pediatric patients.
- Gender
- The mean Cmax and AUC values of pioglitazone were increased 20% to 60% in women compared to men. In controlled clinical trials, HbA1c decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0.5%). Because therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone.
- Ethnicity
- Pharmacokinetic data among various ethnic groups are not available.
- Drug-Drug Interactions
## Nonclinical Toxicology
- A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m2). Drug-induced tumors were not observed in any organ except for the urinary bladder of male rats. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m2). Urinary calculi with subsequent irritation and hyperplasia were postulated as the mechanism for bladder tumors observed in male rats. A two-year mechanistic study in male rats utilizing dietary acidification to reduce calculi formation was completed in 2009. Dietary acidification decreased but did not abolish the hyperplastic changes in the bladder. The presence of calculi exacerbated the hyperplastic response to pioglitazone but was not considered the primary cause of the hyperplastic changes.
- The relevance to humans of the bladder findings in the male rat cannot be excluded.
- A two-year carcinogenicity study was also conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m2). No drug-induced tumors were observed in any organ.
- Pioglitazone hydrochloride was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay.
- No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone hydrochloride daily prior to and throughout mating and gestation (approximately nine times the maximum recommended human oral dose based on mg/m2).
- Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone hydrochloride (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respectively, based on mg/m2). In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m2). Heart enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg and above (approximately four times the maximum recommended human oral dose based on mg/m2), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m2).
# Clinical Studies
- Monotherapy
- Three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of ACTOS as monotherapy in patients with type 2 diabetes. These trials examined ACTOS at doses up to 45 mg or placebo once daily in a total of 865 patients.
- In a 26-week dose-ranging monotherapy trial, 408 patients with type 2 diabetes were randomized to receive 7.5 mg, 15 mg, 30 mg, or 45 mg of ACTOS, or placebo once daily. Therapy with any previous antidiabetic agent was discontinued eight weeks prior to the double-blind period. Treatment with 15 mg, 30 mg, and 45 mg of ACTOS produced statistically significant improvements in HbA1c and fasting plasma glucose (FPG) at endpoint compared to placebo (see Figure 1, Table 17).
- Figure 1 shows the time course for changes in HbA1c in this 26-week study.
- In a 24-week placebo-controlled monotherapy trial, 260 patients with type 2 diabetes were randomized to one of two forced-titration ACTOS treatment groups or a mock-titration placebo group. Therapy with any previous antidiabetic agent was discontinued six weeks prior to the double-blind period. In one ACTOS treatment group, patients received an initial dose of 7.5 mg once daily. After four weeks, the dose was increased to 15 mg once daily and after another four weeks, the dose was increased to 30 mg once daily for the remainder of the trial (16 weeks). In the second ACTOS treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner. Treatment with ACTOS, as described, produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (see Table 18).
- In a 16-week monotherapy trial, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of ACTOS or placebo once daily. Therapy with any previous antidiabetic agent was discontinued six weeks prior to the double-blind period. Treatment with 30 mg of ACTOS produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (see Table 19).
- Combination Therapy
- Three 16-week, randomized, double-blind, placebo-controlled clinical trials were conducted to evaluate the effects of ACTOS (15 mg and/or 30 mg) on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c ≥8%) despite current therapy with a sulfonylurea, metformin, or insulin. In addition, three 24-week randomized, double-blind clinical trials were conducted to evaluate the effects of ACTOS 30 mg vs. ACTOS 45 mg on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c ≥8%) despite current therapy with a sulfonylurea, metformin, or insulin. Previous diabetes treatment may have been monotherapy or combination therapy.
- Add-on to Sulfonylurea Trials
- Two clinical trials were conducted with ACTOS in combination with a sulfonylurea. Both studies included patients with type 2 diabetes on any dose of a sulfonylurea, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn at least three weeks prior to starting study treatment.
- In the first study, 560 patients were randomized to receive 15 mg or 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their current sulfonylurea regimen. Treatment with ACTOS as add-on to sulfonylurea produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo add-on to sulfonylurea (see Table 20).
- In the second trial, 702 patients were randomized to receive 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current sulfonylurea regimen. The mean reduction from baseline at Week 24 in HbA1c was 1.6% for the 30 mg dose and 1.7% for the 45 mg dose (see Table 21). The mean reduction from baseline at Week 24 in FPG was 52 mg/dL for the 30 mg dose and 56 mg/dL for the 45 mg dose.
- The therapeutic effect of ACTOS in combination with sulfonylurea was observed in patients regardless of the sulfonylurea dose.
- Add-on to Metformin Trials
- Two clinical trials were conducted with ACTOS in combination with metformin. Both trials included patients with type 2 diabetes on any dose of metformin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn at least three weeks prior to starting study treatment.
- In the first trial, 328 patients were randomized to receive either 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their current metformin regimen. Treatment with ACTOS as add-on to metformin produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo add-on to metformin (see Table 22).
- In the second trial, 827 patients were randomized to receive either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current metformin regimen. The mean reduction from baseline at Week 24 in HbA1c was 0.8% for the 30 mg dose and 1.0% for the 45 mg dose (see Table 23). The mean reduction from baseline at Week 24 in FPG was 38 mg/dL for the 30 mg dose and 51 mg/dL for the 45 mg dose.
- The therapeutic effect of ACTOS in combination with metformin was observed in patients regardless of the metformin dose.
- Add-on to Insulin Trials
- Two clinical trials were conducted with ACTOS in combination with insulin. Both trials included patients with type 2 diabetes on insulin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first trial, 566 patients were randomized to receive either 15 mg or 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their insulin regimen. Treatment with ACTOS as add-on to insulin produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo add-on to insulin (see Table 24). The mean daily insulin dose at baseline in each treatment group was approximately 70 units. The majority of patients (75% overall, 86% treated with placebo, 77% treated with ACTOS 15 mg, and 61% treated with ACTOS 30 mg) had no change in their daily insulin dose from baseline to the final study visit. The mean change from baseline in daily dose of insulin (including patients with no insulin dose modifications) was -3 units in the patients treated with ACTOS 15 mg, -8 units in the patients treated with ACTOS 30 mg, and -1 unit in patients treated with placebo.
- In the second trial, 690 patients receiving a median of 60 units per day of insulin were randomized to receive either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current insulin regimen. The mean reduction from baseline at Week 24 in HbA1c was 1.2% for the 30 mg dose and 1.5% for the 45 mg dose. The mean reduction from baseline at Week 24 in FPG was 32 mg/dL for the 30 mg dose and 46 mg/dL for the 45 mg dose (see Table 25). The mean daily insulin dose at baseline in both treatment groups was approximately 70 units. The majority of patients (55% overall, 58% treated with ACTOS 30 mg, and 52% treated with ACTOS 45 mg) had no change in their daily insulin dose from baseline to the final study visit. The mean change from baseline in daily dose of insulin (including patients with no insulin dose modifications) was -5 units in the patients treated with ACTOS 30 mg and -8 units in the patients treated with ACTOS 45 mg.
- The therapeutic effect of ACTOS in combination with insulin was observed in patients regardless of the insulin dose.
# How Supplied
- ACTOS is available in 15 mg, 30 mg, and 45 mg tablets as follows:
- 15 mg tablet: White to off-white, round, convex, nonscored tablet with "ACTOS" on one side, and "15" on the other, available in:
NDC 64764-151-04 Bottles of 30
NDC 64764-151-05 Bottles of 90
NDC 64764-151-06 Bottles of 500
- NDC 64764-151-04 Bottles of 30
- NDC 64764-151-05 Bottles of 90
- NDC 64764-151-06 Bottles of 500
- 30 mg tablet: White to off-white, round, flat, nonscored tablet with "ACTOS" on one side, and "30" on the other, available in:
NDC 64764-301-14 Bottles of 30
NDC 64764-301-15 Bottles of 90
NDC 64764-301-16 Bottles of 500
- NDC 64764-301-14 Bottles of 30
- NDC 64764-301-15 Bottles of 90
- NDC 64764-301-16 Bottles of 500
- 45 mg tablet: White to off-white, round, flat, nonscored tablet with "ACTOS" on one side, and "45" on the other, available in:
NDC 64764-451-24 Bottles of 30
NDC 64764-451-25 Bottles of 90
NDC 64764-451-26 Bottles of 500
- NDC 64764-451-24 Bottles of 30
- NDC 64764-451-25 Bottles of 90
- NDC 64764-451-26 Bottles of 500
- Storage
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Keep container tightly closed, and protect from light, moisture and humidity.
## Storage
There is limited information regarding Pioglitazone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly.
- Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on ACTOS should immediately report these symptoms to a physician.
- Tell patients to promptly stop taking ACTOS and seek immediate medical advice if there is unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine as these symptoms may be due to hepatotoxicity.
- Tell patients to promptly report any sign of macroscopic hematuria or other symptoms such as dysuria or urinary urgency that develop or increase during treatment as these may be due to bladder cancer.
- Tell patients to take ACTOS once daily. ACTOS can be taken with or without meals. If a dose is missed on one day, the dose should not be doubled the following day.
- When using combination therapy with insulin or other antidiabetic medications, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members.
- Inform patients that therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Therefore, adequate contraception should be recommended for all premenopausal women who are prescribed ACTOS.
# Precautions with Alcohol
- Alcohol-Pioglitazone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Actos®
# Look-Alike Drug Names
- Actos® — Actonel®
# Drug Shortage Status
# Price
|
Pioglitazone
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
Pioglitazone is a thiazolidinedione and an agonist for peroxisome proliferator-activated receptor (PPAR) gamma that is FDA approved for the {{{indicationType}}} of type 2 diabetes mellitus. There is a Black Box Warning for this drug as shown here. Common adverse reactions include upper respiratory tract infection, headache, sinusitis, myalgia, and pharyngitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Monotherapy and Combination Therapy
- ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings.
- Important Limitations of Use
- ACTOS exerts its antihyperglycemic effect only in the presence of endogenous insulin. ACTOS should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings.
- Use caution in patients with liver disease.
- Recommendations for All Patients
- ACTOS should be taken once daily and can be taken without regard to meals.
- The recommended starting dose for patients without congestive heart failure is 15 mg or 30 mg once daily.
- The recommended starting dose for patients with congestive heart failure (NYHA Class I or II) is 15 mg once daily.
- The dose can be titrated in increments of 15 mg up to a maximum of 45 mg once daily based on glycemic response as determined by HbA1c.
- After initiation of ACTOS or with dose increase, monitor patients carefully for adverse reactions related to fluid retention such as weight gain, edema, and signs and symptoms of congestive heart failure.
- Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be obtained prior to initiating ACTOS. Routine periodic monitoring of liver tests during treatment with ACTOS is not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of ACTOS or who are found to have abnormal liver tests while taking ACTOS should be managed as described under Warnings and Precautions.
- Concomitant Use with an Insulin Secretagogue or Insulin
- If hypoglycemia occurs in a patient co-administered ACTOS and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.
- If hypoglycemia occurs in a patient co-administered ACTOS and insulin, the dose of insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose should be individualized based on glycemic response.
- Concomitant Use with Strong CYP2C8 Inhibitors
- Coadministration of ACTOS and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of ACTOS is 15 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pioglitazone in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Pioglitazone 15 mg/day was increased to 30 mg/day after 2 weeks and to 45 mg/day after another 2 weeks.
- Dosing Information
- Pioglitazone (45 mg/day).[1]
- Dosing Information
- Pioglitazone 15 mg.
- Dosing Information
- Pioglitazone 45 mg/day.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Pioglitazone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pioglitazone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pioglitazone in pediatric patients.
# Contraindications
- Initiation in patients with established NYHA Class III or IV heart failure.
- Use in patients with known hypersensitivity to pioglitazone or any other component of ACTOS.
# Warnings
### Precautions
- Congestive Heart Failure
- ACTOS, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when ACTOS is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Patients should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of ACTOS must be considered.
- Hypoglycemia
- Patients receiving ACTOS in combination with insulin or other antidiabetic medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for hypoglycemia. A reduction in the dose of the concomitant antidiabetic medication may be necessary to reduce the risk of hypoglycemia.
- Hepatic Effects
- There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking ACTOS, although the reports contain insufficient information necessary to establish the probable cause. There has been no evidence of drug-induced hepatotoxicity in the ACTOS controlled clinical trial database to date.
- Patients with type 2 diabetes may have fatty liver disease or cardiac disease with episodic congestive heart failure, both of which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) and assessing the patient is recommended before initiating ACTOS therapy. In patients with abnormal liver tests, ACTOS should be initiated with caution.
- Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (ALT greater than 3 times the upper limit of the reference range), ACTOS treatment should be interrupted and investigation done to establish the probable cause. ACTOS should not be restarted in these patients without another explanation for the liver test abnormalities.
- Patients who have serum ALT greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies are at risk for severe drug-induced liver injury, and should not be restarted on ACTOS. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with ACTOS can be used with caution.
- Urinary Bladder Tumors
- Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study. In two 3-year trials in which ACTOS was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking ACTOS compared to 5/3679 (0.14%) in patients not taking ACTOS. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on ACTOS and two (0.05%) cases on placebo.
- A five-year interim report of an ongoing 10-year observational cohort study found a non-significant increase in the risk for bladder cancer in subjects ever exposed to ACTOS, compared to subjects never exposed to ACTOS (HR 1.2 [95% CI 0.9 –1.5]). Compared to never exposure, a duration of ACTOS therapy longer than 12 months was associated with an increase in risk (HR 1.4 [95% CI 0.9 –2.1]), which reached statistical significance after more than 24 months of ACTOS use (HR 1.4 [95% CI 1.03 –2.0]). Interim results from this study suggested that taking ACTOS longer than 12 months increased the relative risk of developing bladder cancer in any given year by 40% which equates to an absolute increase of three cases in 10,000 (from approximately seven in 10,000 [without ACTOS] to approximately 10 in 10,000 [with ACTOS]).
- There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. Consequently, ACTOS should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with ACTOS should be considered in patients with a prior history of bladder cancer.
- Edema
- In controlled clinical trials, edema was reported more frequently in patients treated with ACTOS than in placebo-treated patients and is dose-related. In postmarketing experience, reports of new onset or worsening edema have been received.
- ACTOS should be used with caution in patients with edema. Because thiazolidinediones, including ACTOS, can cause fluid retention, which can exacerbate or lead to congestive heart failure, ACTOS should be used with caution in patients at risk for congestive heart failure. Patients treated with ACTOS should be monitored for signs and symptoms of congestive heart failure.
- Fractures
- In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to ACTOS (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for ACTOS versus 2.5% (23/905) for placebo. This difference was noted after the first year of treatment and persisted during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. No increase in the incidence of fracture was observed in men treated with ACTOS (1.7%) versus placebo (2.1%). The risk of fracture should be considered in the care of patients, especially female patients, treated with ACTOS and attention should be given to assessing and maintaining bone health according to current standards of care.
- Macular Edema
- Macular edema has been reported in postmarketing experience in diabetic patients who were taking ACTOS or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but others were diagnosed on routine ophthalmologic examination.
- Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of the thiazolidinedione.
- Patients with diabetes should have regular eye exams by an ophthalmologist according to current standards of care. Patients with diabetes who report any visual symptoms should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings.
- Ovulation
- Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. This effect has not been investigated in clinical trials, so the frequency of this occurrence is not known. Adequate contraception in all premenopausal women treated with ACTOS is recommended.
- Macrovascular Outcomes
- There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ACTOS or any other antidiabetic drug.
# 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.
- Over 8500 patients with type 2 diabetes have been treated with ACTOS in randomized, double-blind, controlled clinical trials, including 2605 patients with type 2 diabetes and macrovascular disease treated with ACTOS in the PROactive clinical trial. In these trials, over 6000 patients have been treated with ACTOS for six months or longer, over 4500 patients have been treated with ACTOS for one year or longer, and over 3000 patients have been treated with ACTOS for at least two years.
- In six pooled 16- to 26-week placebo-controlled monotherapy and 16- to 24-week add-on combination therapy trials, the incidence of withdrawals due to adverse events was 4.5% for patients treated with ACTOS and 5.8% for comparator-treated patients. The most common adverse events leading to withdrawal were related to inadequate glycemic control, although the incidence of these events was lower (1.5%) with ACTOS than with placebo (3.0%).
- In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% for patients treated with ACTOS and 7.7% for placebo-treated patients. Congestive heart failure was the most common serious adverse event leading to withdrawal occurring in 1.3% of patients treated with ACTOS and 0.6% of patients treated with placebo.
- Common Adverse Events: 16- to 26-Week Monotherapy Trials
- A summary of the incidence and type of common adverse events reported in three pooled 16- to 26-week placebo-controlled monotherapy trials of ACTOS is provided in Table 1. Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with ACTOS than in patients who received placebo. None of these adverse events were related to ACTOS dose.
- Common Adverse Events: 16- to 24-Week Add-on Combination Therapy Trials
- A summary of the overall incidence and types of common adverse events reported in trials of ACTOS add-on to sulfonylurea is provided in Table 2. Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of ACTOS.
- A summary of the overall incidence and types of common adverse events reported in trials of ACTOS add-on to metformin is provided in Table 3. Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of ACTOS.
- Table 4 summarizes the incidence and types of common adverse events reported in trials of ACTOS add-on to insulin. Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of ACTOS.
- A summary of the overall incidence and types of common adverse events reported in the PROactive trial is provided in Table 5. Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with ACTOS than in patients who received placebo.
- Congestive Heart Failure
- A summary of the incidence of adverse events related to congestive heart failure is provided in Table 6 for the 16- to 24-week add-on to sulfonylurea trials, for the 16- to 24-week add-on to insulin trials, and for the 16- to 24-week add-on to metformin trials. None of the events were fatal.
- Patients with type 2 diabetes and NYHA class II or early class III congestive heart failure were randomized to receive 24 weeks of double-blind treatment with either ACTOS at daily doses of 30 mg to 45 mg (n=262) or glyburide at daily doses of 10 mg to 15 mg (n=256). A summary of the incidence of adverse events related to congestive heart failure reported in this study is provided in Table 7.
- Congestive heart failure events leading to hospitalization that occurred during the PROactive trial are summarized in Table 8.
- Cardiovascular Safety
- In the PROactive trial, 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to ACTOS (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. Almost all patients (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, nitrates, diuretics, aspirin, statins and fibrates). At baseline, patients had a mean age of 62 years, mean duration of diabetes of 9.5 years, and mean HbA1c of 8.1%. Mean duration of follow-up was 34.5 months.
- The primary objective of this trial was to examine the effect of ACTOS on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events. The primary efficacy variable was the time to the first occurrence of any event in a cardiovascular composite endpoint that included all-cause mortality, nonfatal myocardial infarction (MI) including silent MI, stroke, acute coronary syndrome, cardiac intervention including coronary artery bypass grafting or percutaneous intervention, major leg amputation above the ankle, and bypass surgery or revascularization in the leg. A total of 514 (19.7%) patients treated with ACTOS and 572 (21.7%) placebo-treated patients experienced at least one event from the primary composite endpoint (hazard ratio 0.90; 95% Confidence Interval: 0.80, 1.02; p=0.10).
- Although there was no statistically significant difference between ACTOS and placebo for the three-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with ACTOS. The number of first occurrences and total individual events contributing to the primary composite endpoint is shown in Table 9.
- Weight Gain
- Dose-related weight gain occurs when ACTOS is used alone or in combination with other antidiabetic medications. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.
- Tables 10 and 11 summarize the changes in body weight with ACTOS and placebo in the 16- to 26-week randomized, double-blind monotherapy and 16- to 24-week combination add-on therapy trials and in the PROactive trial.
- Edema
- Edema induced from taking ACTOS is reversible when ACTOS is discontinued. The edema usually does not require hospitalization unless there is coexisting congestive heart failure. A summary of the frequency and types of edema adverse events occurring in clinical investigations of ACTOS is provided in Table 12.
- Hepatic Effects
- There has been no evidence of induced hepatotoxicity with ACTOS in the ACTOS controlled clinical trial database to date. One randomized, double-blind 3-year trial comparing ACTOS to glyburide as add-on to metformin and insulin therapy was specifically designed to evaluate the incidence of serum ALT elevation to greater than three times the upper limit of the reference range, measured every eight weeks for the first 48 weeks of the trial then every 12 weeks thereafter. A total of 3/1051 (0.3%) patients treated with ACTOS and 9/1046 (0.9%) patients treated with glyburide developed ALT values greater than three times the upper limit of the reference range. None of the patients treated with ACTOS in the ACTOS controlled clinical trial database to date have had a serum ALT greater than three times the upper limit of the reference range and a corresponding total bilirubin greater than two times the upper limit of the reference range, a combination predictive of the potential for severe drug-induced liver injury.
- Hypoglycemia
- In the ACTOS clinical trials, adverse events of hypoglycemia were reported based on clinical judgment of the investigators and did not require confirmation with fingerstick glucose testing.
- In the 16-week add-on to sulfonylurea trial, the incidence of reported hypoglycemia was 3.7% with ACTOS 30 mg and 0.5% with placebo. In the 16-week add-on to insulin trial, the incidence of reported hypoglycemia was 7.9% with ACTOS 15 mg, 15.4% with ACTOS 30 mg, and 4.8% with placebo.
- The incidence of reported hypoglycemia was higher with ACTOS 45 mg compared to ACTOS 30 mg in both the 24-week add-on to sulfonylurea trial (15.7% vs. 13.4%) and in the 24-week add-on to insulin trial (47.8% vs. 43.5%).
- Three patients in these four trials were hospitalized due to hypoglycemia. All three patients were receiving ACTOS 30 mg (0.9%) in the 24-week add-on to insulin trial. An additional 14 patients reported severe hypoglycemia (defined as causing considerable interference with patient's usual activities) that did not require hospitalization. These patients were receiving ACTOS 45 mg in combination with sulfonylurea (n=2) or ACTOS 30 mg or 45 mg in combination with insulin (n=12).
- Urinary Bladder Tumors
- Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study. In two 3-year trials in which ACTOS was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking ACTOS compared to 5/3679 (0.14%) in patients not taking ACTOS. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on ACTOS and two (0.05%) cases on placebo. There are too few events of bladder cancer to establish causality.
- Laboratory Abnormalities
- Hematologic Effects
- ACTOS may cause decreases in hemoglobin and hematocrit. In placebo-controlled monotherapy trials, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS compared with a mean change in hemoglobin of -1% to +1% in placebo-treated patients. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume associated with ACTOS therapy and are not likely to be associated with any clinically significant hematologic effects.
- Creatine Phosphokinase
- During protocol-specified measurement of serum creatine phosphokinase (CPK) in ACTOS clinical trials, an isolated elevation in CPK to greater than 10 times the upper limit of the reference range was noted in nine (0.2%) patients treated with ACTOS (values of 2150 to 11400 IU/L) and in no comparator-treated patients. Six of these nine patients continued to receive ACTOS, two patients were noted to have the CPK elevation on the last day of dosing and one patient discontinued ACTOS due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to ACTOS therapy is unknown.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of ACTOS. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- New onset or worsening diabetic macular edema with decreased visual acuity.
- Fatal and nonfatal hepatic failure.
- Postmarketing reports of congestive heart failure have been reported in patients treated with ACTOS, both with and without previously known heart disease and both with and without concomitant insulin administration.
- In postmarketing experience, there have been reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure.
# Drug Interactions
- Strong CYP2C8 Inhibitors
- An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the serum concentration-time curve or AUC) and half-life (t1/2) of pioglitazone. Therefore, the maximum recommended dose of ACTOS is 15 mg daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors.
- CYP2C8 Inducers
- An inducer of CYP2C8 (e.g., rifampin) may significantly decrease the exposure (AUC) of pioglitazone. Therefore, if an inducer of CYP2C8 is started or stopped during treatment with ACTOS, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dose of 45 mg for ACTOS.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies of ACTOS in pregnant women. Animal studies show increased rates of post-implantation loss, delayed development, reduced fetal weights, and delayed parturition at doses 10 to 40 times the maximum recommended human dose. ACTOS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Clinical Considerations
- Abnormal blood glucose concentrations during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality. Most experts recommend the use of insulin during pregnancy to maintain blood glucose concentrations as close to normal as possible for patients with diabetes.
- Animal Data
- In animal reproductive studies, pregnant rats and rabbits received pioglitazone at doses up to approximately 17 (rat) and 40 (rabbit) times the maximum recommended human oral dose (MRHD) based on body surface area (mg/m2); no teratogenicity was observed. Increases in embryotoxicity (increased postimplantation losses, delayed development, reduced fetal weights, and delayed parturition) occurred in rats that received oral doses approximately 10 or more times the MRHD (mg/m2 basis). No functional or behavioral toxicity was observed in rat offspring. When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in rat offspring at oral maternal doses approximately two or more times the MRHD (mg/m2 basis). In rabbits, embryotoxicity occurred at oral doses approximately 40 times the MRHD (mg/m2 basis).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pioglitazone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pioglitazone during labor and delivery.
### Nursing Mothers
- It is not known whether ACTOS is secreted in human milk. Pioglitazone is secreted in the milk of lactating rats. Because many drugs are excreted in human milk, and because of the potential for ACTOS to cause serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or discontinue ACTOS, taking into account the importance of ACTOS to the mother.
### Pediatric Use
- Safety and effectiveness of ACTOS in pediatric patients have not been established.
- ACTOS is not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures, and urinary bladder tumors.
### Geriatic Use
- A total of 92 patients (15.2%) treated with ACTOS in the three pooled 16- to 26-week double-blind, placebo-controlled, monotherapy trials were ≥65 years old and two patients (0.3%) were ≥75 years old. In the two pooled 16- to 24-week add-on to sulfonylurea trials, 201 patients (18.7%) treated with ACTOS were ≥65 years old and 19 (1.8%) were ≥75 years old. In the two pooled 16- to 24-week add-on to metformin trials, 155 patients (15.5%) treated with ACTOS were ≥65 years old and 19 (1.9%) were ≥75 years old. In the two pooled 16- to 24-week add-on to insulin trials, 272 patients (25.4%) treated with ACTOS were ≥65 years old and 22 (2.1%) were ≥75 years old.
- In PROactive, 1068 patients (41.0%) treated with ACTOS were ≥65 years old and 42 (1.6%) were ≥75 years old.
- In pharmacokinetic studies with pioglitazone, no significant differences were observed in pharmacokinetic parameters between elderly and younger patients.
- Although clinical experiences have not identified differences in effectiveness and safety between the elderly (≥65 years) and younger patients, these conclusions are limited by small sample sizes for patients ≥75 years old.
### Gender
There is no FDA guidance on the use of Pioglitazone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pioglitazone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pioglitazone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pioglitazone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pioglitazone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pioglitazone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- After initiation of ACTOS, and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema). If heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of ACTOS must be considered.
# IV Compatibility
There is limited information regarding IV Compatibility of Pioglitazone in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- During controlled clinical trials, one case of overdose with ACTOS was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period.
### Management
- In the event of overdosage, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Pioglitazone in the drug label.
# Pharmacology
## Mechanism of Action
- ACTOS is a thiazolidinedione that depends on the presence of insulin for its mechanism of action. ACTOS decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.
- In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.
- Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.
## Structure
- ACTOS tablets are a thiazolidinedione and an agonist for peroxisome proliferator-activated receptor (PPAR) gamma that contains an oral antidiabetic medication: pioglitazone.
- Pioglitazone [(±)-5-[4-[2-(5-ethyl-2-pyridinyl) ethoxy] phenyl] methyl]-2,4-] thiazolidinedione monohydrochloride contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the pharmacologic activity between the two enantiomers. The structural formula is as shown:
- Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of C19H20N2O3S•HCl and a molecular weight of 392.90 daltons. It is soluble in N,N-dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether.
- ACTOS is available as a tablet for oral administration containing 15 mg, 30 mg, or 45 mg of pioglitazone (as the base) formulated with the following excipients: lactose monohydrate NF, hydroxypropylcellulose NF, carboxymethylcellulose calcium NF, and magnesium stearate NF.
## Pharmacodynamics
- Clinical studies demonstrate that ACTOS improves insulin sensitivity in insulin-resistant patients. ACTOS enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal and improves hepatic sensitivity to insulin. In patients with type 2 diabetes, the decreased insulin resistance produced by ACTOS results in lower plasma glucose concentrations, lower plasma insulin concentrations, and lower HbA1c values. In controlled clinical trials, ACTOS had an additive effect on glycemic control when used in combination with a sulfonylurea, metformin, or insulin.
- Patients with lipid abnormalities were included in clinical trials with ACTOS. Overall, patients treated with ACTOS had mean decreases in serum triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. There is no conclusive evidence of macrovascular benefit with ACTOS or any other antidiabetic medication.
- In a 26-week, placebo-controlled, dose-ranging monotherapy study, mean serum triglycerides decreased in the 15 mg, 30 mg, and 45 mg ACTOS dose groups compared to a mean increase in the placebo group. Mean HDL cholesterol increased to a greater extent in patients treated with ACTOS than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with ACTOS compared to placebo (see Table 14).
- In the two other monotherapy studies (16 weeks and 24 weeks) and in combination therapy studies with sulfonylurea (16 weeks and 24 weeks), metformin (16 weeks and 24 weeks) or insulin (16 weeks and 24 weeks), the results were generally consistent with the data above.
## Pharmacokinetics
- Following once-daily administration of ACTOS, steady-state serum concentrations of both pioglitazone and its major active metabolites, M-III (keto derivative of pioglitazone) and M-IV (hydroxyl derivative of pioglitazone), are achieved within seven days. At steady-state, M-III and M-IV reach serum concentrations equal to or greater than that of pioglitazone. At steady-state, in both healthy volunteers and patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the peak total pioglitazone serum concentrations (pioglitazone plus active metabolites) and 20% to 25% of the total AUC.
- Cmax, AUC, and trough serum concentrations (Cmin) for pioglitazone and M-III and M-IV, increased proportionally with administered doses of 15 mg and 30 mg per day.
- Absorption
- Following oral administration of pioglitazone, Tmax of pioglitazone was within two hours. Food delays the Tmax to three to four hours but does not alter the extent of absorption (AUC).
- Distribution
- The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 ± 0.41 (mean ± SD) L/kg of body weight. Pioglitazone is extensively protein bound (>99%) in human serum, principally to serum albumin. Pioglitazone also binds to other serum proteins, but with lower affinity. M-III and M-IV are also extensively bound (>98%) to serum albumin.
- Metabolism
- Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-III and M-IV are the major circulating active metabolites in humans.
- In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone, which include CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo study of pioglitazone in combination with gemfibrozil, a strong CYP2C8 inhibitor, showed that pioglitazone is a CYP2C8 substrate. Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with ACTOS showed that pioglitazone is not a strong CYP3A4 enzyme inducer.
- Excretion and Elimination
- Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.
- The mean serum half-life (t1/2) of pioglitazone and its metabolites (M-III and M-IV) range from three to seven hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be five to seven L/hr.
- Renal Impairment
- The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance [CLcr] 30 to 50 mL/min) and severe (CLcr <30 mL/min) renal impairment when compared to subjects with normal renal function. Therefore, no dose adjustment in patients with renal impairment is required.
- Hepatic Impairment
- Compared with healthy controls, subjects with impaired hepatic function (Child-Turcotte-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone (pioglitazone, M-III, and M-IV) mean Cmax but no change in the mean AUC values. Therefore, no dose adjustment in patients with hepatic impairment is required.
- There are postmarketing reports of liver failure with ACTOS and clinical trials have generally excluded patients with serum ALT >2.5 times the upper limit of the reference range. Use caution in patients with liver disease.
- Geriatric Patients
- In healthy elderly subjects, Cmax of pioglitazone was not significantly different, but AUC values were approximately 21% higher than those achieved in younger subjects. The mean t1/2 of pioglitazone was also prolonged in elderly subjects (about ten hours) as compared to younger subjects (about seven hours). These changes were not of a magnitude that would be considered clinically relevant.
- Pediatric Patients
- Safety and efficacy of pioglitazone in pediatric patients have not been established. ACTOS is not recommended for use in pediatric patients.
- Gender
- The mean Cmax and AUC values of pioglitazone were increased 20% to 60% in women compared to men. In controlled clinical trials, HbA1c decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0.5%). Because therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone.
- Ethnicity
- Pharmacokinetic data among various ethnic groups are not available.
- Drug-Drug Interactions
## Nonclinical Toxicology
- A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m2). Drug-induced tumors were not observed in any organ except for the urinary bladder of male rats. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m2). Urinary calculi with subsequent irritation and hyperplasia were postulated as the mechanism for bladder tumors observed in male rats. A two-year mechanistic study in male rats utilizing dietary acidification to reduce calculi formation was completed in 2009. Dietary acidification decreased but did not abolish the hyperplastic changes in the bladder. The presence of calculi exacerbated the hyperplastic response to pioglitazone but was not considered the primary cause of the hyperplastic changes.
- The relevance to humans of the bladder findings in the male rat cannot be excluded.
- A two-year carcinogenicity study was also conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m2). No drug-induced tumors were observed in any organ.
- Pioglitazone hydrochloride was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay.
- No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone hydrochloride daily prior to and throughout mating and gestation (approximately nine times the maximum recommended human oral dose based on mg/m2).
- Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone hydrochloride (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respectively, based on mg/m2). In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m2). Heart enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg and above (approximately four times the maximum recommended human oral dose based on mg/m2), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m2).
# Clinical Studies
- Monotherapy
- Three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of ACTOS as monotherapy in patients with type 2 diabetes. These trials examined ACTOS at doses up to 45 mg or placebo once daily in a total of 865 patients.
- In a 26-week dose-ranging monotherapy trial, 408 patients with type 2 diabetes were randomized to receive 7.5 mg, 15 mg, 30 mg, or 45 mg of ACTOS, or placebo once daily. Therapy with any previous antidiabetic agent was discontinued eight weeks prior to the double-blind period. Treatment with 15 mg, 30 mg, and 45 mg of ACTOS produced statistically significant improvements in HbA1c and fasting plasma glucose (FPG) at endpoint compared to placebo (see Figure 1, Table 17).
- Figure 1 shows the time course for changes in HbA1c in this 26-week study.
- In a 24-week placebo-controlled monotherapy trial, 260 patients with type 2 diabetes were randomized to one of two forced-titration ACTOS treatment groups or a mock-titration placebo group. Therapy with any previous antidiabetic agent was discontinued six weeks prior to the double-blind period. In one ACTOS treatment group, patients received an initial dose of 7.5 mg once daily. After four weeks, the dose was increased to 15 mg once daily and after another four weeks, the dose was increased to 30 mg once daily for the remainder of the trial (16 weeks). In the second ACTOS treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner. Treatment with ACTOS, as described, produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (see Table 18).
- In a 16-week monotherapy trial, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of ACTOS or placebo once daily. Therapy with any previous antidiabetic agent was discontinued six weeks prior to the double-blind period. Treatment with 30 mg of ACTOS produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (see Table 19).
- Combination Therapy
- Three 16-week, randomized, double-blind, placebo-controlled clinical trials were conducted to evaluate the effects of ACTOS (15 mg and/or 30 mg) on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c ≥8%) despite current therapy with a sulfonylurea, metformin, or insulin. In addition, three 24-week randomized, double-blind clinical trials were conducted to evaluate the effects of ACTOS 30 mg vs. ACTOS 45 mg on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c ≥8%) despite current therapy with a sulfonylurea, metformin, or insulin. Previous diabetes treatment may have been monotherapy or combination therapy.
- Add-on to Sulfonylurea Trials
- Two clinical trials were conducted with ACTOS in combination with a sulfonylurea. Both studies included patients with type 2 diabetes on any dose of a sulfonylurea, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn at least three weeks prior to starting study treatment.
- In the first study, 560 patients were randomized to receive 15 mg or 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their current sulfonylurea regimen. Treatment with ACTOS as add-on to sulfonylurea produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo add-on to sulfonylurea (see Table 20).
- In the second trial, 702 patients were randomized to receive 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current sulfonylurea regimen. The mean reduction from baseline at Week 24 in HbA1c was 1.6% for the 30 mg dose and 1.7% for the 45 mg dose (see Table 21). The mean reduction from baseline at Week 24 in FPG was 52 mg/dL for the 30 mg dose and 56 mg/dL for the 45 mg dose.
- The therapeutic effect of ACTOS in combination with sulfonylurea was observed in patients regardless of the sulfonylurea dose.
- Add-on to Metformin Trials
- Two clinical trials were conducted with ACTOS in combination with metformin. Both trials included patients with type 2 diabetes on any dose of metformin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn at least three weeks prior to starting study treatment.
- In the first trial, 328 patients were randomized to receive either 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their current metformin regimen. Treatment with ACTOS as add-on to metformin produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo add-on to metformin (see Table 22).
- In the second trial, 827 patients were randomized to receive either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current metformin regimen. The mean reduction from baseline at Week 24 in HbA1c was 0.8% for the 30 mg dose and 1.0% for the 45 mg dose (see Table 23). The mean reduction from baseline at Week 24 in FPG was 38 mg/dL for the 30 mg dose and 51 mg/dL for the 45 mg dose.
- The therapeutic effect of ACTOS in combination with metformin was observed in patients regardless of the metformin dose.
- Add-on to Insulin Trials
- Two clinical trials were conducted with ACTOS in combination with insulin. Both trials included patients with type 2 diabetes on insulin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first trial, 566 patients were randomized to receive either 15 mg or 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their insulin regimen. Treatment with ACTOS as add-on to insulin produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo add-on to insulin (see Table 24). The mean daily insulin dose at baseline in each treatment group was approximately 70 units. The majority of patients (75% overall, 86% treated with placebo, 77% treated with ACTOS 15 mg, and 61% treated with ACTOS 30 mg) had no change in their daily insulin dose from baseline to the final study visit. The mean change from baseline in daily dose of insulin (including patients with no insulin dose modifications) was -3 units in the patients treated with ACTOS 15 mg, -8 units in the patients treated with ACTOS 30 mg, and -1 unit in patients treated with placebo.
- In the second trial, 690 patients receiving a median of 60 units per day of insulin were randomized to receive either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current insulin regimen. The mean reduction from baseline at Week 24 in HbA1c was 1.2% for the 30 mg dose and 1.5% for the 45 mg dose. The mean reduction from baseline at Week 24 in FPG was 32 mg/dL for the 30 mg dose and 46 mg/dL for the 45 mg dose (see Table 25). The mean daily insulin dose at baseline in both treatment groups was approximately 70 units. The majority of patients (55% overall, 58% treated with ACTOS 30 mg, and 52% treated with ACTOS 45 mg) had no change in their daily insulin dose from baseline to the final study visit. The mean change from baseline in daily dose of insulin (including patients with no insulin dose modifications) was -5 units in the patients treated with ACTOS 30 mg and -8 units in the patients treated with ACTOS 45 mg.
- The therapeutic effect of ACTOS in combination with insulin was observed in patients regardless of the insulin dose.
# How Supplied
- ACTOS is available in 15 mg, 30 mg, and 45 mg tablets as follows:
- 15 mg tablet: White to off-white, round, convex, nonscored tablet with "ACTOS" on one side, and "15" on the other, available in:
NDC 64764-151-04 Bottles of 30
NDC 64764-151-05 Bottles of 90
NDC 64764-151-06 Bottles of 500
- NDC 64764-151-04 Bottles of 30
- NDC 64764-151-05 Bottles of 90
- NDC 64764-151-06 Bottles of 500
- 30 mg tablet: White to off-white, round, flat, nonscored tablet with "ACTOS" on one side, and "30" on the other, available in:
NDC 64764-301-14 Bottles of 30
NDC 64764-301-15 Bottles of 90
NDC 64764-301-16 Bottles of 500
- NDC 64764-301-14 Bottles of 30
- NDC 64764-301-15 Bottles of 90
- NDC 64764-301-16 Bottles of 500
- 45 mg tablet: White to off-white, round, flat, nonscored tablet with "ACTOS" on one side, and "45" on the other, available in:
NDC 64764-451-24 Bottles of 30
NDC 64764-451-25 Bottles of 90
NDC 64764-451-26 Bottles of 500
- NDC 64764-451-24 Bottles of 30
- NDC 64764-451-25 Bottles of 90
- NDC 64764-451-26 Bottles of 500
- Storage
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Keep container tightly closed, and protect from light, moisture and humidity.
## Storage
There is limited information regarding Pioglitazone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly.
- Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on ACTOS should immediately report these symptoms to a physician.
- Tell patients to promptly stop taking ACTOS and seek immediate medical advice if there is unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine as these symptoms may be due to hepatotoxicity.
- Tell patients to promptly report any sign of macroscopic hematuria or other symptoms such as dysuria or urinary urgency that develop or increase during treatment as these may be due to bladder cancer.
- Tell patients to take ACTOS once daily. ACTOS can be taken with or without meals. If a dose is missed on one day, the dose should not be doubled the following day.
- When using combination therapy with insulin or other antidiabetic medications, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members.
- Inform patients that therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Therefore, adequate contraception should be recommended for all premenopausal women who are prescribed ACTOS.
# Precautions with Alcohol
- Alcohol-Pioglitazone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Actos®[2]
# Look-Alike Drug Names
- Actos® — Actonel®[3]
# Drug Shortage Status
# Price
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https://www.wikidoc.org/index.php/Actos
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e633feabe26cd65c83dfdb35e9c3ab290a5004bb
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wikidoc
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Encephalitis
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Encephalitis
Common encephalidites include:
## Viral encephalitis
- Herpes simplex encephalitis
- VZV encephalitis
- Nipah virus encephalitis
## Vector-borne encephalitis
- Tick-borne encephalitis
- California encephalitis
- Eastern equine encephalitis
- Western equine encephalitis
- Japanese encephalitis
- Venezuelan equine encephalitis
- West Nile encephalitis
- La Crosse encephalitis
- St. Louis encephalitis
## Fungal encephalitis
## Protozoan encephalitis
- Granulomatous amebic encephalitis
- Toxoplasmic encephalitis
## Bacterial encephalitis
# Differential diagnosis
Encephalitis must be differentiated from other causes of headache, seizures and loss of consciousness.
# Comprehensive List of Causes of Encephalitis & Encephalopathy
- ↑ Carbonnelle E (2009). "". Med Mal Infect. 39 (7–8): 581–605. doi:10.1016/j.medmal.2009.02.017. PMID 19398286..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}
- ↑ Morgenstern LB, Frankowski RF (1999). "Brain tumor masquerading as stroke". J Neurooncol. 44 (1): 47–52. PMID 10582668.
- ↑ Weston CL, Glantz MJ, Connor JR (2011). "Detection of cancer cells in the cerebrospinal fluid: current methods and future directions". Fluids Barriers CNS. 8 (1): 14. doi:10.1186/2045-8118-8-14. PMC 3059292. PMID 21371327.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 4.0 4.1 Birenbaum D, Bancroft LW, Felsberg GJ (2011). "Imaging in acute stroke". West J Emerg Med. 12 (1): 67–76. PMC 3088377. PMID 21694755.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 5.0 5.1 DeLaPaz RL, Wippold FJ, Cornelius RS, Amin-Hanjani S, Angtuaco EJ, Broderick DF; et al. (2011). "ACR Appropriateness Criteria® on cerebrovascular disease". J Am Coll Radiol. 8 (8): 532–8. doi:10.1016/j.jacr.2011.05.010. PMID 21807345.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Lee MC, Heaney LM, Jacobson RL, Klassen AC (1975). "Cerebrospinal fluid in cerebral hemorrhage and infarction". Stroke. 6 (6): 638–41. PMID 1198628.CS1 maint: Multiple names: authors list (link)
- ↑ Liu LL, Zheng WH, Tong ML, Liu GL, Zhang HL, Fu ZG; et al. (2012). "Ischemic stroke as a primary symptom of neurosyphilis among HIV-negative emergency patients". J Neurol Sci. 317 (1–2): 35–9. doi:10.1016/j.jns.2012.03.003. PMID 22482824.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Berger JR, Dean D (2014). "Neurosyphilis". Handb Clin Neurol. 121: 1461–72. doi:10.1016/B978-0-7020-4088-7.00098-5. PMID 24365430.
- ↑ Ho EL, Marra CM (2012). "Treponemal tests for neurosyphilis--less accurate than what we thought?". Sex Transm Dis. 39 (4): 298–9. doi:10.1097/OLQ.0b013e31824ee574. PMC 3746559. PMID 22421697.
- ↑ Giang DW, Grow VM, Mooney C, Mushlin AI, Goodman AD, Mattson DH; et al. (1994). "Clinical diagnosis of multiple sclerosis. The impact of magnetic resonance imaging and ancillary testing. Rochester-Toronto Magnetic Resonance Study Group". Arch Neurol. 51 (1): 61–6. PMID 8274111.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Manford M (2001). "Assessment and investigation of possible epileptic seizures". J Neurol Neurosurg Psychiatry. 70 Suppl 2: II3–8. PMC 1765557. PMID 11385043.
|
Encephalitis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Common encephalidites include:
## Viral encephalitis
- Herpes simplex encephalitis
- VZV encephalitis
- Nipah virus encephalitis
## Vector-borne encephalitis
- Tick-borne encephalitis
- California encephalitis
- Eastern equine encephalitis
- Western equine encephalitis
- Japanese encephalitis
- Venezuelan equine encephalitis
- West Nile encephalitis
- La Crosse encephalitis
- St. Louis encephalitis
## Fungal encephalitis
## Protozoan encephalitis
- Granulomatous amebic encephalitis
- Toxoplasmic encephalitis
## Bacterial encephalitis
# Differential diagnosis
Encephalitis must be differentiated from other causes of headache, seizures and loss of consciousness.
# Comprehensive List of Causes of Encephalitis & Encephalopathy
- ↑ Carbonnelle E (2009). "[Laboratory diagnosis of bacterial meningitis: usefulness of various tests for the determination of the etiological agent]". Med Mal Infect. 39 (7–8): 581–605. doi:10.1016/j.medmal.2009.02.017. PMID 19398286..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}
- ↑ Morgenstern LB, Frankowski RF (1999). "Brain tumor masquerading as stroke". J Neurooncol. 44 (1): 47–52. PMID 10582668.
- ↑ Weston CL, Glantz MJ, Connor JR (2011). "Detection of cancer cells in the cerebrospinal fluid: current methods and future directions". Fluids Barriers CNS. 8 (1): 14. doi:10.1186/2045-8118-8-14. PMC 3059292. PMID 21371327.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 4.0 4.1 Birenbaum D, Bancroft LW, Felsberg GJ (2011). "Imaging in acute stroke". West J Emerg Med. 12 (1): 67–76. PMC 3088377. PMID 21694755.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 5.0 5.1 DeLaPaz RL, Wippold FJ, Cornelius RS, Amin-Hanjani S, Angtuaco EJ, Broderick DF; et al. (2011). "ACR Appropriateness Criteria® on cerebrovascular disease". J Am Coll Radiol. 8 (8): 532–8. doi:10.1016/j.jacr.2011.05.010. PMID 21807345.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Lee MC, Heaney LM, Jacobson RL, Klassen AC (1975). "Cerebrospinal fluid in cerebral hemorrhage and infarction". Stroke. 6 (6): 638–41. PMID 1198628.CS1 maint: Multiple names: authors list (link)
- ↑ Liu LL, Zheng WH, Tong ML, Liu GL, Zhang HL, Fu ZG; et al. (2012). "Ischemic stroke as a primary symptom of neurosyphilis among HIV-negative emergency patients". J Neurol Sci. 317 (1–2): 35–9. doi:10.1016/j.jns.2012.03.003. PMID 22482824.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Berger JR, Dean D (2014). "Neurosyphilis". Handb Clin Neurol. 121: 1461–72. doi:10.1016/B978-0-7020-4088-7.00098-5. PMID 24365430.
- ↑ Ho EL, Marra CM (2012). "Treponemal tests for neurosyphilis--less accurate than what we thought?". Sex Transm Dis. 39 (4): 298–9. doi:10.1097/OLQ.0b013e31824ee574. PMC 3746559. PMID 22421697.
- ↑ Giang DW, Grow VM, Mooney C, Mushlin AI, Goodman AD, Mattson DH; et al. (1994). "Clinical diagnosis of multiple sclerosis. The impact of magnetic resonance imaging and ancillary testing. Rochester-Toronto Magnetic Resonance Study Group". Arch Neurol. 51 (1): 61–6. PMID 8274111.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Manford M (2001). "Assessment and investigation of possible epileptic seizures". J Neurol Neurosurg Psychiatry. 70 Suppl 2: II3–8. PMC 1765557. PMID 11385043.
|
https://www.wikidoc.org/index.php/Acute_Bokhoror
| |
7ef4efc5ff3aa16b3ef10b3cabf8292778b164c1
|
wikidoc
|
Endometritis
|
Endometritis
Synonyms and keywords: acute endometritis, chronic endometritis, postpartum endometritis, puerperal endometritis
# Overview
Endometritis is classified histopathologically into two subtypes: acute endometritis and chronic endometritis (CE). Acute endometritis occurs following abortion, childbirth, menstruation, curettage, or IUD insertion. Symptoms of acute endometritis may include fever, pelvic pain, and vaginal discharge. On histopathology, many neutrophils are seen in the endometrial stroma in acute endometritis. Chronic endometritis may cause infertility. Chronic endometritis (CE) is mostly asymptomatic but may have vague symptoms. On histopathology, plasma cells are seen in the endometrial stroma in chronic endometritis (CE). Endometritis is mostly caused by infection and treated with antibiotics. Pyometra is a rare disorder with pus accumulation in the uterine cavity due to abnormal drainage of the uterus.
# Historical Perspective
There is limited information on the historical perspective of endometritis.
# Classification
Endometritis may be classified according to histopathology into two subtypes:
- Acute endometritis
Following abortion, childbirth, menstruation, curettage, or IUD insertion.
The time following childbirth until about 6 weeks after childbirth is traditionally referred to as puerperium (postpartum).
- Following abortion, childbirth, menstruation, curettage, or IUD insertion.
- The time following childbirth until about 6 weeks after childbirth is traditionally referred to as puerperium (postpartum).
- Chronic endometritis (CE)
Mycobacterium tuberculosis causes a subtype of chronic endometritis (CE) (chronic granulomatous endometritis) in some developing countries.
- Mycobacterium tuberculosis causes a subtype of chronic endometritis (CE) (chronic granulomatous endometritis) in some developing countries.
## Pyometra
- Pyometra is a rare disorder with pus accumulation in the uterine cavity due to abnormal drainage of the uterus.
- Pyometra is caused by:
Atrophic cervicitis due to aging
IUD use
Malignant or benign gynecologic tumors
Radiation cervicitis
- Atrophic cervicitis due to aging
- IUD use
- Malignant or benign gynecologic tumors
- Radiation cervicitis
- Mostly seen in postmenopausal women and rarely in the premenopausal women
- The classic triad of symptoms in pyometra includes:
Lower abdominal pain
Purulent vaginal discharge
Postmenopausal bleeding
- Lower abdominal pain
- Purulent vaginal discharge
- Postmenopausal bleeding
# Pathophysiology
## Postpartum endometritis
Postpartum endometritis is caused by bacteria (vaginal microflora) ascending from the lower genital tract during labor.
- These bacteria colonize the cervix and then ascend into the lower part of the uterus and enter the amniotic fluid.
- The amniotic membranes are weakened and ruptured due to the collagenases and proteases that are produced.
Artificial or spontaneous rupture of membranes may also happen without bacterial colonization.
- In these cases bacteria may colonize the decidua and amniotic fluid.
- An amnionitis without deciduitis is caused when bacteria do not colonize the decidua. Chorioamnionitis occurs but the uterus is not infected.
- Deciduitis may result in the infection of the myometrium that may not be diagnosed initially. However, it may not lead to postpartum endometritis with antibiotic treatment after delivery.
## Chronic Endometritis
In the normal endometrium, B-cells are mostly seen in the basal layer.
- The basal layer is the layer that remains across the menstrual cycle.
- In the lymphocyte aggregates, B-cells are the central cells that are surrounded by CD8 T-cells and macrophages.
In chronic endometritis (CE):
- B-cells are seen in the endometrial functional and basal layers.
The endometrial functional layer is the layer that sheds in menstruation.
These increased numbers of B-cells in the endometrial stroma invade into the gland lumina.
- The endometrial functional layer is the layer that sheds in menstruation.
- These increased numbers of B-cells in the endometrial stroma invade into the gland lumina.
- Decreased CD16negative CD56positive/bright natural killer cells and increased T-cells in the secretory phase of the endometrium.
- Abnormal expression of some adhesion molecules and chemokines in the endometrial endothelial and epithelial cells.
CD62E, CXCL1, and CXCL13 (these are involved in B-cell extravasation and migration).
- CD62E, CXCL1, and CXCL13 (these are involved in B-cell extravasation and migration).
- IL-6 is increased in the menstrual flow.
IL-6 is a differentiation factor of mature B-cells.
- IL-6 is a differentiation factor of mature B-cells.
- Increase in IL-1b and tumor necrosis factor (TNF)-a.
TNF-a increases estrogen biosynthesis in the endometrial glandular cells.
May be associated with endometrial micropolyposis which is seen in the hysteroscopy of patients with CE.
- TNF-a increases estrogen biosynthesis in the endometrial glandular cells.
May be associated with endometrial micropolyposis which is seen in the hysteroscopy of patients with CE.
- May be associated with endometrial micropolyposis which is seen in the hysteroscopy of patients with CE.
- Increased immunoglobulin subclasses (IgM, IgA1, IgA2, IgG1, and IgG2), especially IgG2.
Negatively affect embryo implantation.
Rarely cause systemic inflammation or affect leukocyte counts, CRP, or cause fever.
- Negatively affect embryo implantation.
- Rarely cause systemic inflammation or affect leukocyte counts, CRP, or cause fever.
- Delayed differentiation of endometrium in the mid-secretory phase.
One-third of biopsies from infertile patients with CE have 'out-of-phase' morphology.
Pseudostratification and mitotic nuclei in the glandular and surface epithelial cells.
- One-third of biopsies from infertile patients with CE have 'out-of-phase' morphology.
- Pseudostratification and mitotic nuclei in the glandular and surface epithelial cells.
- In the secretory phase, the expression of the followings are upregulated:
Antiapoptotic genes (BCL2 and BAX)
Nuclear marker associated with proliferation (Ki-67)
Ovarian steroid receptors (estrogen receptor-a, and -b, progesterone receptor-A, and -B)
- Antiapoptotic genes (BCL2 and BAX)
- Nuclear marker associated with proliferation (Ki-67)
- Ovarian steroid receptors (estrogen receptor-a, and -b, progesterone receptor-A, and -B)
- The expression of the followings are downregulated:
Genes associated with embryo receptivity (IL11, CCL4, IGF1, and CASP8)
Decidualization (PRL and IGFBP1)
- Genes associated with embryo receptivity (IL11, CCL4, IGF1, and CASP8)
- Decidualization (PRL and IGFBP1)
## Histopathology
Mycobacterium tuberculosis causes a subtype of chronic endometritis (CE) (chronic granulomatous endometritis) in some developing countries. Histopathologically, chronic granulomatous endometritis has caseating granuloma surrounded by infiltrates of lymphocytes which include endometrial stromal plasmacytes (ESPCs).
# Causes
Acute endometritis may be caused by Chlamydia trachomatis and Neisseria gonorrhea.
The rate of infections with Chlamydia trachomatis (2%–7%) and Neisseria gonorrhea (0%–8%) in chronic endometritis (CE) are very low.
Mycobacterium tuberculosis causes a subtype of chronic endometritis (CE) (chronic granulomatous endometritis) in some developing countries.
The association of viral infections as causes of chronic endometritis (CE) is still unclear.
# Differentiating Endometritis from other Diseases
Puerperal endometritis must be differentiated from:
- Respiratory disorders
- Pyelonephritis
- Appendicitis
To view more differential diagnosis, click here.
# Epidemiology
Puerperal Endometritis
The prevalence of endometritis is 1% to 2% of births and 27% of cesarean births.
Chronic Endometritis
The prevalence of chronic endometritis (CE) is about 10% to 11% on biopsies performed from hysterectomies of patients with gynecologic conditions.
In a study, the prevalence of CE has been reported to be 15% in infertile women with in vitro fertilization (IVF) and 42% in women with recurrent implantation failure (RIF).
The prevalence of CE has been reported to be 57.8% in women with three or more recurrent pregnancy losses (RPLs).
In one study, the prevalence of CE has been reported to be 14% and 27% in patients with RIF or RPL, respectively.
# Risk Factors
# Screening
Routine antepartum screening for GBS infection and treatment of genital tract infections are important in preventing puerperal genital tract infection.
There is insufficient evidence to recommend routine screening for chronic endometritis (CE). However, it has been suggested that hysteroscopy may have the potential to be a screening tool for CE.
# Natural History, Complications, and Prognosis
## Natural History
Studies have suggested that patients with chronic endometritis (CE) may develop:
- Infertility
- Recurrent implantation failure (RIF)
- Recurrent pregnancy losses (RPLs)
## Complications
## Prognosis
A study showed that after antibiotic treatment of patients with CE and recurrent pregnancy losses (RPLs), the pre-pregnancy live birth rate increased from 7% (before treatment) to 56% (after treatment).
Another study showed that after antibiotic treatment of patients with CE, the implantation rate and pregnancy rate increased from 4.9% and 7.4% (before treatment) to 18.6% and 29.3% (after treatment), respectively.
# Diagnosis
## Diagnostic Study of Choice
The histological finding of acute endometritis includes a large number of neutrophils in the endometrial stroma.
The diagnosis of chronic endometritis (CE) is made with endometrial biopsy and the histological diagnostic criterion is plasma cells in the endometrial stroma.
## History and Symptoms
## Physical Examination
Clinical findings found on physical examination in puerperal endometritis may include:
- Fever
- Tachycardia
- Uterine tenderness
- Pelvic pain on bimanual examination
- Lochia
- Subinvolution of uterus
## Laboratory Findings
Laboratory tests in puerperal endometritis include:
- Complete blood count with differential
- Metabolic panel
- Urine culture
- Blood culture
There is insufficient evidence that suggests obtaining endometrial or cervical cultures in puerperal endometritis due to contamination while obtaining an endometrial culture.
Laboratory findings in acute endometritis may include:
- Leukocytosis
- Elevated serum inflammatory markers
Staining used in histological detection of chronic endometritis (CE) include:
- Hematoxylin and eosin (H&E)
- Immunohistochemical (IHC) stain that detects CD38 and CD138 plasma cell-specific surface antigens:
Confirms the presence of plasma cells in the endometrium.
IHC staining for CD138 has higher sensitivity for diagnosing CE compared to H&E staining (56% vs. 13%).
- Confirms the presence of plasma cells in the endometrium.
- IHC staining for CD138 has higher sensitivity for diagnosing CE compared to H&E staining (56% vs. 13%).
## Electrocardiogram
There are no ECG findings associated with endometritis.
## X-ray
There are no x-ray findings associated with endometritis. However, a chest x-ray should be performed if there is suspicion of a respiratory disorder.
## Echocardiography or Ultrasound
There are no echocardiography findings associated with endometritis.
Ultrasound is usually not helpful in the diagnosis of endometritis. However, an ultrasound may be helpful to rule out other disorders in postpartum patients that are nonresponsive to therapy.
Ultrasound and CT findings in postpartum endometritis may include:
- Normal uterus
- Nonspecific findings due to retained products of conception:
Intrauterine fluid (with or without internal echoes due to blood, gas, or retained products of pregnancy)
Thickened heterogeneous endometrium
- Intrauterine fluid (with or without internal echoes due to blood, gas, or retained products of pregnancy)
- Thickened heterogeneous endometrium
## CT scan
Ultrasound and CT findings in postpartum endometritis may include:
- Normal uterus
- Nonspecific findings due to retained products of conception:
Intrauterine fluid (with or without internal echoes due to blood, gas, or retained products of pregnancy)
Thickened heterogeneous endometrium
- Intrauterine fluid (with or without internal echoes due to blood, gas, or retained products of pregnancy)
- Thickened heterogeneous endometrium
Compared to ultrasound, CT scan is more helpful in identifying the inflammation of the soft tissues and pelvic abscesses.
## MRI
There are no specific MRI findings associated with endometritis. However, MRI may be helpful if there is suspicion of septic pelvic thrombophlebitis.
## Other Imaging Findings
Fluid hysteroscopy is helpful in diagnosing chronic endometritis (CE) and the findings include:
- Edema of the stroma
- Micropolyps
- Focal or diffuse hyperemia
# Treatment
## Medical Therapy
## Surgery
Surgery may be indicated if there is drainable fluid collection due to infection.
## Primary Prevention
The American College of Obstetricians and Gynecologists (ACOG) and the World Health Organization (WHO) recommend antimicrobial prophylaxis 60 minutes prior to incision of cesarean birth.
A Conchrane study showed that antimicrobial prophylaxis decreases uterine and wound infections.
Some of the measures that should be considered in order to reduce genital tract infections include:
- Routine antepartum screening and treatment of GBS and infections
- Handwashing
- Aseptic procedure
- Decrease in vaginal examinations
- Limiting use of invasive procedures
- Limiting episiotomies
- Synthetic suture use
- Decrease in cesarean births
- Rapid repair of lacerations
- Standard suture techniques
- Prophylaxis with antibiotics in anal sphincter injuries
## Secondary Prevention
There are no established measures for the secondary prevention of endometritis.
|
Endometritis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shakiba Hassanzadeh, MD[2]
Synonyms and keywords: acute endometritis, chronic endometritis, postpartum endometritis, puerperal endometritis
# Overview
Endometritis is classified histopathologically into two subtypes: acute endometritis and chronic endometritis (CE). Acute endometritis occurs following abortion, childbirth, menstruation, curettage, or IUD insertion. Symptoms of acute endometritis may include fever, pelvic pain, and vaginal discharge. On histopathology, many neutrophils are seen in the endometrial stroma in acute endometritis. Chronic endometritis may cause infertility. Chronic endometritis (CE) is mostly asymptomatic but may have vague symptoms. On histopathology, plasma cells are seen in the endometrial stroma in chronic endometritis (CE). Endometritis is mostly caused by infection and treated with antibiotics. Pyometra is a rare disorder with pus accumulation in the uterine cavity due to abnormal drainage of the uterus.
# Historical Perspective
There is limited information on the historical perspective of endometritis.
# Classification
Endometritis may be classified according to histopathology into two subtypes:[1]
- Acute endometritis
Following abortion, childbirth, menstruation, curettage, or IUD insertion.[2]
The time following childbirth until about 6 weeks after childbirth is traditionally referred to as puerperium (postpartum).[3]
- Following abortion, childbirth, menstruation, curettage, or IUD insertion.[2]
- The time following childbirth until about 6 weeks after childbirth is traditionally referred to as puerperium (postpartum).[3]
- Chronic endometritis (CE)
Mycobacterium tuberculosis causes a subtype of chronic endometritis (CE) (chronic granulomatous endometritis) in some developing countries.[4]
- Mycobacterium tuberculosis causes a subtype of chronic endometritis (CE) (chronic granulomatous endometritis) in some developing countries.[4]
## Pyometra
- Pyometra is a rare disorder with pus accumulation in the uterine cavity due to abnormal drainage of the uterus.[5]
- Pyometra is caused by:[6][7][7]
Atrophic cervicitis due to aging
IUD use
Malignant or benign gynecologic tumors
Radiation cervicitis
- Atrophic cervicitis due to aging
- IUD use
- Malignant or benign gynecologic tumors
- Radiation cervicitis
- Mostly seen in postmenopausal women and rarely in the premenopausal women[7]
- The classic triad of symptoms in pyometra includes:[7][8]
Lower abdominal pain
Purulent vaginal discharge
Postmenopausal bleeding
- Lower abdominal pain
- Purulent vaginal discharge
- Postmenopausal bleeding
# Pathophysiology
## Postpartum endometritis
Postpartum endometritis is caused by bacteria (vaginal microflora) ascending from the lower genital tract during labor.[9]
- These bacteria colonize the cervix and then ascend into the lower part of the uterus and enter the amniotic fluid.
- The amniotic membranes are weakened and ruptured due to the collagenases and proteases that are produced.
Artificial or spontaneous rupture of membranes may also happen without bacterial colonization.[9]
- In these cases bacteria may colonize the decidua and amniotic fluid.
- An amnionitis without deciduitis is caused when bacteria do not colonize the decidua. Chorioamnionitis occurs but the uterus is not infected.
- Deciduitis may result in the infection of the myometrium that may not be diagnosed initially. However, it may not lead to postpartum endometritis with antibiotic treatment after delivery.
## Chronic Endometritis
In the normal endometrium, B-cells are mostly seen in the basal layer.[10]
- The basal layer is the layer that remains across the menstrual cycle.
- In the lymphocyte aggregates, B-cells are the central cells that are surrounded by CD8 T-cells and macrophages.
In chronic endometritis (CE):[11]
- B-cells are seen in the endometrial functional and basal layers.[12][13]
The endometrial functional layer is the layer that sheds in menstruation.
These increased numbers of B-cells in the endometrial stroma invade into the gland lumina.
- The endometrial functional layer is the layer that sheds in menstruation.
- These increased numbers of B-cells in the endometrial stroma invade into the gland lumina.
- Decreased CD16negative CD56positive/bright natural killer cells and increased T-cells in the secretory phase of the endometrium.[14]
- Abnormal expression of some adhesion molecules and chemokines in the endometrial endothelial and epithelial cells.[13]
CD62E, CXCL1, and CXCL13 (these are involved in B-cell extravasation and migration).
- CD62E, CXCL1, and CXCL13 (these are involved in B-cell extravasation and migration).
- IL-6 is increased in the menstrual flow.[15]
IL-6 is a differentiation factor of mature B-cells.
- IL-6 is a differentiation factor of mature B-cells.
- Increase in IL-1b and tumor necrosis factor (TNF)-a.[15]
TNF-a increases estrogen biosynthesis in the endometrial glandular cells. [16]
May be associated with endometrial micropolyposis which is seen in the hysteroscopy of patients with CE.[17][18]
- TNF-a increases estrogen biosynthesis in the endometrial glandular cells. [16]
May be associated with endometrial micropolyposis which is seen in the hysteroscopy of patients with CE.[17][18]
- May be associated with endometrial micropolyposis which is seen in the hysteroscopy of patients with CE.[17][18]
- Increased immunoglobulin subclasses (IgM, IgA1, IgA2, IgG1, and IgG2), especially IgG2.[19]
Negatively affect embryo implantation.
Rarely cause systemic inflammation or affect leukocyte counts, CRP, or cause fever.[20][21]
- Negatively affect embryo implantation.
- Rarely cause systemic inflammation or affect leukocyte counts, CRP, or cause fever.[20][21]
- Delayed differentiation of endometrium in the mid-secretory phase.
One-third of biopsies from infertile patients with CE have 'out-of-phase' morphology.[20]
Pseudostratification and mitotic nuclei in the glandular and surface epithelial cells.
- One-third of biopsies from infertile patients with CE have 'out-of-phase' morphology.[20]
- Pseudostratification and mitotic nuclei in the glandular and surface epithelial cells.
- In the secretory phase, the expression of the followings are upregulated:[22][23][24][25]
Antiapoptotic genes (BCL2 and BAX)
Nuclear marker associated with proliferation (Ki-67)
Ovarian steroid receptors (estrogen receptor-a, and -b, progesterone receptor-A, and -B)
- Antiapoptotic genes (BCL2 and BAX)
- Nuclear marker associated with proliferation (Ki-67)
- Ovarian steroid receptors (estrogen receptor-a, and -b, progesterone receptor-A, and -B)
- The expression of the followings are downregulated:[22][25]
Genes associated with embryo receptivity (IL11, CCL4, IGF1, and CASP8)
Decidualization (PRL and IGFBP1)
- Genes associated with embryo receptivity (IL11, CCL4, IGF1, and CASP8)
- Decidualization (PRL and IGFBP1)
## Histopathology
Mycobacterium tuberculosis causes a subtype of chronic endometritis (CE) (chronic granulomatous endometritis) in some developing countries. Histopathologically, chronic granulomatous endometritis has caseating granuloma surrounded by infiltrates of lymphocytes which include endometrial stromal plasmacytes (ESPCs).[4]
# Causes
Acute endometritis may be caused by Chlamydia trachomatis and Neisseria gonorrhea.[30]
The rate of infections with Chlamydia trachomatis (2%–7%) and Neisseria gonorrhea (0%–8%) in chronic endometritis (CE) are very low. [27][31][32]
Mycobacterium tuberculosis causes a subtype of chronic endometritis (CE) (chronic granulomatous endometritis) in some developing countries.[4]
The association of viral infections as causes of chronic endometritis (CE) is still unclear.[11]
# Differentiating Endometritis from other Diseases
Puerperal endometritis must be differentiated from:[3]
- Respiratory disorders
- Pyelonephritis
- Appendicitis
To view more differential diagnosis, click here.
# Epidemiology
Puerperal Endometritis
The prevalence of endometritis is 1% to 2% of births and 27% of cesarean births.[33][34]
Chronic Endometritis
The prevalence of chronic endometritis (CE) is about 10% to 11% on biopsies performed from hysterectomies of patients with gynecologic conditions.[20][32]
In a study, the prevalence of CE has been reported to be 15% in infertile women with in vitro fertilization (IVF) and 42% in women with recurrent implantation failure (RIF).[35]
The prevalence of CE has been reported to be 57.8% in women with three or more recurrent pregnancy losses (RPLs).[36]
In one study, the prevalence of CE has been reported to be 14% and 27% in patients with RIF or RPL, respectively.[37]
# Risk Factors
# Screening
Routine antepartum screening for GBS infection and treatment of genital tract infections are important in preventing puerperal genital tract infection.[48]
There is insufficient evidence to recommend routine screening for chronic endometritis (CE). However, it has been suggested that hysteroscopy may have the potential to be a screening tool for CE.[11]
# Natural History, Complications, and Prognosis
## Natural History
Studies have suggested that patients with chronic endometritis (CE) may develop:[49][35][36]
- Infertility
- Recurrent implantation failure (RIF)
- Recurrent pregnancy losses (RPLs)
## Complications
## Prognosis
A study showed that after antibiotic treatment of patients with CE and recurrent pregnancy losses (RPLs), the pre-pregnancy live birth rate increased from 7% (before treatment) to 56% (after treatment).[52]
Another study showed that after antibiotic treatment of patients with CE, the implantation rate and pregnancy rate increased from 4.9% and 7.4% (before treatment) to 18.6% and 29.3% (after treatment), respectively.[55]
# Diagnosis
## Diagnostic Study of Choice
The histological finding of acute endometritis includes a large number of neutrophils in the endometrial stroma.[56]
The diagnosis of chronic endometritis (CE) is made with endometrial biopsy and the histological diagnostic criterion is plasma cells in the endometrial stroma.[20][57]
## History and Symptoms
## Physical Examination
Clinical findings found on physical examination in puerperal endometritis may include:[59]
- Fever
- Tachycardia
- Uterine tenderness
- Pelvic pain on bimanual examination
- Lochia
- Subinvolution of uterus
## Laboratory Findings
Laboratory tests in puerperal endometritis include:[48][3]
- Complete blood count with differential
- Metabolic panel
- Urine culture
- Blood culture
There is insufficient evidence that suggests obtaining endometrial or cervical cultures in puerperal endometritis due to contamination while obtaining an endometrial culture.[62][63]
Laboratory findings in acute endometritis may include:[64]
- Leukocytosis
- Elevated serum inflammatory markers
Staining used in histological detection of chronic endometritis (CE) include:
- Hematoxylin and eosin (H&E)[52][57]
- Immunohistochemical (IHC) stain that detects CD38 and CD138 plasma cell-specific surface antigens:
Confirms the presence of plasma cells in the endometrium.[65]
IHC staining for CD138 has higher sensitivity for diagnosing CE compared to H&E staining (56% vs. 13%).[66]
- Confirms the presence of plasma cells in the endometrium.[65]
- IHC staining for CD138 has higher sensitivity for diagnosing CE compared to H&E staining (56% vs. 13%).[66]
## Electrocardiogram
There are no ECG findings associated with endometritis.
## X-ray
There are no x-ray findings associated with endometritis. However, a chest x-ray should be performed if there is suspicion of a respiratory disorder.[3]
## Echocardiography or Ultrasound
There are no echocardiography findings associated with endometritis.
Ultrasound is usually not helpful in the diagnosis of endometritis. However, an ultrasound may be helpful to rule out other disorders in postpartum patients that are nonresponsive to therapy.[67]
Ultrasound and CT findings in postpartum endometritis may include:[67][68][69][70][71]
- Normal uterus
- Nonspecific findings due to retained products of conception:
Intrauterine fluid (with or without internal echoes due to blood, gas, or retained products of pregnancy)
Thickened heterogeneous endometrium
- Intrauterine fluid (with or without internal echoes due to blood, gas, or retained products of pregnancy)
- Thickened heterogeneous endometrium
## CT scan
Ultrasound and CT findings in postpartum endometritis may include:[67][68][69][70][71]
- Normal uterus
- Nonspecific findings due to retained products of conception:
Intrauterine fluid (with or without internal echoes due to blood, gas, or retained products of pregnancy)
Thickened heterogeneous endometrium
- Intrauterine fluid (with or without internal echoes due to blood, gas, or retained products of pregnancy)
- Thickened heterogeneous endometrium
Compared to ultrasound, CT scan is more helpful in identifying the inflammation of the soft tissues and pelvic abscesses.[72]
## MRI
There are no specific MRI findings associated with endometritis. However, MRI may be helpful if there is suspicion of septic pelvic thrombophlebitis.[62]
## Other Imaging Findings
Fluid hysteroscopy is helpful in diagnosing chronic endometritis (CE) and the findings include:[18][27]
- Edema of the stroma
- Micropolyps
- Focal or diffuse hyperemia
# Treatment
## Medical Therapy
## Surgery
Surgery may be indicated if there is drainable fluid collection due to infection.[62]
## Primary Prevention
The American College of Obstetricians and Gynecologists (ACOG) and the World Health Organization (WHO) recommend antimicrobial prophylaxis 60 minutes prior to incision of cesarean birth.[74][75][76]
A Conchrane study showed that antimicrobial prophylaxis decreases uterine and wound infections.[75]
Some of the measures that should be considered in order to reduce genital tract infections include:[48][75][77][78]
- Routine antepartum screening and treatment of GBS and infections
- Handwashing
- Aseptic procedure
- Decrease in vaginal examinations
- Limiting use of invasive procedures
- Limiting episiotomies
- Synthetic suture use
- Decrease in cesarean births
- Rapid repair of lacerations
- Standard suture techniques
- Prophylaxis with antibiotics in anal sphincter injuries
## Secondary Prevention
There are no established measures for the secondary prevention of endometritis.
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https://www.wikidoc.org/index.php/Acute_endometritis
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6224b8a2ea0706ecc8aa2ac69aa66f266bb21660
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wikidoc
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Sialadenitis
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Sialadenitis
Synonyms and keywords:Sialadenitis, salivary gland inflammation
# Overview
Sialadenitis is the inflammation of a salivary gland. The causes of sialadenitis include bacterial and viral infections, such as mumps and HIV, obstruction from stones or radiation, and autoimmune disorders such as Sjogren's syndrome. The complications of sialadenitis include recurrence, abscess, and chronic sialadenitis. Sialadenitis must be differentiated from other diseases that can cause swelling in the salivary glands, such as sialolithiasis, human immunodeficiency virus, radiation, and systemic diseases such as, sarcoidosis, and sjögren's syndrome. History from the patient will reveal symptoms of sialadenitis that include fever, redness of overlying skin, pain, and difficulty in opening the mouth. The diagnosis of choice is a high resolution CT scan. Sialoendoscopy can be used in the diagnosis of small stones and differentiate them from polyps. Conservative treatment is the first line of therapy in the most patients and it involves Hydration, applying moist heat, massaging the gland, duct milking, discontinuation of medication that can decrease the saliva flow, such as the TCAs (because of their anticholinergic effects). Also, antibiotics can be used in the case of superimposed infection. Preferred regimens are Dicloxacillin 500 mg q 6h PO for 7 to 10 days, or Cephalexin 500 mg q 6h PO for 7 to 10 days.
# Historical Perspective
The historical perspective of sialadenitis is as follows:
- In 17th century, major salivary gland ductal system in anatomical human studies was first reported.
- In 1990, , Konigsberger et al. performed the first successful salivary endoscopy.
- In 2004, Zenk et al. reported the use of semirigid sialendoscope in different types of obstructive salivary disorders.
- In 2006, Nahlieli et al. described sialendoscopy in the management of radioiodine sialadenitis.
# Classification
- There is no established system for the classification of sialadenitis, but it can be classified according to location of the stone.
- Submandibular stones can be classified further as anterior, or posterior in relation to the mandibular first molar teeth.
- Stones may be radiopaque, where they can be radiopaque or radiolucent.
- Stones may also be symptomatic or asymptomatic.
# Pathophysiology
- Sialadenitis is the inflammation of a salivary gland.
- Swelling is usually present in this condition.
- Acute sialadenitis may be caused by viral or bacterial infection
Parotid and submandibular glands are more involved in acute sialadenitis. Approximately 10% sialadenitis cases are related to the involvement of submandibular gland.
- Parotid and submandibular glands are more involved in acute sialadenitis. Approximately 10% sialadenitis cases are related to the involvement of submandibular gland.
- Chronic sialadenitis is caused by repeated episodes of inflammation and finally it progresses in to salivary gland dysfunction.
# Causes
Common causes of sialadenitis include the following:
Bacterial and viral infections:
- Mumps
- HIV
- Staph aureus
- Streptococci viridans
- Pseudomonas aeruginosa
- Escherichia coli
- Moraxella catarrhalis
- Tuberculosis
Obstruction:
- Stones
- Radiation
- Strictures
- Sarcoidosis
Autoimmune disorders:
- Sjogren's syndrome
# Differentiating sialadenitis from Other Diseases
- Sialadenitis must be differentiated from other diseases that cause swelling in salivary glands, such as sialolithiasis, human immunodeficiency virus, radiation, and systemic diseases such as, sarcoidosis, and sjögren's syndrome.
# Epidemiology and Demographics
- The exact prevalence of submandibular sialadenitis is unclear.
- The incidence of acute sialadenitis is approximately 275 per 100,000 individuals in United Kingdom.
- Patients of all age groups may develop sialadenitis.
- Sialadenitis commonly affects older and dehydrated patients.
# Risk Factors
## Common Risk Factors
Common risk factors in the development of sialolithisis which can lead to sialadenitis include:
- Dehydration
- Diuretics
- Local trauma
- Sjögren's syndrome
- Gout
- Anticholinergic medications
- Smoking
- History of nephrolithiasis
- Chronic periodontal disease
- Head and neck radiotherapy
# Screening
There is insufficient evidence to recommend routine screening for sialadenitis.
# Natural History, Complications, and Prognosis
## Natural History
- If left untreated, patients with sialadeitis may progress to develop secondary infection and chronic sialadenitis including gland atrophy.
## Complications
- Common complications of sialadenitis include:
Recurrence
Abscess
Cellulitis
- Recurrence
- Abscess
- Cellulitis
## Prognosis
- Prognosis is generally good with fluid management and antimicrobial therapy, but edema in the gland may persist for several weeks.
# Diagnosis
## Diagnostic Criteria
Acute sialadenitis is a clinical diagnosis and presents with pain, swelling, and redness of skin.
## History and Symptoms
The most common symptoms of sialadenitis include fever and pain.
- A positive history of pain, swelling, overlying skin redness, and hard lump is suggestive of sialadenitis.
## Physical Examination
## Vital Signs
- Vital signs are usually normal, but fever may be seen in sialadenititis as a complication of sialolithiasis.
## HEENT
Normal salivary gland is spongy.
In sialadenitis:
- Tenderness of the involved gland
- Palpable hard lump near the end of the involved duct or under the tongue in submandibular duct stone.
Stones, sometimes may be felt smooth or irregular.
- Stones, sometimes may be felt smooth or irregular.
- In total obstruction, no saliva is being produced from the duct.
- Erythema of the floor of the mouth
- Pus discharging from the duct
- Stone in the minor salivary glands can be felt as a small nodule
- Stones are typically rock hard and small; they may be smooth or irregular. They are most commonly felt within the ductal system.
## Neck
- Cervical lymphadenitis in cases of infection.
# Laboratory Findings
- There are no diagnostic laboratory findings associated with sialadenitis. In the case of superimposed inflammation and infection, high ESR or leukocytosis may be seen.
- Duct discharge should be used for culture.
## Electrocardiogram
There are no ECG findings associated with sialadenitis.
## X-ray
- An x-ray is not diagnostic in sialadenitis.
- An x-ray may be helpful in the diagnosis of chronic sialadenitis. Findings on an x-ray suggestive of chronic sialadenitis include:
Radiopaque stones: 43-60% of the parotid stones and 80-95% of the submandibular stones are radiopaque and can be seen in x-ray.
- Radiopaque stones: 43-60% of the parotid stones and 80-95% of the submandibular stones are radiopaque and can be seen in x-ray.
## Ultrasound
- There are no ultrasound findings associated with acute sialadenitis.
## CT scan
- There are no CT scan findings associated with acute sialadenitis. However, a CT scan may be helpful in the diagnosis of complications of sialadenitis, which include abscess.
Most stones contain enough calcium, so they can be visible on non-contrast CT scan.
- Most stones contain enough calcium, so they can be visible on non-contrast CT scan.
- The following results are seen in acute obstruction of the salivary duct due to sialadenitis after administration of contrast:
The gland may appear enlarged
Hyperdensity of gland with stranding
- The gland may appear enlarged
- Hyperdensity of gland with stranding
- In chronic sialadenitis, fat atrophy and reduction in salivary gland parenchymal volume may be seen.
## Other Imaging Findings
Sialography is contraindicated in active infection of the involved gland.
## Other Diagnostic Studies
- There are no other diagnostic studies associated with sialadenitis.
# Treatment
## Medical Therapy
- Most cases are easily treated with conservative medical management. Acute symptoms resolve within 1 week; however, edema in the area may last for several weeks.
- Antibiotics usage in the case of superimposed infection:
Preferred regimen (1): Dicloxacillin 500 mg q 6h PO for 7 to 10 days.
Preferred regimen (2): Cephalexin 500 mg q 6h PO for 7 to 10 days.
- Preferred regimen (1): Dicloxacillin 500 mg q 6h PO for 7 to 10 days.
- Preferred regimen (2): Cephalexin 500 mg q 6h PO for 7 to 10 days.
- If the patients clinics did not change in five days of using above antibiotics, change to:
Preferred regimen (1): Amoxicillin/clavulanate 625 mg q 8h PO for 7 to 10 days.
Preferred regimen (2): Clindamycin 300 mg q 8h PO for 7 to 10 days.\
- Preferred regimen (1): Amoxicillin/clavulanate 625 mg q 8h PO for 7 to 10 days.
- Preferred regimen (2): Clindamycin 300 mg q 8h PO for 7 to 10 days.\
- Many cases of sialadenitis cannot be cured by using medical therapy alone; invasive, or open surgery methods can be used for salivary gland stones. The interventional methods are discussed in the sialadenitis surgery page.
## Surgery
- Certain individuals with chronic bacterial infections who do not respond to appropriate conservative and antibiotic measures may require either radiation or removal of the affected gland to control its symptoms.
- The mainstay of treatment for acute siladenitis is medical therapy. Surgery is not the first-line treatment option for patients with acute siladenitis. Surgery is usually reserved for patients with abscess that do not respond to medical therapy.
- Surgical resection of involved gland in chronic bacterial sialadenitis may be considered if it does not respond to medical therapy.
## Surgical intervention
For surgical intervention of sialolithiasis please click here.
## Primary Prevention
- Effective measures for the primary prevention of sialadenitis include:
Healthy oral care regimen ( brushing teeth)
Increased water intake
- Healthy oral care regimen ( brushing teeth)
- Increased water intake
- There are no available vaccines against sialolithiasis
## Secondary Prevention
Effective measures for the secondary prevention of acute sialadenitis include hygiene and repeated massaging of the gland when tenderness had subsided.
- Prevention of dehydration
- Healthy oral care regimen (brushing teeth)
- Treatment of underlying disease such as Sjögren's syndrome and gout
- Avoid anticholinergic and diuretic medications
|
Sialadenitis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hamid Qazi, MD, BSc [2] Mahda Alihashemi M.D. [3]
Synonyms and keywords:Sialadenitis, salivary gland inflammation
# Overview
Sialadenitis is the inflammation of a salivary gland. The causes of sialadenitis include bacterial and viral infections, such as mumps and HIV, obstruction from stones or radiation, and autoimmune disorders such as Sjogren's syndrome. The complications of sialadenitis include recurrence, abscess, and chronic sialadenitis. Sialadenitis must be differentiated from other diseases that can cause swelling in the salivary glands, such as sialolithiasis, human immunodeficiency virus, radiation, and systemic diseases such as, sarcoidosis, and sjögren's syndrome. History from the patient will reveal symptoms of sialadenitis that include fever, redness of overlying skin, pain, and difficulty in opening the mouth. The diagnosis of choice is a high resolution CT scan. Sialoendoscopy can be used in the diagnosis of small stones and differentiate them from polyps. Conservative treatment is the first line of therapy in the most patients and it involves Hydration, applying moist heat, massaging the gland, duct milking, discontinuation of medication that can decrease the saliva flow, such as the TCAs (because of their anticholinergic effects). Also, antibiotics can be used in the case of superimposed infection. Preferred regimens are Dicloxacillin 500 mg q 6h PO for 7 to 10 days, or Cephalexin 500 mg q 6h PO for 7 to 10 days.
# Historical Perspective
The historical perspective of sialadenitis is as follows:[1]
- In 17th century, major salivary gland ductal system in anatomical human studies was first reported.
- In 1990, , Konigsberger et al. performed the first successful salivary endoscopy.[2]
- In 2004, Zenk et al. reported the use of semirigid sialendoscope in different types of obstructive salivary disorders.[3]
- In 2006, Nahlieli et al. described sialendoscopy in the management of radioiodine sialadenitis.[4]
# Classification
- There is no established system for the classification of sialadenitis, but it can be classified according to location of the stone.[5]
- Submandibular stones can be classified further as anterior, or posterior in relation to the mandibular first molar teeth.
- Stones may be radiopaque, where they can be radiopaque or radiolucent.
- Stones may also be symptomatic or asymptomatic.
# Pathophysiology
- Sialadenitis is the inflammation of a salivary gland. [6]
- Swelling is usually present in this condition.
- Acute sialadenitis may be caused by viral or bacterial infection[7]
Parotid and submandibular glands are more involved in acute sialadenitis. Approximately 10% sialadenitis cases are related to the involvement of submandibular gland.
- Parotid and submandibular glands are more involved in acute sialadenitis. Approximately 10% sialadenitis cases are related to the involvement of submandibular gland.
- Chronic sialadenitis is caused by repeated episodes of inflammation and finally it progresses in to salivary gland dysfunction.
# Causes
Common causes of sialadenitis include the following:
Bacterial and viral infections:[8]
- Mumps
- HIV
- Staph aureus
- Streptococci viridans
- Pseudomonas aeruginosa
- Escherichia coli
- Moraxella catarrhalis
- Tuberculosis[9]
Obstruction:
- Stones
- Radiation
- Strictures
- Sarcoidosis
Autoimmune disorders:
- Sjogren's syndrome
# Differentiating sialadenitis from Other Diseases
- Sialadenitis must be differentiated from other diseases that cause swelling in salivary glands, such as sialolithiasis, human immunodeficiency virus, radiation, and systemic diseases such as, sarcoidosis, and sjögren's syndrome.[10][11][12][13][14][15][16][17]
# Epidemiology and Demographics
- The exact prevalence of submandibular sialadenitis is unclear.
- The incidence of acute sialadenitis is approximately 275 per 100,000 individuals in United Kingdom.[18]
- Patients of all age groups may develop sialadenitis.
- Sialadenitis commonly affects older and dehydrated patients.
# Risk Factors
## Common Risk Factors
Common risk factors in the development of sialolithisis which can lead to sialadenitis include:[19]
- Dehydration
- Diuretics
- Local trauma
- Sjögren's syndrome
- Gout
- Anticholinergic medications
- Smoking
- History of nephrolithiasis
- Chronic periodontal disease
- Head and neck radiotherapy[20]
# Screening
There is insufficient evidence to recommend routine screening for sialadenitis.
# Natural History, Complications, and Prognosis
## Natural History
- If left untreated, patients with sialadeitis may progress to develop secondary infection and chronic sialadenitis including gland atrophy.[21]
## Complications
- Common complications of sialadenitis include:[22]
Recurrence
Abscess
Cellulitis
- Recurrence
- Abscess
- Cellulitis
## Prognosis
- Prognosis is generally good with fluid management and antimicrobial therapy, but edema in the gland may persist for several weeks.[16]
# Diagnosis
## Diagnostic Criteria
Acute sialadenitis is a clinical diagnosis and presents with pain, swelling, and redness of skin.[23]
## History and Symptoms
The most common symptoms of sialadenitis include fever and pain.[22]
- A positive history of pain, swelling, overlying skin redness, and hard lump is suggestive of sialadenitis.
## Physical Examination
## Vital Signs
- Vital signs are usually normal, but fever may be seen in sialadenititis as a complication of sialolithiasis.[7]
## HEENT
Normal salivary gland is spongy.
In sialadenitis:[24][25]
- Tenderness of the involved gland
- Palpable hard lump near the end of the involved duct or under the tongue in submandibular duct stone.
Stones, sometimes may be felt smooth or irregular.
- Stones, sometimes may be felt smooth or irregular.
- In total obstruction, no saliva is being produced from the duct.
- Erythema of the floor of the mouth
- Pus discharging from the duct
- Stone in the minor salivary glands can be felt as a small nodule
- Stones are typically rock hard and small; they may be smooth or irregular. They are most commonly felt within the ductal system.
## Neck
- Cervical lymphadenitis in cases of infection.
# Laboratory Findings
- There are no diagnostic laboratory findings associated with sialadenitis. In the case of superimposed inflammation and infection, high ESR or leukocytosis may be seen.
- Duct discharge should be used for culture.[26]
## Electrocardiogram
There are no ECG findings associated with sialadenitis.
## X-ray
- An x-ray is not diagnostic in sialadenitis.
- An x-ray may be helpful in the diagnosis of chronic sialadenitis. Findings on an x-ray suggestive of chronic sialadenitis include:[27]
Radiopaque stones: 43-60% of the parotid stones and 80-95% of the submandibular stones are radiopaque and can be seen in x-ray.
- Radiopaque stones: 43-60% of the parotid stones and 80-95% of the submandibular stones are radiopaque and can be seen in x-ray.
## Ultrasound
- There are no ultrasound findings associated with acute sialadenitis.
## CT scan
- There are no CT scan findings associated with acute sialadenitis. However, a CT scan may be helpful in the diagnosis of complications of sialadenitis, which include abscess.[28][23]
Most stones contain enough calcium, so they can be visible on non-contrast CT scan.
- Most stones contain enough calcium, so they can be visible on non-contrast CT scan.
- The following results are seen in acute obstruction of the salivary duct due to sialadenitis after administration of contrast:
The gland may appear enlarged
Hyperdensity of gland with stranding
- The gland may appear enlarged
- Hyperdensity of gland with stranding
- In chronic sialadenitis, fat atrophy and reduction in salivary gland parenchymal volume may be seen.
## Other Imaging Findings
Sialography is contraindicated in active infection of the involved gland.
## Other Diagnostic Studies
- There are no other diagnostic studies associated with sialadenitis.
# Treatment
## Medical Therapy
- Most cases are easily treated with conservative medical management. Acute symptoms resolve within 1 week; however, edema in the area may last for several weeks.[29]
- Antibiotics usage in the case of superimposed infection:[23]
Preferred regimen (1): Dicloxacillin 500 mg q 6h PO for 7 to 10 days.
Preferred regimen (2): Cephalexin 500 mg q 6h PO for 7 to 10 days.
- Preferred regimen (1): Dicloxacillin 500 mg q 6h PO for 7 to 10 days.
- Preferred regimen (2): Cephalexin 500 mg q 6h PO for 7 to 10 days.
- If the patients clinics did not change in five days of using above antibiotics, change to:
Preferred regimen (1): Amoxicillin/clavulanate 625 mg q 8h PO for 7 to 10 days.
Preferred regimen (2): Clindamycin 300 mg q 8h PO for 7 to 10 days.\
- Preferred regimen (1): Amoxicillin/clavulanate 625 mg q 8h PO for 7 to 10 days.
- Preferred regimen (2): Clindamycin 300 mg q 8h PO for 7 to 10 days.\
- Many cases of sialadenitis cannot be cured by using medical therapy alone; invasive, or open surgery methods can be used for salivary gland stones. The interventional methods are discussed in the sialadenitis surgery page.
## Surgery
- Certain individuals with chronic bacterial infections who do not respond to appropriate conservative and antibiotic measures may require either radiation or removal of the affected gland to control its symptoms.
- The mainstay of treatment for acute siladenitis is medical therapy. Surgery is not the first-line treatment option for patients with acute siladenitis. Surgery is usually reserved for patients with abscess that do not respond to medical therapy.[23]
- Surgical resection of involved gland in chronic bacterial sialadenitis may be considered if it does not respond to medical therapy. [22]
## Surgical intervention
For surgical intervention of sialolithiasis please click here.
## Primary Prevention
- Effective measures for the primary prevention of sialadenitis include:[19][29][23]
Healthy oral care regimen ( brushing teeth)
Increased water intake
- Healthy oral care regimen ( brushing teeth)
- Increased water intake
- There are no available vaccines against sialolithiasis
## Secondary Prevention
Effective measures for the secondary prevention of acute sialadenitis include hygiene and repeated massaging of the gland when tenderness had subsided. [22][17][1][29][30]
- Prevention of dehydration
- Healthy oral care regimen (brushing teeth)
- Treatment of underlying disease such as Sjögren's syndrome and gout
- Avoid anticholinergic and diuretic medications
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https://www.wikidoc.org/index.php/Acute_sialadenitis
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5b5e932d207ce6c7685543cb7659fb2a4d6db5e5
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wikidoc
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Adamantinoma
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Adamantinoma
Synonyms and keywords:
# Overview
- Adamantinoma was first discovered by Fischer in 1913. Adamantinoma is classified into 2 distinct types: classic and differentiated (Osteofibrous dysplasia (OFD) - like). Adamantinoma is a low grade, malignant bone tumor. This tumor is predominantly located in tibia ( most in mid-portion of tibia). Most locations of the tumor include tibia, ipsilateral fibula, humerus, ulna, femur, fibula. It is a Yellow gray or grayish white tumor. In microscopic examination admixture of both epithelial and osteofibrous component can be seen. Adamantinoma may be caused by displacement of basal epithelium of skin during embryogenesis, traumatic implantation. Adamantinoma is a rare bone cancer ( 0.1–0.5% of all primary bone tumors ). Risk factors in the development of adamantinoma may include benign osteofibrous dysplasia. If left untreated, 15-30% of patients with adamantinoma may metastasize to other parts of the body such as lungs or nearby lymph nodes. The diagnosis of adamantinoma is based on the findings of radiologic studies such as x-ray, CT, and MRI. The most common symptoms of adamantinoma include swelling with or without pain. Less common symptoms of adamantinoma include pathological fracture. Adamantinoma may present with bowing deformity of the tibia. There is no medical therapy for adamantinoma. Radiation therapy and chemotherapy are not effective. Surgery is the mainstay of treatment for adamantinoma.
# Historical Perspective
Adamantinoma was first discovered by Fischer in 1913.
# Classification
Adamantinoma is classified into 2 distinct types: classic and differentiated (Osteofibrous dysplasia (OFD) - like)
# Pathophysiology
Adamantinoma is a low grade, malignant bone tumor. This tumor is predominatly located in tibia ( most in mid-portion of tibia). It is a biphasic tumor including epithelial and osteofibrous components..
Most locations of the tumor include:
- Tibia ( 80 to 85 percent of cases)
- Ipsilateral fibula (10 to15% of cases)
- Humerus
- Ulna
- Femur
- Fibula
- Radius
- Ribs
- Spine
- Small bones of the hand and foot
- Yellow gray or grayish white tumor
- Fleshy or firm in consistency
- Some OFD like adamantinomas are solid
- Macroscopic cysts containing blood like fluid, occasionally
- Admixture of both epithelial and osteofibrous component, most commonly solid nests of basaloid cells in classic adamantinoma
- Nuclear atypia in a few cases
- Several patterns of growth including
Tubular
Basaloid
Squamous
Spindle-cell
Osteofibrous dysplasia-like variant
- Tubular
- Basaloid
- Squamous
- Spindle-cell
- Osteofibrous dysplasia-like variant
- A few cases from a large series have exhibited nuclear atypia
- Foci of calcification, giant cells
- Foci of xanthoma and spindle cells
- Positives for keratins 14 and 19
# Causes
Adamantinoma may be caused by:
- Displacement of basal epithelium of skin during embrogenesis
- Traumatic implantation
- Synovial origin
# Differentiating Adamantinoma from Other Diseases
Adamantinoma must be differentiated from aneurrysmal bone cyst, unicameral bone cyst, fibrous dysplasia, chondromyxoid fibroma, eosinophilic granuloma, giant cell tumor, chondromyxoid fibroma, osteomyelitis, chondrosarcoma, epithelial metastasis, hemangioendothelioma, nonossifying fibromas, angiosarcoma.
# Epidemiology and Demographics
Adamantinoma is a rare bone cnacer ( 0.1–0.5% of all primary bone tumors ).
The prevalence of Adamantinoma is approximately 0.11 per 100000 individuals in Europe.
The incidence of Adamantinoma was estimated to be less than 300 cases worldwide.
Patients of all age groups may develop adamantinoma. The median age at diagnosis is 25 to 35 years.
Men are more commonly affected by adamantinoma than women. The men to women ratio is approximately 5 to 4.
# Risk Factors
Risk factors in the development of adamantinoma may include benign osteofibrous dysplasia. It maybe a precursor of adamantinoma.
# Screening
There is insufficient evidence to recommend routine screening for adamantinoma.
# Natural History, Complications, and Prognosis
If left untreated, 15-30% of patients with adamantinoma may metastasize to other parts of the body such as lungs or nearby lymph nodes. . Adamantinoma has mortality rate of 13%to 18%.
Complications of adamantinoma include metastases to the lungs.
Prognosis is generally good. Male patint, short duration of symtoms, young age ( less than 20 years) and lack of squamous differentiantion of tumor are related with unfavorable clinical outcome.
# Diagnosis
## Diagnostic Study of Choice
The diagnosis of adamantinoma is based on the findings of radiologic studies such as x-ray, CT, and MRI.
## History and Symptoms
The initial symptoms of adamantinoma are often nonspecific. The most common symptoms of adamantinoma include swelling with or without pain. Less common symptoms of adamantinoma include pathological fracture( 23% of patients) and neurological symptoms in spinal lesions.
## Physical Examination
Adamantinoma may present with bowing deformity of the tibia.
Spinal lesions may be manifested by neurologic symptoms in addition to pain.
## Laboratory Findings
Paraneoplastic hypercalcemia can be seen in tibial adamantinoma and pulmonary metastasis
## Electrocardiogram
There are no ECG findings associated with adamantinoma.
## X-ray
An x-ray may be helpful in the diagnosis of adamantinoma. Findings on an x-ray suggestive of adamantinoma include central or eccentric, multilocular lesion in tibia. The tumor is found in the diaphyseal location. Metaphyseal extention or only involvement of metaphysis is seen occationally. The lesions are well circumscribed surrounded ring-shaped densities ( soap -bubble appearance). The lesion are more intra-cortical, but if they destroy cortex, extracortical soft tisuue invasion can be seen. The periosteal reaction can be minimal to prominnet.
## Echocardiography or Ultrasound
There are no echocardiography/ultrasound findings associated with adamantinoma.
## CT scan
CT scan may be helpful in the diagnosis of adamantinoma. Findings on CT scan suggestive of adamantinoma include cortical involvement and the soft tissue extension if it exist.
Chest CT scan can detect pulmonary metastasis.
## MRI
MRI is helpful in the diagnosis of adamantinoma. It is useful in detection distant cortical foci, soft tissue, and intramedullary extension. MRI is a very important diagnostic study for stating of tumor and tumor-free margins. Findings on MRI suggestive of adamantinoma include a solitary lobulated focus or multiple small nodules in one or more foci. Tumors demonstrate low signal intensity on T1-weighted images and high signal on T2-weighted images.
## Other Imaging Findings
Bone scan may be helpful in the diagnosis of adamantinoma. Findings on a nuclear medicine suggestive of adamantioma include:
- Increased blood flow in the region of the tumor
- Increased accumulation of technetium-99m methylene diphosphate in the area of the tumor
## Other Diagnostic Studies
There are no other diagnostic studies associated with adamantinoma.
# Treatment
## Medical Therapy
There is no medical therapy for adamantinoma. Radition therapy and chemotherapy are not effective.
## Surgery
Surgery is the mainstay of treatment for adamantinoma.
- Tumor resection with wide operative margins and then limb reconstruction
- Amputation
## Primary Prevention
There are no established measures for the primary prevention of adamantinoma.
## Secondary Prevention
There are no established measures for the secondary prevention of adamantinoma.
|
Adamantinoma
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mahda Alihashemi M.D. [2] [3] [4] [5] [6]
Synonyms and keywords:
# Overview
- Adamantinoma was first discovered by Fischer in 1913. Adamantinoma is classified into 2 distinct types: classic and differentiated (Osteofibrous dysplasia (OFD) - like). Adamantinoma is a low grade, malignant bone tumor. This tumor is predominantly located in tibia ( most in mid-portion of tibia). Most locations of the tumor include tibia, ipsilateral fibula, humerus, ulna, femur, fibula. It is a Yellow gray or grayish white tumor. In microscopic examination admixture of both epithelial and osteofibrous component can be seen. Adamantinoma may be caused by displacement of basal epithelium of skin during embryogenesis, traumatic implantation. Adamantinoma is a rare bone cancer ( 0.1–0.5% of all primary bone tumors ). Risk factors in the development of adamantinoma may include benign osteofibrous dysplasia. If left untreated, 15-30% of patients with adamantinoma may metastasize to other parts of the body such as lungs or nearby lymph nodes. The diagnosis of adamantinoma is based on the findings of radiologic studies such as x-ray, CT, and MRI. The most common symptoms of adamantinoma include swelling with or without pain. Less common symptoms of adamantinoma include pathological fracture. Adamantinoma may present with bowing deformity of the tibia. There is no medical therapy for adamantinoma. Radiation therapy and chemotherapy are not effective. Surgery is the mainstay of treatment for adamantinoma.
# Historical Perspective
Adamantinoma was first discovered by Fischer in 1913.[1]
# Classification
Adamantinoma is classified into 2 distinct types: classic and differentiated (Osteofibrous dysplasia (OFD) - like)
# Pathophysiology
Adamantinoma is a low grade, malignant bone tumor. This tumor is predominatly located in tibia ( most in mid-portion of tibia). [2] It is a biphasic tumor including epithelial and osteofibrous components.[3].
Most locations of the tumor include:[4]
- Tibia ( 80 to 85 percent of cases)
- Ipsilateral fibula (10 to15% of cases)
- Humerus
- Ulna
- Femur
- Fibula
- Radius
- Ribs
- Spine
- Small bones of the hand and foot
- Yellow gray or grayish white tumor
- Fleshy or firm in consistency
- Some OFD like adamantinomas are solid
- Macroscopic cysts containing blood like fluid, occasionally
- Admixture of both epithelial and osteofibrous component, most commonly solid nests of basaloid cells in classic adamantinoma
- Nuclear atypia in a few cases
- Several patterns of growth including
Tubular
Basaloid
Squamous
Spindle-cell
Osteofibrous dysplasia-like variant
- Tubular
- Basaloid
- Squamous
- Spindle-cell
- Osteofibrous dysplasia-like variant
- A few cases from a large series have exhibited nuclear atypia
- Foci of calcification, giant cells [7]
- Foci of xanthoma and spindle cells[8]
- Positives for keratins 14 and 19[9]
# Causes
Adamantinoma may be caused by: [10]
- Displacement of basal epithelium of skin during embrogenesis
- Traumatic implantation
- Synovial origin
# Differentiating Adamantinoma from Other Diseases
Adamantinoma must be differentiated from aneurrysmal bone cyst, unicameral bone cyst, fibrous dysplasia, chondromyxoid fibroma, eosinophilic granuloma, giant cell tumor, chondromyxoid fibroma, osteomyelitis, chondrosarcoma, epithelial metastasis, hemangioendothelioma, nonossifying fibromas, angiosarcoma.
# Epidemiology and Demographics
Adamantinoma is a rare bone cnacer ( 0.1–0.5% of all primary bone tumors ).[11]
The prevalence of Adamantinoma is approximately 0.11 per 100000 individuals in Europe.
The incidence of Adamantinoma was estimated to be less than 300 cases worldwide.
Patients of all age groups may develop adamantinoma. The median age at diagnosis is 25 to 35 years.
Men are more commonly affected by adamantinoma than women. The men to women ratio is approximately 5 to 4.[12]
# Risk Factors
Risk factors in the development of adamantinoma may include benign osteofibrous dysplasia. It maybe a precursor of adamantinoma.[13]
# Screening
There is insufficient evidence to recommend routine screening for adamantinoma.
# Natural History, Complications, and Prognosis
If left untreated, 15-30% of patients with adamantinoma may metastasize to other parts of the body such as lungs or nearby lymph nodes. [14]. Adamantinoma has mortality rate of 13%to 18%. [15]
Complications of adamantinoma include metastases to the lungs.
Prognosis is generally good. Male patint, short duration of symtoms, young age ( less than 20 years) and lack of squamous differentiantion of tumor are related with unfavorable clinical outcome. [16]
# Diagnosis
## Diagnostic Study of Choice
The diagnosis of adamantinoma is based on the findings of radiologic studies such as x-ray, CT, and MRI.
## History and Symptoms
The initial symptoms of adamantinoma are often nonspecific. The most common symptoms of adamantinoma include swelling with or without pain. Less common symptoms of adamantinoma include pathological fracture( 23% of patients) [17] and neurological symptoms in spinal lesions.[18]
## Physical Examination
Adamantinoma may present with bowing deformity of the tibia.[19]
Spinal lesions may be manifested by neurologic symptoms in addition to pain.
## Laboratory Findings
Paraneoplastic hypercalcemia can be seen in tibial adamantinoma and pulmonary metastasis[20]
## Electrocardiogram
There are no ECG findings associated with adamantinoma.
## X-ray
An x-ray may be helpful in the diagnosis of adamantinoma. Findings on an x-ray suggestive of adamantinoma include central or eccentric, multilocular lesion in tibia. The tumor is found in the diaphyseal location. Metaphyseal extention or only involvement of metaphysis is seen occationally. The lesions are well circumscribed surrounded ring-shaped densities ( soap -bubble appearance). The lesion are more intra-cortical, but if they destroy cortex, extracortical soft tisuue invasion can be seen. The periosteal reaction can be minimal to prominnet.[21]
## Echocardiography or Ultrasound
There are no echocardiography/ultrasound findings associated with adamantinoma.
## CT scan
CT scan may be helpful in the diagnosis of adamantinoma. Findings on CT scan suggestive of adamantinoma include cortical involvement and the soft tissue extension if it exist.
Chest CT scan can detect pulmonary metastasis. [22]
## MRI
MRI is helpful in the diagnosis of adamantinoma. It is useful in detection distant cortical foci, soft tissue, and intramedullary extension. MRI is a very important diagnostic study for stating of tumor and tumor-free margins. Findings on MRI suggestive of adamantinoma include a solitary lobulated focus or multiple small nodules in one or more foci. Tumors demonstrate low signal intensity on T1-weighted images and high signal on T2-weighted images.[23]
## Other Imaging Findings
Bone scan may be helpful in the diagnosis of adamantinoma. Findings on a nuclear medicine suggestive of adamantioma include:[24]
- Increased blood flow in the region of the tumor
- Increased accumulation of technetium-99m methylene diphosphate in the area of the tumor
## Other Diagnostic Studies
There are no other diagnostic studies associated with adamantinoma.
# Treatment
## Medical Therapy
There is no medical therapy for adamantinoma. Radition therapy and chemotherapy are not effective. [25]
## Surgery
Surgery is the mainstay of treatment for adamantinoma.
- Tumor resection with wide operative margins and then limb reconstruction [26]
- Amputation[27]
## Primary Prevention
There are no established measures for the primary prevention of adamantinoma.
## Secondary Prevention
There are no established measures for the secondary prevention of adamantinoma.
|
https://www.wikidoc.org/index.php/Adamantinoma
| |
90e960f80c501c7a7c3071dc5be40d527348c45b
|
wikidoc
|
Adenoviridae
|
Adenoviridae
Synonyms and keywords: Adenoviruses
# Overview
Adenoviridae are medium-sized (90-100 nm), nonenveloped (naked) icosahedral viruses composed of a nucleocapsid and a double-stranded linear DNA genome. There are over 52 different serotypes in humans, which are responsible for 5–10% of upper respiratory infections in children, and many infections in adults as well.
# Causes
Viruses of the family Adenoviridae infect various species of animals, including humans. Adenoviruses were first isolated in human adenoids (tonsils), from which the name is derived, and are classified as group I under the Baltimore classification scheme. Adenoviruses represent the largest nonenveloped viruses, because they are the maximum size able to be transported through the endosome (i.e. envelope fusion is not necessary). The virion also has a unique "spike" or fiber associated with each penton base of the capsid (see picture below) that aids in attachment to the host cell via the coxsackie-adenovirus receptor on the surface of the host cell. There are 51 immunologically distinct human adenovirus serotypes (6 species: Human adenovirus A through F) that can cause human infections ranging from respiratory disease (mainly species HAdV-B and C), and conjunctivitis (HAdV-B and D), to gastroenteritis (HAdV-F serotypes 40 and 41). Adenoviruses are unusually stable to chemical or physical agents and adverse pH conditions, allowing for prolonged survival outside of the body and water. Adenoviruses are primarily spread via respiratory droplets, however they can also be spread by fecal routes as well.
Most infections with adenovirus result in infections of the upper respiratory tract. Adenovirus infections often show up as conjunctivitis, tonsilitis (which may look exactly like strep throat and cannot be distinguished from strep except by throat culture), an ear infection, or croup. Adenoviruses can also cause gastroenteritis (stomach flu). A combination of conjunctivitis and tonsilitis is particularly common with adenovirus infections. Some children (especially small ones) can develop adenovirus bronchiolitis or pneumonia, both of which can be severe. In babies, adenoviruses can also cause coughing fits that look almost exactly like whooping cough. Adenoviruses can also cause viral meningitis or encephalitis. Rarely, adenovirus can cause cystitis (inflammation of the urinary bladder—a form of urinary tract infection—with blood in the urine).
Most people recover from adenovirus infections by themselves, but people with immunodeficiency sometimes die of adenovirus infections, and—rarely—even previously healthy people can die of these infections.
Adenoviruses are often transmitted by coughed-out droplets, but can also be transmitted by contact with an infected person, or by virus particles left on objects such as towels and faucet handles. Some people with adenovirus gastroenteritis may shed the virus in their stools for months after getting over the symptoms. The virus can be passed from one person to another through some sexual practices, and through water in swimming pools that do not have enough chlorine in them. As with many other illnesses, good handwashing is one way to lessen the spread of adenoviruses from one person to another. Heat and bleach will kill adenoviruses on objects.
# Genera
This family contains the following genera:
- Genus Aviadenovirus; type species: Fowl adenovirus A
- Genus Atadenovirus; type species: Ovine adenovirus D
- Genus Mastadenovirus; type species: Human adenovirus C; others include AD-36
- Genus Siadenovirus; type species: Frog adenovirus
## Adenoviruses in humans
- See Adenovirus infection
- See Adenovirus serotype 14
# Genome
The adenovirus genome is linear, non-segmented double stranded (ds) DNA which is around 30–38 Kbp. This allows the virus to theoretically carry 30 to 40 genes. Although this is significantly larger than other viruses in its Baltimore group it is still a very simple virus and is heavily reliant on the host cell for survival and replication. An interesting feature of this viral genome is that it has a terminal 55 kDa protein associated with each of the 5' ends of the linear dsDNA, these are used as primers in viral replication and ensure that the ends of the virus' linear genome are adequately replicated.
# Replication
Adenoviruses possess a linear dsDNA genome and are able to replicate in the nucleus of mammalian cells using the host’s replication machinery.
Entry of adenoviruses into the host cell involves two sets of interactions between the virus and the host cell. Entry into the host cell is initiated by the knob domain of the fiber protein binding to the cell receptor. The two currently established receptors are: CD46 for the group B human adenovirus serotypes and the coxsackievirus adenovirus receptor (CAR) for all other serotypes. There are some reports suggesting MHC molecules and sialic acid residues functioning in this capacity as well. This is followed by a secondary interaction, where a specialized motif in the penton base protein interacts with an integrin molecule. It is the co-receptor interaction that stimulates internalization of the adenovirus. This co-receptor molecule is αv integrin. Binding to αv integrin results in endocytosis of the virus particle via clathrin-coated pits. Attachment to αv integrin stimulates cell signaling and thus induces actin polymerization resulting in entry of the virion into the host cell within an endosome.
Once the virus has successfully gained entry into the host cell the endosome acidifies, which alters virus topology by causing capsid components to disassociate. These changes as well as the toxic nature of the pentons results in the release of the virion into the cytoplasm. With the help of cellular microtubules the virus is transported to the nuclear pore complex whereby the adenovirus particle disassembles. Viral DNA is subsequently released which can enter the nucleus via the nuclear pore. After this the DNA associates with histone molecules. Thus viral gene expression can occur and new virus particles can be generated.
The adenovirus life cycle is separated, by the DNA replication process, into two phases: an early and a late phase. In both phases a primary transcript is generated which is alternatively spliced to generate monocistronic mRNAs compatible with the host’s ribosome, allowing for the products to be translated.
The early genes are responsible for expressing mainly non-structural, regulatory proteins. The goal of these proteins is threefold: to alter the expression of host proteins that are necessary for DNA synthesis; to activate other virus genes (such as the virus-encoded DNA polymerase); and to avoid premature death of the infected cell by the host-immune defenses (blockage of apoptosis, blockage of interferon activity, and blockage of MHC class I translocation and expression).
Some adenoviruses under specialized conditions can transform cells using their early gene products. E1a (binds Retinoblastoma tumor suppressor protein) has been found to immortalize primary cells in vitro allowing E1b (binds p53 tumor suppressor) to assist and stably transform the cells. Nevertheless, they are reliant upon each other to successfully transform the host cell and form tumors.
DNA replication separates the early and late phases. Once the early genes have liberated adequate virus proteins, replication machinery and replication substrates, replication of the adenovirus genome can occur. A terminal protein that is covalently bound to the 5’ end of the adenovirus genome acts as a primer for replication. The viral DNA polymerase then uses a strand displacement mechanism, as opposed to the conventional Okazaki fragments used in mammalian DNA replication, to replicate the genome.
The late phase of the adenovirus life cycle is focused on producing sufficient quantities of structural protein to pack all the genetic material produced by DNA replication. Once the viral components have successfully been replicated the virus is assembled into its protein shells and released from the cell as a result of virally induced cell lysis.
# Differential diagnosis
Adenoviridae infection must be differentiated from other causes of viral, bacterial, and parasitic gastroentritis.
8Small bowel diarrhea: watery, voluminous with less than 5 WBC/high power field
Large bowel diarrhea: Mucousy and/or bloody with less volume and more than 10 WBC/high power field
† It could be as high as 1000 based on patient's immunity system.
The table below summarizes the findings that differentiate inflammatory causes of chronic diarrhea
# Adenoviruses in animals
Two types of canine adenoviruses are well known, type 1 and 2. Type 1 causes infectious canine hepatitis, a potentially fatal disease involving vasculitis and hepatitis. Type 1 infection also can cause respiratory and eye infections. Canine adenovirus 2 (CAdV-2) is one of the potential causes of kennel cough. Core vaccines for dogs include attenuated live CAdV-2, which produces immunity to CAdV-1 and CAdV-2. CAdV-1 was initially used in a vaccine for dogs, but corneal edema was a common complication.
Adenoviruses are also known to cause respiratory infections in horses, cattle, pigs, sheep, and goats. Equine adenovirus 1 can also cause fatal disease in immunocompromised Arabian foals, involving pneumonia and destruction of pancreatic and salivary gland tissue.
# Treatment and prevention
As with almost all viruses, there are no antibiotics that help with an adenoviral infection, so treatment is largely directed at the symptoms (such as acetaminophen for fever). A doctor may give antibiotic eyedrops for conjunctivitis, since it takes a while to test to see if the eye infection is bacterial or viral and to help prevent secondary bacterial infections.
In the past, US military recruits were vaccinated against two serotypes of adenotypes, with a corresponding decrease in illnesses caused by those serotypes. The vaccine is no longer manufactured, and there are currently no vaccines available to protect against the adenovirus. Good hygiene, including handwashing, is still the best way to avoid picking up the adenovirus from an infected person.
# Treatment Regimen
- Adenovirus
- 1. In severe cases of pneumonia or post hematopoietic stem cell transplantation
- Preferred regimen (1): Cidofovir 5 mg/kg/week IV for 2 weeks, then every 2 weeks AND Probenecid 1.25 g/M2 PO given 3 hours before Cidofovir and 3 & 9 hours after each infusion
- Preferred regimen (2): Cidofovir 1 mg/kg IV 3 times per week
- Note: Ganciclovir, Foscarnet and Ribavirin are not recommended for use on adenovirus infection.
- 2. For hemorrhagic cystitis
- Preferred regimen: Cidofovir (5 mg/kg in 100 mL saline instilled into bladder) intravesical
- 3. Pink eye (viral conjunctivitis)
- Preferred regimen: No specific treatment available. If symptomatic, cold artificial tears may help.
- 4.Bronchitis
- Preferred regimen: No specific therapy recommended, treatment is symptomatic.
|
Adenoviridae
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Adenoviruses
# Overview
Adenoviridae are medium-sized (90-100 nm), nonenveloped (naked) icosahedral viruses composed of a nucleocapsid and a double-stranded linear DNA genome. There are over 52 different serotypes in humans, which are responsible for 5–10% of upper respiratory infections in children, and many infections in adults as well.
# Causes
Viruses of the family Adenoviridae infect various species of animals, including humans. Adenoviruses were first isolated in human adenoids (tonsils), from which the name is derived, and are classified as group I under the Baltimore classification scheme. Adenoviruses represent the largest nonenveloped viruses, because they are the maximum size able to be transported through the endosome (i.e. envelope fusion is not necessary). The virion also has a unique "spike" or fiber associated with each penton base of the capsid (see picture below) that aids in attachment to the host cell via the coxsackie-adenovirus receptor on the surface of the host cell. There are 51 immunologically distinct human adenovirus serotypes (6 species: Human adenovirus A through F) that can cause human infections ranging from respiratory disease (mainly species HAdV-B and C), and conjunctivitis (HAdV-B and D), to gastroenteritis (HAdV-F serotypes 40 and 41). Adenoviruses are unusually stable to chemical or physical agents and adverse pH conditions, allowing for prolonged survival outside of the body and water. Adenoviruses are primarily spread via respiratory droplets, however they can also be spread by fecal routes as well.
Most infections with adenovirus result in infections of the upper respiratory tract. Adenovirus infections often show up as conjunctivitis, tonsilitis (which may look exactly like strep throat and cannot be distinguished from strep except by throat culture), an ear infection, or croup. Adenoviruses can also cause gastroenteritis (stomach flu). A combination of conjunctivitis and tonsilitis is particularly common with adenovirus infections. Some children (especially small ones) can develop adenovirus bronchiolitis or pneumonia, both of which can be severe. In babies, adenoviruses can also cause coughing fits that look almost exactly like whooping cough. Adenoviruses can also cause viral meningitis or encephalitis. Rarely, adenovirus can cause cystitis (inflammation of the urinary bladder—a form of urinary tract infection—with blood in the urine).
Most people recover from adenovirus infections by themselves, but people with immunodeficiency sometimes die of adenovirus infections, and—rarely—even previously healthy people can die of these infections.[1]
Adenoviruses are often transmitted by coughed-out droplets, but can also be transmitted by contact with an infected person, or by virus particles left on objects such as towels and faucet handles. Some people with adenovirus gastroenteritis may shed the virus in their stools for months after getting over the symptoms. The virus can be passed from one person to another through some sexual practices, and through water in swimming pools that do not have enough chlorine in them. As with many other illnesses, good handwashing is one way to lessen the spread of adenoviruses from one person to another. Heat and bleach will kill adenoviruses on objects.
# Genera
This family contains the following genera:
- Genus Aviadenovirus; type species: Fowl adenovirus A
- Genus Atadenovirus; type species: Ovine adenovirus D
- Genus Mastadenovirus; type species: Human adenovirus C; others include AD-36
- Genus Siadenovirus; type species: Frog adenovirus
## Adenoviruses in humans
- See Adenovirus infection
- See Adenovirus serotype 14
# Genome
The adenovirus genome is linear, non-segmented double stranded (ds) DNA which is around 30–38 Kbp. This allows the virus to theoretically carry 30 to 40 genes. Although this is significantly larger than other viruses in its Baltimore group it is still a very simple virus and is heavily reliant on the host cell for survival and replication. An interesting feature of this viral genome is that it has a terminal 55 kDa protein associated with each of the 5' ends of the linear dsDNA, these are used as primers in viral replication and ensure that the ends of the virus' linear genome are adequately replicated.
# Replication
Adenoviruses possess a linear dsDNA genome and are able to replicate in the nucleus of mammalian cells using the host’s replication machinery.
Entry of adenoviruses into the host cell involves two sets of interactions between the virus and the host cell. Entry into the host cell is initiated by the knob domain of the fiber protein binding to the cell receptor. The two currently established receptors are: CD46 for the group B human adenovirus serotypes and the coxsackievirus adenovirus receptor (CAR) for all other serotypes. There are some reports suggesting MHC molecules and sialic acid residues functioning in this capacity as well. This is followed by a secondary interaction, where a specialized motif in the penton base protein interacts with an integrin molecule. It is the co-receptor interaction that stimulates internalization of the adenovirus. This co-receptor molecule is αv integrin. Binding to αv integrin results in endocytosis of the virus particle via clathrin-coated pits. Attachment to αv integrin stimulates cell signaling and thus induces actin polymerization resulting in entry of the virion into the host cell within an endosome.[2]
Once the virus has successfully gained entry into the host cell the endosome acidifies, which alters virus topology by causing capsid components to disassociate. These changes as well as the toxic nature of the pentons results in the release of the virion into the cytoplasm. With the help of cellular microtubules the virus is transported to the nuclear pore complex whereby the adenovirus particle disassembles. Viral DNA is subsequently released which can enter the nucleus via the nuclear pore.[3] After this the DNA associates with histone molecules. Thus viral gene expression can occur and new virus particles can be generated.
The adenovirus life cycle is separated, by the DNA replication process, into two phases: an early and a late phase. In both phases a primary transcript is generated which is alternatively spliced to generate monocistronic mRNAs compatible with the host’s ribosome, allowing for the products to be translated.
The early genes are responsible for expressing mainly non-structural, regulatory proteins. The goal of these proteins is threefold: to alter the expression of host proteins that are necessary for DNA synthesis; to activate other virus genes (such as the virus-encoded DNA polymerase); and to avoid premature death of the infected cell by the host-immune defenses (blockage of apoptosis, blockage of interferon activity, and blockage of MHC class I translocation and expression).
Some adenoviruses under specialized conditions can transform cells using their early gene products. E1a (binds Retinoblastoma tumor suppressor protein) has been found to immortalize primary cells in vitro allowing E1b (binds p53 tumor suppressor) to assist and stably transform the cells. Nevertheless, they are reliant upon each other to successfully transform the host cell and form tumors.
DNA replication separates the early and late phases. Once the early genes have liberated adequate virus proteins, replication machinery and replication substrates, replication of the adenovirus genome can occur. A terminal protein that is covalently bound to the 5’ end of the adenovirus genome acts as a primer for replication. The viral DNA polymerase then uses a strand displacement mechanism, as opposed to the conventional Okazaki fragments used in mammalian DNA replication, to replicate the genome.
The late phase of the adenovirus life cycle is focused on producing sufficient quantities of structural protein to pack all the genetic material produced by DNA replication. Once the viral components have successfully been replicated the virus is assembled into its protein shells and released from the cell as a result of virally induced cell lysis.
# Differential diagnosis
Adenoviridae infection must be differentiated from other causes of viral, bacterial, and parasitic gastroentritis.
8Small bowel diarrhea: watery, voluminous with less than 5 WBC/high power field
Large bowel diarrhea: Mucousy and/or bloody with less volume and more than 10 WBC/high power field
† It could be as high as 1000 based on patient's immunity system.
The table below summarizes the findings that differentiate inflammatory causes of chronic diarrhea[4][5][6][7][7]
# Adenoviruses in animals
Two types of canine adenoviruses are well known, type 1 and 2. Type 1 causes infectious canine hepatitis, a potentially fatal disease involving vasculitis and hepatitis. Type 1 infection also can cause respiratory and eye infections. Canine adenovirus 2 (CAdV-2) is one of the potential causes of kennel cough. Core vaccines for dogs include attenuated live CAdV-2, which produces immunity to CAdV-1 and CAdV-2. CAdV-1 was initially used in a vaccine for dogs, but corneal edema was a common complication.[8]
Adenoviruses are also known to cause respiratory infections in horses, cattle, pigs, sheep, and goats. Equine adenovirus 1 can also cause fatal disease in immunocompromised Arabian foals, involving pneumonia and destruction of pancreatic and salivary gland tissue.[8]
# Treatment and prevention
As with almost all viruses, there are no antibiotics that help with an adenoviral infection, so treatment is largely directed at the symptoms (such as acetaminophen for fever). A doctor may give antibiotic eyedrops for conjunctivitis, since it takes a while to test to see if the eye infection is bacterial or viral and to help prevent secondary bacterial infections.
In the past, US military recruits were vaccinated against two serotypes of adenotypes, with a corresponding decrease in illnesses caused by those serotypes. The vaccine is no longer manufactured, and there are currently no vaccines available to protect against the adenovirus. Good hygiene, including handwashing, is still the best way to avoid picking up the adenovirus from an infected person.
# Treatment Regimen
- Adenovirus[9]
- 1. In severe cases of pneumonia or post hematopoietic stem cell transplantation
- Preferred regimen (1): Cidofovir 5 mg/kg/week IV for 2 weeks, then every 2 weeks AND Probenecid 1.25 g/M2 PO given 3 hours before Cidofovir and 3 & 9 hours after each infusion
- Preferred regimen (2): Cidofovir 1 mg/kg IV 3 times per week
- Note: Ganciclovir, Foscarnet and Ribavirin are not recommended for use on adenovirus infection.[10]
- 2. For hemorrhagic cystitis
- Preferred regimen: Cidofovir (5 mg/kg in 100 mL saline instilled into bladder) intravesical[11]
- 3. Pink eye (viral conjunctivitis)
- Preferred regimen: No specific treatment available. If symptomatic, cold artificial tears may help.
- 4.Bronchitis
- Preferred regimen: No specific therapy recommended, treatment is symptomatic.
|
https://www.wikidoc.org/index.php/Adeno_associated_virus_group
| |
8c306d0a6285139491a2a8079d532534e387fa05
|
wikidoc
|
Adiponitrile
|
Adiponitrile
Adiponitrile is the chemical compound with the formula (CH2)4(CN)2. This dinitrile is an important precursor to the polymer nylon 6.6.
Because of the industrial value of adiponitrile, many routes have been developed for its synthesis. In one method, acrylonitrile is dimerized via electrosynthesis:
It has also been prepared by the nickel-catalysed hydrocyanation of butadiene:
Adiponitrile can be hydrogenated to 1,6-diaminohexane and hydrolysed to adipic acid.
|
Adiponitrile
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Adiponitrile is the chemical compound with the formula (CH2)4(CN)2. This dinitrile is an important precursor to the polymer nylon 6.6.
Because of the industrial value of adiponitrile, many routes have been developed for its synthesis. In one method, acrylonitrile is dimerized via electrosynthesis:
It has also been prepared by the nickel-catalysed hydrocyanation of butadiene:
Adiponitrile can be hydrogenated to 1,6-diaminohexane and hydrolysed to adipic acid.
# External links
- Template:ICSC
- Template:PGCH
- www.chemicalland.com
- www.nist.gov
de:Adiponitril
it:Adiponitrile
fi:Adiponitriili
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https://www.wikidoc.org/index.php/Adiponitrile
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7f8060fa9572aafbfbfca67d65cbf9b068814548
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wikidoc
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Adnexal mass
|
Adnexal mass
Synonyms and keywords:
# Overview
Adnexal mass is a disease with multiple gynecological and nongynecological causes. It affects females of all ages, from childbirth to postmenopause. It is critical to early detect malignant causes such as ovarian cancer. Most causes are benign and either remain stable or spontaneously resolve within few weeks. complications such as ovarian torsion and cyst rupture necessitate immediate surgical intervention.
# Historical Perspective
In 2007, transvaginal ultrasound was considered by the American College of Obstetricians and Gynecologists to be the first imaging tool to rule out adnexal mass malignancy.
# Classification
Adnexal masses are divided into two types based on their origin: gynecological origin and non-gynecological origin. Each group is further subdivided into benign and malignant.
# Pathophysiology
The pathophysiology of adnexal mass depends on the histological subtype and varies according to age, reproductive status, and location.
- Endometrioma is an ectopic endometrial tissue that bleeds in a single or both ovaries leading to the development of hemorrhagic/ chocolate cyst.
- Ovarian tumors most commonly have an epithelial origin, leading tohigh-grade serous carcinoma in the ovaries, fallopian tubes, or the peritoneum. The second common origin is primordial germ cells developing teratoma ( dermoid cyst), which is the most common benign germ cell tumor in the ovaries, dysgerminomas, mixed germ cell tumors and yolk sac tumors which are malignant.
- Krukenberg tumors develop as hematogenous of the colon, breasts, and endometrial tumors to the ovaries and fallopian tubes.
- Physiologic cysts, such as follicular cysts, which form due to the failure of formed follicles to rupture, and corpus leutum cysts, which form due to the failure of corpus leutum involution during early pregnancy. Leutoma of pregnancy is the corpus leutum cyst in a solid form rather than cystic.
- Tubo-ovarian abscess, hydrosalpinx, pyosalpinx are inflammatory complications of untreated pelvic inflammatory disease.
# Causes
Adnexal mass is most commonly caused by ovaries and fallopian tube masses, with etiologies that differ depending on the patient's age and reproductive status. Endometrioma is the most common benign cause of the adnexal mass. While ovarian epithelial carcinoma is the most common malignant cause.
# Differentiating Adnexal mass from other Diseases
Adnexal mass must be differentiated from other causes of pelvic mass such as uterine carcinoma/sarcoma, colorectal cancer, diverticular abscess,iliopsoas abscess, and renal tumors.
# Epidemiology and Demographics
At the age of 35, the prevalence of adnexal mass in the United States of America is approximately 153 per 100,000 women. However, Women of all ages can develop adnexal mass with no racial preference .
# Risk Factors
Common risk factors in the development of adnexal mass include induction of ovulation, increasing age, genital tract infection, and family history of ovarian/endometrial cancer.
# Screening
According to the American College of Physicians and the United States Preventive Services Taskforce, do not recommend screening for ovarian cancer with a bimanual pelvic examination in asymptomatic and non-pregnant women .
# Natural History, Complications, and Prognosis
Common complications of adnexal mass include hemorrhagic ovarian cysts, ovarian cyst rupture, and adnexal torsion with resulting in ischemia and necrosis.
# Diagnosis
## Diagnostic Study of Choice
There are no established criteria for the diagnosis of adnexal mass.
## History and Symptoms
The most common symptom is lower abdominal or pelvic pain with pressure character that can be associated with vaginal bleeding. Other associated symptoms such as dyspareunia, bloating, and abdominal distension, urinary symptoms raise suspicion of malignancy
The onset and duration of the pain dictate the urgency of intervention. Sudden onset of severe pelvic pain during the first trimester of pregnancy, or associated with fever require immediate evaluation in the urgent care clinic or the emergency department to exclude ruptured ectopic pregnancy, ruptures ovarian cyst, tubo-ovarian abscess, or ovarian torsion12
The broad spectrum of diseases causing adnexal mass is guided by age, parity, contraception methods, use of ovulation induction medication, and family history of breast or gynecological tumors particularly of associated with BRCA1/BRCA2 mutations.
## Physical Examination
The presence of a palpable mass on pelvic examination is diagnostic of adnexal mass. Although not palpating any mass does not exclude the diagnosis and still requires imagining studies.
## Laboratory Findings
Some patients with adnexal masses may have elevated concentrations of CA125, which is usually suggestive of epithelial ovarian cancer.
## Electrocardiogram
There are no ECG findings associated with an adnexal mass.
## X-ray
There are no x-ray findings associated with adnexal masses.
## Ultrasound
Transvaginal ultrasound is necessary to diagnose adnexal mass. The best modality is to combine transvaginal ultrasound with transabdominal ultrasound to better realize the characteristics of the mass and whether benign or malignant. Findings on a transvaginal ultrasound suggestive of simple cyst include thin-walled, anechoic/black, and rounded shape. Endometrioma appears as a homogenous cystic mass with medium echogenicity. While, hydrosalpinx emerges as a septated or nodular tube. Malignancy is suspected when a grey scale solid mass with thick irregular septations is seen.
## CT scan
There are no CT scan findings associated with adnexal masses. However, a CT scan may help stage ovarian cancer.
## MRI
A series of basic T1 and T2 pelvic MRIs may be helpful in the diagnosis of ultrasonically indeterminant adnexal masses such as hemorrhagic cysts with a mural clot, atypical mature teratoma, and solid ovarian neoplasms. This can be a cost-effective approach to avoid unnecessary surgical intervention.
## Other Imaging Findings
There are no other imaging findings associated with an adnexal mass.
## Other Diagnostic Studies
Other diagnostic studies for adnexal mass include serum or urine BHCG for all women of premenopausal age, which is positive in cases of ectopic pregnancy. Estradiol and total testosterone levels should be measured with signs of excess estrogen as virilization and hirsutism. Surgical exploration either through a laparotomy or laparoscopic approach aids in staging and prognosis of suspected malignancy.
# Treatment
## Medical Therapy
Most benign causes of adnexal masses need frequent follow-up with transvaginal ultrasound and symptomatic treatment as they self-resolved within a few weeks of intervention. Pharmacologic medical therapy is recommended for patients with polycystic ovarian syndrome.
## Surgery
Surgery is not the first-line treatment option for patients with an adnexal mass. Surgery is usually reserved for patients with either complication and urgent presentations as ectopic pregnancy, Tubo ovarian abscess, ovarian torsion, hemorrhagic cysts, and cyst rupture. At the early stages of ovarian cancer, oophorectomy is recommended.
## Primary Prevention
There are no established measures for the primary prevention of adnexal mass.
## Secondary Prevention
There are no established measures for the secondary prevention of adnexal mass. However, in low malignancy risk masses, follow up with ultrasound at a frequency of 6 weeks to 6 months can be beneficial.
|
Adnexal mass
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sarah Elsayed, MD., MPH.[2]
Synonyms and keywords:
# Overview
Adnexal mass is a disease with multiple gynecological and nongynecological causes. It affects females of all ages, from childbirth to postmenopause. It is critical to early detect malignant causes such as ovarian cancer. Most causes are benign and either remain stable or spontaneously resolve within few weeks. complications such as ovarian torsion and cyst rupture necessitate immediate surgical intervention.
# Historical Perspective
In 2007, transvaginal ultrasound was considered by the American College of Obstetricians and Gynecologists to be the first imaging tool to rule out adnexal mass malignancy[1].
# Classification
Adnexal masses are divided into two types based on their origin: gynecological origin and non-gynecological origin. Each group is further subdivided into benign and malignant. [2]
# Pathophysiology
The pathophysiology of adnexal mass depends on the histological subtype and varies according to age, reproductive status, and location.
- Endometrioma is an ectopic endometrial tissue that bleeds in a single or both ovaries leading to the development of hemorrhagic/ chocolate cyst[3].
- Ovarian tumors most commonly have an epithelial origin, leading tohigh-grade serous carcinoma in the ovaries, fallopian tubes, or the peritoneum[4]. The second common origin is primordial germ cells developing teratoma ( dermoid cyst), which is the most common benign germ cell tumor in the ovaries, dysgerminomas, mixed germ cell tumors and yolk sac tumors which are malignant[5].
- Krukenberg tumors develop as hematogenous of the colon, breasts, and endometrial tumors to the ovaries and fallopian tubes[6].
- Physiologic cysts, such as follicular cysts, which form due to the failure of formed follicles to rupture, and corpus leutum cysts, which form due to the failure of corpus leutum involution during early pregnancy[7]. Leutoma of pregnancy is the corpus leutum cyst in a solid form rather than cystic[8].
- Tubo-ovarian abscess, hydrosalpinx, pyosalpinx are inflammatory complications of untreated pelvic inflammatory disease[9].
# Causes
Adnexal mass is most commonly caused by ovaries and fallopian tube masses, with etiologies that differ depending on the patient's age and reproductive status. Endometrioma is the most common benign cause of the adnexal mass. While ovarian epithelial carcinoma is the most common malignant cause. [10]
# Differentiating Adnexal mass from other Diseases
Adnexal mass must be differentiated from other causes of pelvic mass such as uterine carcinoma/sarcoma, colorectal cancer, diverticular abscess,iliopsoas abscess, and renal tumors.
# Epidemiology and Demographics
At the age of 35, the prevalence of adnexal mass in the United States of America is approximately 153 per 100,000 women. However, Women of all ages can develop adnexal mass with no racial preference [11].
# Risk Factors
Common risk factors in the development of adnexal mass include induction of ovulation, increasing age, genital tract infection, and family history of ovarian/endometrial cancer.
# Screening
According to the American College of Physicians and the United States Preventive Services Taskforce, do not recommend screening for ovarian cancer with a bimanual pelvic examination in asymptomatic and non-pregnant women [12].
# Natural History, Complications, and Prognosis
Common complications of adnexal mass include hemorrhagic ovarian cysts, ovarian cyst rupture, and adnexal torsion with resulting in ischemia and necrosis.
# Diagnosis
## Diagnostic Study of Choice
There are no established criteria for the diagnosis of adnexal mass.
## History and Symptoms
The most common symptom is lower abdominal or pelvic pain with pressure character that can be associated with vaginal bleeding[13]. Other associated symptoms such as dyspareunia, bloating, and abdominal distension, urinary symptoms raise suspicion of malignancy[12]
The onset and duration of the pain dictate the urgency of intervention. Sudden onset of severe pelvic pain during the first trimester of pregnancy, or associated with fever require immediate evaluation in the urgent care clinic or the emergency department to exclude ruptured ectopic pregnancy, ruptures ovarian cyst, tubo-ovarian abscess, or ovarian torsion12
The broad spectrum of diseases causing adnexal mass is guided by age, parity, contraception methods, use of ovulation induction medication, and family history of breast or gynecological tumors particularly of associated with BRCA1/BRCA2 mutations[12].
## Physical Examination
The presence of a palpable mass on pelvic examination is diagnostic of adnexal mass. Although not palpating any mass does not exclude the diagnosis and still requires imagining studies.
## Laboratory Findings
Some patients with adnexal masses may have elevated concentrations of CA125, which is usually suggestive of epithelial ovarian cancer[14].
## Electrocardiogram
There are no ECG findings associated with an adnexal mass.
## X-ray
There are no x-ray findings associated with adnexal masses.
## Ultrasound
Transvaginal ultrasound is necessary to diagnose adnexal mass. The best modality is to combine transvaginal ultrasound with transabdominal ultrasound to better realize the characteristics of the mass and whether benign or malignant[15]. Findings on a transvaginal ultrasound suggestive of simple cyst include thin-walled, anechoic/black, and rounded shape. Endometrioma appears as a homogenous cystic mass with medium echogenicity[16]. While, hydrosalpinx emerges as a septated or nodular tube[17]. Malignancy is suspected when a grey scale solid mass with thick irregular septations is seen[18].
## CT scan
There are no CT scan findings associated with adnexal masses. However, a CT scan may help stage ovarian cancer.
## MRI
A series of basic T1 and T2 pelvic MRIs may be helpful in the diagnosis of ultrasonically indeterminant adnexal masses such as hemorrhagic cysts with a mural clot, atypical mature teratoma, and solid ovarian neoplasms. This can be a cost-effective approach to avoid unnecessary surgical intervention[19].
## Other Imaging Findings
There are no other imaging findings associated with an adnexal mass.
## Other Diagnostic Studies
Other diagnostic studies for adnexal mass include serum or urine BHCG for all women of premenopausal age, which is positive in cases of ectopic pregnancy. Estradiol and total testosterone levels should be measured with signs of excess estrogen as virilization and hirsutism[20]. Surgical exploration either through a laparotomy or laparoscopic approach aids in staging and prognosis of suspected malignancy[21].
# Treatment
## Medical Therapy
Most benign causes of adnexal masses need frequent follow-up with transvaginal ultrasound and symptomatic treatment as they self-resolved within a few weeks of intervention. Pharmacologic medical therapy is recommended for patients with polycystic ovarian syndrome.
## Surgery
Surgery is not the first-line treatment option for patients with an adnexal mass. Surgery is usually reserved for patients with either complication and urgent presentations as ectopic pregnancy, Tubo ovarian abscess, ovarian torsion, hemorrhagic cysts, and cyst rupture. At the early stages of ovarian cancer, oophorectomy is recommended[22].
## Primary Prevention
There are no established measures for the primary prevention of adnexal mass.
## Secondary Prevention
There are no established measures for the secondary prevention of adnexal mass. However, in low malignancy risk masses, follow up with ultrasound at a frequency of 6 weeks to 6 months can be beneficial[23].
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https://www.wikidoc.org/index.php/Adnexal_mass
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8fa41b0d9c57753cea618556379eeb19890720ff
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wikidoc
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Adson's sign
|
Adson's sign
# Overview
Adson's sign is seen during abduction and external rotation at the shoulder, where there is loss of the radial pulse in the arm. It can be a sign of thoracic outlet syndrome. Thoracic outlet obstruction may be caused by a number of abnormalities, including degenerative or bony disorders, trauma to the cervical spine, fibromuscular bands, vascular abnormalities, and spasm of the anterior scalene muscle. Symptoms are due to compression of the brachial plexus and subclavian vasculature, and consist of complaints ranging from diffuse arm pain to a sensation of arm fatigue, frequently aggravated by carrying anything in the ipsilateral hand or doing overhead work such as window cleaning.
As cited in the literature the Adson's sign is loss of radial pulse while turning the head to the contralateral side, slightly elevating the chin and breathing in.
# Causes
## Common Causes
- Thoracic outlet syndrome
## Causes by Organ System
## Causes in Alphabetical Order
- Thoracic outlet syndrome
## How to perform Adson's Test?
With the patient in a sitting position, hands resting on thighs, the examiner palpates both radial pulses as The patient rapidly fills the lungs by deep inspiration and, with breath held, hyperextends the neck and turns the head toward the 'affected' side. If the radial pulse on that side is decidedly or completely obliterated, the result is considered positive.
|
Adson's sign
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Adson's sign is seen during abduction and external rotation at the shoulder, where there is loss of the radial pulse in the arm. It can be a sign of thoracic outlet syndrome. Thoracic outlet obstruction may be caused by a number of abnormalities, including degenerative or bony disorders, trauma to the cervical spine, fibromuscular bands, vascular abnormalities, and spasm of the anterior scalene muscle. Symptoms are due to compression of the brachial plexus and subclavian vasculature, and consist of complaints ranging from diffuse arm pain to a sensation of arm fatigue, frequently aggravated by carrying anything in the ipsilateral hand or doing overhead work such as window cleaning.
As cited in the literature the Adson's sign is loss of radial pulse while turning the head to the contralateral side, slightly elevating the chin and breathing in.
# Causes
## Common Causes
- Thoracic outlet syndrome
## Causes by Organ System
## Causes in Alphabetical Order
- Thoracic outlet syndrome
## How to perform Adson's Test?
With the patient in a sitting position, hands resting on thighs, the examiner palpates both radial pulses as The patient rapidly fills the lungs by deep inspiration and, with breath held, hyperextends the neck and turns the head toward the 'affected' side. If the radial pulse on that side is decidedly or completely obliterated, the result is considered positive.
|
https://www.wikidoc.org/index.php/Adson%27s_sign
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3f4c9141fdea6ce4e691b6b6eeeeb7672b30557a
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wikidoc
|
Fibrosarcoma
|
Fibrosarcoma
Synonyms and keywords: Malignant fibromatous neoplasm, Fibroblastic sarcoma; Malignant fibrous histiocytoma
# Overview
Fibrosarcoma (fibroblastic sarcoma) is a malignant tumor derived from fibrous connective tissue and characterized by immature proliferating fibroblasts or undifferentiated anaplastic spindle cells. Fibrosarcoma is classified into 3 grades: low grade (differentiated), intermediate, and high grade (anaplastic). There are 3 stages of fibrosarcoma based on the grade and extent of the lesion. The tumor may be localized at the end of the long bones. Most often it affects the upper end of tibia or lower end of femur. Fibrosarcoma is a rare disease that affects approximately one in two million people annually. Patients of all age groups may develop fibrosarcoma, but are most common between the third and sixth decades of life. Fibrosarcoma is associated with a 5-year survival rate of 30% among patients with high grade medullary lesions and 50-80% among patients with surface fibrosarcomas and low grade fibrosarcomas. Common risk factors for the development of fibrosarcoma are preexisting benign lesions, radiation therapy, surgically treated fractures, and infarction of bone. The most common symptoms of fibrosarcoma include pain, swelling, loss of range of motion. Fibrosarcoma must be differentiated from other conditions that cause pain, swelling, and lesions that may appear similar to fibrosarcoma on radiological imaging.
# Classification
## Grade
Fibrosarcoma may be classified according to degrees of differentiation into three subtypes
- Low grade malignancy (differentiated)
- Intermediate malignancy
- High grade malignancy (anaplastic)
## Stage
Fibrosarcoma may be classified into 3 stages based on grade and extent of lesion.
- Stage I
Stage IA: Low grade lesion that is confined to its anatomic compartment
Stage IB: Low grade lesion that have extended outside of its compartment
- Stage II
Stage IIA: High grade lesion that is confined to its anatomic compartment
Stage IIB: High grade lesion that have extended outside of its compartment
- Stage III
lesions are any grade or anatomic site that have metastasized
# Pathophysiology
## Gross Pathology
The tumor may be localized at the end of the long bones. Most often it affects the upper end of tibia or lower end of femur. The tumor is typically well demarcated but not encapsulated.
## Microscopic Pathology
Tumor cells may resemble mature fibroblasts (spindle-shaped), secreting collagen, with rare mitoses. These cells are arranged in short fascicles which split and merge, giving the appearance of "fish bone". Poorly differentiated tumors consist in more atypical cells, pleomorphic, giant cells, multinucleated, numerous atypical mitoses and reduced collagen production. Presence of immature blood vessels (sarcomatous vessels lacking endothelial cells) favors the bloodstream metastasizing. The malignant cells are characteristically arranged in a "herringbone" pattern.
# Epidemiology and Demographics
Fibrosarcoma accounts for about 5% of all primary bone sarcomas.
## Incidence
Fibrosarcoma is a rare disease. Worldwide, the incidence of fibrosarcoma is 0.05 per 100,000 persons.
## Age
Patients of all age groups may develop fibrosarcoma, but are most common between the third and sixth decades of life. In infants, fibrosarcoma is usually congenital. Children presenting with fibrosarcoma usually do so in the first two years of their life.
## Gender
It affects men and women equally.
# Natural History, Complications, and Prognosis
## Prognosis
- Prognosis of fibrosarcoma depends on the tumor grade. It is associated with a 5-year survival rate of 30% among patients with high grade medullary lesions and 50-80% among patients with surface fibrosarcomas and low grade fibrosarcomas.
- Secondary sarcoma, presence of eccentric permeative lesions, primary tumor in the axial skeleton are associated with a particularly poor prognosis among patients with fibrosarcoma.
# Risk Factors
Common risk factors for the development of fibrosarcoma are preexisting benign lesions such as:
- Giant cell tumor
- Enchondroma
- Fibrous dysplasia
- Bizarre parosteal osteochondromatous proliferation
- Chronic osteomyelitis
Other risk factors include Paget's disease, radiation therapy, surgically treated fracture and infarction of bone.
# Screening
Screening for fibrosarcoma is not recommended.
# History and Symptoms
The most common symptoms of fibrosarcoma include:
- Localized Pain
- Swelling
- Loss of range of motion
Pain with weight-bearing that is relieved by rest and night pain may be observed. Many patients with fibrosarcoma neither feel sick nor experience classic symptoms of cancer such as weight loss and fatigue. Sometimes, patients with fibrosarcoma may present with pathological fracture of the affected bone.
# Differential Diagnosis
Fibrosarcoma must be differentiated from other conditions that cause pain, swelling, and lesions that may appear similar to fibrosarcoma on radiological imaging such as
- Osteosarcoma
- Chondrosarcoma
- Leiomyosarcoma
- Malignant fibrous histiocytoma
- Myofibromatosis
- Desmoplastic fibroma
Intra-osseous fibrosarcoma that affects the jaw must be differentiated from odontogenic sarcomas such as
- Ameloblastic fibrodentinosarcoma
- Ameloblastic fibrosarcoma
- Odontogenic carcinosarcoma
# Diagnosis
## X Ray
The radiological picture of fibrosarcoma typically shows the osteolytic lesion with a permeative or moth-eaten appearance. Margins of lesion can range from well-demarcated to ragged appearance.
## CT scan
CT scan is performed at initial diagnosis of fibrosarcoma to determine the metastasis of the tumor to the lungs. The lungs are most common site of fibrosarcoma metastasis.
## MRI
MRI of the entire bone is necessary among patients with fibrosarcoma. The benefits include:
- Determination of the extent of bone marrow and soft tissue involvement
- Identification of non-contiguous skip lesions that can arise within the same bone
# Treatment
- Surgery is the mainstay of treatment for fibrosarcoma.
- Chemotherapy and radiation therapy have not proven to be effective.
- Radiation therapy may be administered as palliative therapy.
|
Fibrosarcoma
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Suveenkrishna Pothuru, M.B,B.S. [2]
Synonyms and keywords: Malignant fibromatous neoplasm, Fibroblastic sarcoma; Malignant fibrous histiocytoma
# Overview
Fibrosarcoma (fibroblastic sarcoma) is a malignant tumor derived from fibrous connective tissue and characterized by immature proliferating fibroblasts or undifferentiated anaplastic spindle cells. Fibrosarcoma is classified into 3 grades: low grade (differentiated), intermediate, and high grade (anaplastic). There are 3 stages of fibrosarcoma based on the grade and extent of the lesion. The tumor may be localized at the end of the long bones. Most often it affects the upper end of tibia or lower end of femur. Fibrosarcoma is a rare disease that affects approximately one in two million people annually. Patients of all age groups may develop fibrosarcoma, but are most common between the third and sixth decades of life. Fibrosarcoma is associated with a 5-year survival rate of 30% among patients with high grade medullary lesions and 50-80% among patients with surface fibrosarcomas and low grade fibrosarcomas. Common risk factors for the development of fibrosarcoma are preexisting benign lesions, radiation therapy, surgically treated fractures, and infarction of bone. The most common symptoms of fibrosarcoma include pain, swelling, loss of range of motion. Fibrosarcoma must be differentiated from other conditions that cause pain, swelling, and lesions that may appear similar to fibrosarcoma on radiological imaging.
# Classification
## Grade
Fibrosarcoma may be classified according to degrees of differentiation into three subtypes
- Low grade malignancy (differentiated)
- Intermediate malignancy
- High grade malignancy (anaplastic)
## Stage
Fibrosarcoma may be classified into 3 stages based on grade and extent of lesion.
- Stage I
Stage IA: Low grade lesion that is confined to its anatomic compartment
Stage IB: Low grade lesion that have extended outside of its compartment
- Stage II
Stage IIA: High grade lesion that is confined to its anatomic compartment
Stage IIB: High grade lesion that have extended outside of its compartment
- Stage III
lesions are any grade or anatomic site that have metastasized
# Pathophysiology
## Gross Pathology
The tumor may be localized at the end of the long bones. Most often it affects the upper end of tibia or lower end of femur. The tumor is typically well demarcated but not encapsulated.
## Microscopic Pathology
Tumor cells may resemble mature fibroblasts (spindle-shaped), secreting collagen, with rare mitoses. These cells are arranged in short fascicles which split and merge, giving the appearance of "fish bone". Poorly differentiated tumors consist in more atypical cells, pleomorphic, giant cells, multinucleated, numerous atypical mitoses and reduced collagen production. Presence of immature blood vessels (sarcomatous vessels lacking endothelial cells) favors the bloodstream metastasizing. The malignant cells are characteristically arranged in a "herringbone" pattern.
# Epidemiology and Demographics
Fibrosarcoma accounts for about 5% of all primary bone sarcomas.
## Incidence
Fibrosarcoma is a rare disease. Worldwide, the incidence of fibrosarcoma is 0.05 per 100,000 persons.
## Age
Patients of all age groups may develop fibrosarcoma, but are most common between the third and sixth decades of life. In infants, fibrosarcoma is usually congenital. Children presenting with fibrosarcoma usually do so in the first two years of their life.
## Gender
It affects men and women equally.
# Natural History, Complications, and Prognosis
## Prognosis
- Prognosis of fibrosarcoma depends on the tumor grade. It is associated with a 5-year survival rate of 30% among patients with high grade medullary lesions and 50-80% among patients with surface fibrosarcomas and low grade fibrosarcomas.
- Secondary sarcoma, presence of eccentric permeative lesions, primary tumor in the axial skeleton are associated with a particularly poor prognosis among patients with fibrosarcoma.
# Risk Factors
Common risk factors for the development of fibrosarcoma are preexisting benign lesions such as:
- Giant cell tumor
- Enchondroma
- Fibrous dysplasia
- Bizarre parosteal osteochondromatous proliferation
- Chronic osteomyelitis
Other risk factors include Paget's disease, radiation therapy, surgically treated fracture and infarction of bone.
# Screening
Screening for fibrosarcoma is not recommended.
# History and Symptoms
The most common symptoms of fibrosarcoma include:
- Localized Pain
- Swelling
- Loss of range of motion
Pain with weight-bearing that is relieved by rest and night pain may be observed. Many patients with fibrosarcoma neither feel sick nor experience classic symptoms of cancer such as weight loss and fatigue. Sometimes, patients with fibrosarcoma may present with pathological fracture of the affected bone.
# Differential Diagnosis
Fibrosarcoma must be differentiated from other conditions that cause pain, swelling, and lesions that may appear similar to fibrosarcoma on radiological imaging such as
- Osteosarcoma
- Chondrosarcoma
- Leiomyosarcoma
- Malignant fibrous histiocytoma
- Myofibromatosis
- Desmoplastic fibroma
Intra-osseous fibrosarcoma that affects the jaw must be differentiated from odontogenic sarcomas such as
- Ameloblastic fibrodentinosarcoma
- Ameloblastic fibrosarcoma
- Odontogenic carcinosarcoma
# Diagnosis
## X Ray
The radiological picture of fibrosarcoma typically shows the osteolytic lesion with a permeative or moth-eaten appearance. Margins of lesion can range from well-demarcated to ragged appearance.
## CT scan
CT scan is performed at initial diagnosis of fibrosarcoma to determine the metastasis of the tumor to the lungs. The lungs are most common site of fibrosarcoma metastasis.
## MRI
MRI of the entire bone is necessary among patients with fibrosarcoma. The benefits include:
- Determination of the extent of bone marrow and soft tissue involvement
- Identification of non-contiguous skip lesions that can arise within the same bone
# Treatment
- Surgery is the mainstay of treatment for fibrosarcoma.
- Chemotherapy and radiation therapy have not proven to be effective.
- Radiation therapy may be administered as palliative therapy.
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https://www.wikidoc.org/index.php/Adult_Fibrosarcoma
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48e4debbb0ee2a846ae2810752245135a0b71ec7
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wikidoc
|
Theophylline
|
Theophylline
# 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
Theophylline is an anti-asthmatic that is FDA approved for the treatment of is indicated for the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.. Common adverse reactions include vomiting, diarrhea, abdominal pain, hematemesis, acid-base disturbances, rhabdomyolysis, supraventricular tachycardia, shock, nervousness, tremors, disorientation and seziures.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The steady-state peak serum theophylline concentration is a function of the dose, the dosing interval, and the rate of theophylline absorption and clearance in the individual patient.
- Because of marked individual differences in the rate of theophylline clearance, the dose required to achieve a peak serum theophylline concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter theophylline clearance (e.g., 400-1600 mg/day in adults <60 years old and 10-36 mg/kg/day in children 1-9 years old).
- For a given population there is no single theophylline dose that will provide both safe and effective serum concentrations for all patients.
- Administration of the median theophylline dose required to achieve a therapeutic serum theophylline concentration in a given population may result in either sub-therapeutic or potentially toxic serum theophylline concentrations in individual patients.
- For example, at a dose of 900 mg/d in adults <60 years or 22 mg/kg/d in children 1-9 years, the steady state peak serum theophylline concentration will be <10 mcg/mL in about 30% of patients, 10-20 mcg/mL in about 50% and 20-30 mcg/mL in about 20% of patients.
- The dose of theophylline must be individualized on the basis of peak serum theophylline concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk to adverse effects.
- Transient caffeine-like adverse effects and excessive serum concentrations in slow metabolizers can be avoided in most patients by starting with a sufficiently low dose and slowly increasing the dose, if judged to be clinically indicated, in small increments (See Table V).
- Dose increases should only be made if the previous dosage is well tolerated and at intervals of no less than 3 days to allow serum theophylline concentrations to reach the new steady state. Dosage adjustment should be guided by serum theophylline concentration measurement.
- Health care providers should instruct patients and care givers to discontinue any dosage that causes adverse effects, to withhold the medication until these symptoms are gone and to then resume therapy at a lower, previously tolerated dosage.
- If the patient’s symptoms are well controlled, there are no apparent adverse effects, and no intervening factors that might alter dosage requirements , serum theophylline concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others.
- In acutely ill patients, serum theophylline concentrations should be monitored at frequent intervals, e.g., every 24 hours.
- Theophylline distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight.
- Table V contains theophylline dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for theophylline dosage adjustment based upon serum theophylline concentrations.
- Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient.
- In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum theophylline concentration.
- Premature Neonates
- < 24 days postnatal age; 1.0 mg/kg every 12 hr
- >24 days postnatal age; 1.5 mg/kg every 12 hr
- Full term infants and infants up to 52 weeks of age:
- Total daily dose (mg) = x (Kg body Wt).
- Up to age 26 weeks; divide dose into 3 equal amounts administered at 8 hour intervals.
- >26 weeks of age; divide dose into 4 equal amounts administered at 6 hour intervals.
- Final Dosage.
- Adjusted to maintain a peak steady state serum theophylline concentration of 5-10 mcg/ml in neonates and 10-15 mcg/mL in older infants (see Table VI). :- Since the time required to reach steady-state is a function of theophylline half-life, up to 5 days may be required to achieve steady state in a premature neonate while only 2-3 days may be required in a 6 month old infant without other risk factors for impaired clearance in the absence of a loading dose.
- If a serum theophylline concentration is obtained before steady state is achieved, the maintenance dose should not be increased, even if the serum theophylline concentration is <10 mcg/mL.
- In children 1-15 years of age, the final theophylline dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS) or if it is not feasible to monitor serum theophylline concentrations.
- In adolescents ≥16 years and adults, including the elderly, the final theophylline dose should not exceed 400 mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS) or if it is not feasible to monitor serum theophylline concentrations.
- An inhaled beta-2 selective agonist, alone or in combination with a systemically administered corticosteroid, is the most effective treatment for acute exacerbations of reversible airways obstruction.
- Theophylline is a relatively weak bronchodilator, is less effective than an inhaled beta-2 selective agonist and provides no added benefit in the treatment of acute bronchospasm.
- If an inhaled or parenteral beta agonist is not available, a loading dose of an oral immediate release theophylline can be used as a temporary measure. - A single 5 mg/kg dose of theophylline, in a patient who has not received any theophylline in the previous 24 hours, will produce an average peak serum theophylline concentration of 10 mcg/mL (range 5-15 mcg/mL).
- If dosing with theophylline is to be continued beyond the loading dose, the guidelines in Sections A.1.b., B.3, or C., above, should be utilized and serum theophylline concentration monitored at 24 hour intervals to adjust final dosage.
- Patients with more rapid metabolism, clinically identified by higher than average dose requirements, should receive a smaller dose more frequently to prevent breakthrough symptoms resulting from low trough concentrations before the next dose.
- A reliably absorbed slow-release formulation will decrease fluctuations and permit longer dosing intervals.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Theophylline in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Theophylline in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Theophylline in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Theophylline in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Theophylline in pediatric patients.
# Contraindications
- ELIXOPHYLLIN Elixir is contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.
# Warnings
- Theophylline should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition:
- Active peptic ulcer disease
- Seizure disorders
- Cardiac arrhythmias (not including bradyarrhythmias)
- Conditions That Reduce Theophylline Clearance:
- Age
- Neonates (term and premature)
- Children <1 year
- Elderly (>60 years)
- Concurrent Diseases
- Acute pulmonary edema
- Congestive heart failure
- Cor pulmonale
- Fever; ≥102oF for 24 hours or more; or lesser temperature elevations for longer periods
- Hypothyroidism
- Liver disease; cirrhosis, acute hepatitis
- Reduced renal function in infants <3 months of age
- Sepsis with multi-organ failure
- Shock
- Cessation of Smoking
- Drug Interactions Adding a drug that inhibits theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin).
- Whenever a patient receiving theophylline develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with theophylline toxicity (even if another cause may be suspected), additional doses of theophylline should be withheld and a serum theophylline concentration measured immediately.
- Patients should be instructed not to continue any dosage that causes adverse effects and to withhold subsequent doses until the symptoms have resolved, at which time the clinician may instruct the patient to resume the drug at a lower dosage
- Increases in the dose of theophylline should not be made in response to an acute exacerbation of symptoms of chronic lung disease since theophylline provides little added benefit to inhaled beta2-selective agonists and systemically administered corticosteroids in this circumstance and increases the risk of adverse effects.
- A peak steady state serum theophylline concentration should be measured before increasing the dose in response to persistent chronic symptoms to ascertain whether an increase in dose is safe.
- Before increasing the theophylline dose on the basis of a low serum concentration, the clinician should consider whether the blood sample was obtained at an appropriate time in relationship to the dose and whether the patient has adhered to the prescribed regimen.
- As the rate of theophylline clearance may be dose-dependent (i.e., steady-state serum concentrations may increase disproportionately to the increase in dose), an increase in dose based upon a sub-therapeutic serum concentration measurement should be conservative.
- In general, limiting dose increases to about 25% of the previous total daily dose will reduce the risk of unintended excessive increases in serum theophylline concentration.
# Adverse Reactions
## Clinical Trials Experience
- Adverse reactions associated with theophylline are generally mild when peak serum theophylline concentrations are <20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia.
- When peak serum theophylline concentrations exceed 20 mcg/mL, however, theophylline produces a wide range of adverse reactions including persistent vomiting, cardiac arrhythmias, and intractable seizures which can be lethal. - The transient caffeine-like adverse reactions occur in about 50% of patients when theophylline therapy is initiated at doses higher than recommended initial doses (e.g., >300 mg/day in adults and >12 mg/kg/day in children beyond >1 year of age).
- During the initiation of theophylline therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists.
- Initiation of theophylline therapy at a low dose with subsequent slow titration to a predetermined age-related maximum dose will significantly reduce the frequency of these transient adverse effects (see DOSAGE AND ADMINISTRATION , TABLE V).
- In a small percentage of patients (<3% of children and <10% of adults) the caffeine-like adverse effects persist during maintenance therapy, even at peak serum theophylline concentrations within the therapeutic range (i.e., 10-20 mcg/mL).
- Dosage reduction may alleviate the caffeine-like adverse effects in these patients, however, persistent adverse effects should result in a reevaluation of the need for continued theophylline therapy and the potential therapeutic benefit of alternative treatment.
- Other adverse reactions that have been reported at serum theophylline concentrations <20 mcg/mL include diarrhea, irritability, restlessness, fine skeletal muscle tremors, and transient diuresis.
- In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum theophylline concentrations ≥15 mcg/mL.
- There have been a few isolated reports of seizures at serum theophylline concentrations <20 mcg/mL in patients with an underlying neurological disease or in elderly patients.
- The occurrence of seizures in elderly patients with serum theophylline concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form.
- The clinical characteristics of the seizures reported in patients with serum theophylline concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum theophylline concentrations resulting from an overdose (i.e., they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua).
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Theophylline in the drug label.
# Drug Interactions
There is limited information regarding Theophylline Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Theophylline in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Theophylline during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Theophylline with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Theophylline with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Theophylline with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Theophylline with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Theophylline with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Theophylline in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Theophylline in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Theophylline in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Theophylline in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Theophylline in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Theophylline in the drug label.
# Overdosage
- The chronicity and pattern of theophylline overdosage significantly influences clinical manifestations of toxicity, management and outcome.
- There are two common presentations: (1) acute overdose, i.e., ingestion of a single large excessive dose (>10 mg/kg) as occurs in the context of an attempted suicide or isolated medication error, and (2) chronic overdosage, i.e., ingestion of repeated doses that are excessive for the patient’s rate of theophylline clearance. The most common causes of chronic theophylline overdosage include patient or care giver error in dosing, clinician prescribing of an excessive dose or a normal dose in the presence of factors known to decrease the rate of theophylline clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum theophylline concentration to determine whether a dose increase is safe.
- Severe toxicity from theophylline overdose is a relatively rare event. In one health maintenance organization, the frequency of hospital admissions for chronic overdosage of theophylline was about 1 per 1000 person-years exposure.
- In another study, among 6000 blood samples obtained for measurement of serum theophylline concentration, for any reason, from patients treated in an emergency department, 7% were in the 20-30 mcg/mL range and 3% were >30 mcg/mL.
- Approximately two-thirds of the patients with serum theophylline concentrations in the 20-30 mcg/mL range had one or more manifestations of toxicity while >90% of patients with serum theophylline concentrations >30mcg/mL were clinically intoxicated.
- Similarly, in other reports, serious toxicity from theophylline is seen principally at serum concentrations >30 mcg/mL.
- Several studies have described the clinical manifestations of theophylline overdose and attempted to determine the factors that predict life-threatening toxicity.
- In general, patients who experience an acute overdose are less likely to experience seizures than patients who have experienced a chronic overdosage, unless the peak serum theophylline concentration is >100 mcg/mL.
- After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum theophylline concentrations >30 mcg/mL.
- The severity of toxicity after chronic overdosage is more strongly correlated with the patient’s age than the peak serum theophylline concentration; patients >60 years are at the greatest risk for severe toxicity and mortality after a chronic overdosage.
- Pre-existing or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e.g., patients with neurologic disorders have an increased risk of seizures and patients with cardiac disease have an increased risk of cardiac arrhythmias for a given serum theophylline concentration compared to patients without the underlying disease.
- The frequency of various reported manifestations of theophylline overdose according to the mode of overdose are listed in Table IV.
- Other manifestations of theophylline toxicity include increases in serum calcium, creatine kinase, myoglobin and leukocyte count, decreases in serum phosphate and magnesium, acute myocardial infarction, and urinary retention in men with obstructive uropathy.
- Seizures associated with serum theophylline concentrations >30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled.
- Death from theophylline toxicity is most often secondary to cardiorespiratory arrest and/or hypoxic encephalopathy following prolonged generalized seizures or intractable cardiac arrhythmias causing hemodynamic compromise.
- General Recommendations for Patients with Symptoms of Theophylline Overdose or Serum Theophylline Concentrations >30 mcg/mL (Note: Serum theophylline concentrations may continue to increase after presentation of the patient for medical care.)
- While simultaneously instituting treatment, contact a regional poison center to obtain updated information and advice on individualizing the recommendations that follow.
- Institute supportive care, including establishment of intravenous access, maintenance of the airway, and electrocardiographic monitoring.
- Treatment of seizures Because of the high morbidity and mortality associated with theophylline-induced seizures, treatment should be rapid and aggressive.
- Anticonvulsant therapy should be initiated with an intravenous benzodiazepine, e.g., diazepam, in increments of 0.1-0.2 mg/kg every 1-3 minutes until seizures are terminated. Repetitive seizures should be treated with a loading dose of phenobarbital (20 mg/kg infused over 30- 60 minutes). - Case reports of theophylline overdose in humans and animal studies suggest that phenytoin is ineffective in terminating theophylline-induced seizures.
- The doses of benzodiazepines and phenobarbital required to terminate theophylline-induced seizures are close to the doses that may cause severe respiratory depression or respiratory arrest; the clinician should therefore be prepared to provide assisted ventilation.
- Elderly patients and patients with COPD may be more susceptible to the respiratory depressant effects of anticonvulsants.
- Barbiturate-induced coma or administration of general anesthesia may be required to terminate repetitive seizures or status epilepticus. General anesthesia should be used with caution in patients with theophylline overdose because fluorinated volatile anesthetics may sensitize the myocardium to endogenous catecholamines released by theophylline.
- Enflurane appears to less likely to be associated with this effect than halothane and may, therefore, be safer.
- Neuromuscular blocking agents alone should not be used to terminate seizures since they abolish the musculoskeletal manifestations without terminating seizure activity in the brain.
- Anticipate Need for Anticonvulsants In patients with theophylline overdose who are at high risk for theophylline induced seizures, e.g., patients with acute overdoses and serum theophylline concentrations >100 mcg/mL chronic overdosage in patients >60 years of age with serum theophylline concentrations >30 mcg/mL, the need for anticonvulsant therapy should be anticipated.
- A benzodiazepine such as diazepam should be drawn into a syringe and kept at the patient’s bedside and medical personnel qualified to treat seizures should be immediately available.
- In selected patients at high risk for theophylline-induced seizures, consideration should be given to the administration of prophylactic anticonvulsant therapy.
- Situations where prophylactic anticonvulsant therapy should be considered in high risk patients include anticipated delays in instituting methods for extracorporeal removal of theophylline (e.g., transfer of a high risk patient from one health care facility to another for extracorporeal removal) and clinical circumstances that significantly interfere with efforts to enhance theophylline clearance (e.g., a neonate where dialysis may not be technically feasible or a patient with vomiting unresponsive to antiemetics who is unable to tolerate multiple-dose oral activated charcoal).
- In animal studies, prophylactic administration of phenobarbital, but not phenytoin, has been shown to delay the onset of theophylline induced generalized seizures and to increase the dose of theophylline required to induce seizures (i.e., markedly increases the LD50).
- Although there are no controlled studies in humans, a loading dose of intravenous phenobarbital (20 mg/kg infused over 60 minutes) may delay or prevent life-threatening seizures in high risk patients while efforts to enhance theophylline clearance are continued.
- Phenobarbital may cause respiratory depression, particularly in elderly patients and patients with COPD.
- Treatment of cardiac arrhythmias Sinus tachycardia and simple ventricular premature beats are not harbingers of life-threatening arrhythmias, they do not require treatment in the absence of hemodynamic compromise, and they resolve with declining serum theophylline concentrations.
- Other arrhythmias, especially those associated with hemodynamic compromise, should be treated with antiarrhythmic therapy appropriate for the type of arrhythmia.
- Gastrointestinal decontamination Oral activated charcoal (0.5 g/kg up to 20 g and repeat at least once 1-2 hours after the first dose) is extremely effective in blocking the absorption of theophylline throughout the gastrointestinal tract, even when administered several hours after ingestion. - If the patient is vomiting, the charcoal should be administered through a nasogastric tube or after administration of an antiemetic. Phenothiazine antiemetics such as prochlorperazine or perphenazine should be avoided since they can lower the seizure threshold and frequently cause dystonic reactions. - A single dose of sorbitol may be used to promote stooling to facilitate removal of theophylline bound to charcoal from the gastrointestinal tract.
- Sorbitol, however, should be dosed with caution since it is a potent purgative which can cause profound fluid and electrolyte abnormalities, particularly after multiple doses.
- Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing.
- Ipecac syrup should be avoided in theophylline overdoses. Although ipecac induces emesis, it does not reduce the absorption of theophylline unless administered within 5 minutes of ingestion and even then is less effective than oral activated charcoal.
- Moreover, ipecac induced emesis may persist for several hours after a single dose and significantly decrease the retention and the effectiveness of oral activated charcoal.
- Serum Theophylline Concentration Monitoring The serum theophylline concentration should be measured immediately upon presentation, 2-4 hours later, and then at sufficient intervals, e.g., every 4 hours, to guide treatment decisions and to assess the effectiveness of therapy.
- Serum theophylline concentrations may continue to increase after presentation of the patient for medical care as a result of continued absorption of theophylline from the gastrointestinal tract.
- Serial monitoring of serum theophylline serum concentrations should be continued until it is clear that the concentration is no longer rising and has returned to non-toxic levels.
- General Monitoring Procedures Electrocardiographic monitoring should be initiated on presentation and continued until the serum theophylline level has returned to a non-toxic level.
- Serum electrolytes and glucose should be measured on presentation and at appropriate intervals indicated by clinical circumstances. Fluid and electrolyte abnormalities should be promptly corrected. Monitoring and treatment should be continued until the serum concentration decreases below 20 mcg/mL.
- Enhance clearance of theophylline Multiple-dose oral activated charcoal (e.g., 0.5 mg/kg up to 20 g, every two hours) increases the clearance of theophylline at least twofold by adsorption of theophylline secreted into gastrointestinal fluids.
- Charcoal must be retained in, and pass through, the gastrointestinal tract to be effective; emesis should therefore be controlled by administration of appropriate antiemetics.
- Alternatively, the charcoal can be administered continuously through a nasogastric tube in conjunction with appropriate antiemetics.
- A single dose of sorbitol may be administered with the activated charcoal to promote stooling to facilitate clearance of the adsorbed theophylline from the gastrointestinal tract.
- Sorbitol alone does not enhance clearance of theophylline and should be dosed with caution to prevent excessive stooling which can result in severe fluid and electrolyte imbalances.
- Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing.
- In patients with intractable vomiting, extracorporeal methods of theophylline removal should be instituted.
- Serum Concentration >20<30 mcg/mL
- Administer a single dose of oral activated charcoal.
- Monitor the patient and obtain a serum theophylline concentration in 2-4 hours to insure that the concentration is not increasing.
- Serum Concentration >30<100 mcg/mL
- Administer multiple dose oral activated charcoal and measures to control emesis.
- Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
- Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled.
- Serum Concentration >100 mcg/mL
- Consider prophylactic anticonvulsant therapy.
- Administer multiple-dose oral activated charcoal and measures to control emesis.
- Consider extracorporeal removal, even if the patient has not experienced a seizure (see OVERDOSAGE, EXTRACORPOREAL REMOVAL).
- Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
- Serum Concentration >20<30 mcg/mL (with manifestations of theophylline toxicity)
- Administer a single dose of oral activated charcoal.
- Monitor the patient and obtain a serum theophylline concentration in 2-4 hours to insure that the concentration is not increasing.
- Serum Concentration >30 mcg/mL in patients <60 years of age
- Administer multiple-dose oral activated charcoal and measures to control emesis.
- Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
- Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled.
- Serum Concentration >30 mcg/mL in patients ≥60 years of age.
- Consider prophylactic anticonvulsant therapy.
- Administer multiple-dose oral activated charcoal and measures to control emesis.
- Consider extracorporeal removal even if the patient has not experienced a seizure (see OVERDOSAGE, EXTRACORPOREAL REMOVAL).
- Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
- Increasing the rate of theophylline clearance by extracorporeal methods may rapidly decrease serum concentrations, but the risks of the procedure must be weighed against the potential benefit. Charcoal hemoperfusion is the most effective method of extracorporeal removal, increasing theophylline clearance up to six fold, but serious complications, including hypotension, hypocalcemia, platelet consumption and bleeding diatheses may occur.
- Hemodialysis is about as efficient as multiple-dose oral activated charcoal and has a lower risk of serious complications than charcoal hemoperfusion.
- Hemodialysis should be considered as an alternative when charcoal hemoperfusion is not feasible and multiple-dose oral charcoal is ineffective because of intractable emesis.
- Serum theophylline concentrations may rebound 5-10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of theophylline from the tissue compartment. Peritoneal dialysis is ineffective for theophylline removal; exchange transfusions in neonates have been minimally effective.
# Pharmacology
## Mechanism of Action
- Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects).
- While the mechanisms of action of theophylline are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE III or antagonism of adenosine receptors.
- Some of the adverse effects associated with theophylline appear to be mediated by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow).
- Theophylline increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel.
## Structure
## Pharmacodynamics
There is limited information regarding Theophylline Pharmacodynamics in the drug label.
## Pharmacokinetics
- Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Theophylline does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver.
- The pharmacokinetics of theophylline vary widely among similar patients and cannot be predicted by age, sex, body weight or other demographic characteristics.
- In addition, certain concurrent illnesses and alterations in normal physiology and co-administration of other drugs (see Table II) can significantly alter the pharmacokinetic characteristics of theophylline. Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients.
- It is, therefore, recommended that serum theophylline concentrations be measured frequently in acutely ill patients (e.g., at 24-hour intervals) and periodically in patients receiving long-term therapy, e.g., at 6-12 month intervals. More frequent measurements should be made in the presence of any condition that may significantly alter theophylline clearance
- Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. After a single dose of 5 mg/kg in adults, a mean peak serum concentration of about 10 mcg/mL (range 5-15 mcg/mL) can be expected 1-2 hr after the dose.
- Co-administration of theophylline with food or antacids does not cause clinically significant changes in the absorption of theophylline from immediate-release dosage forms.
- Once theophylline enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound theophylline distributes throughout body water, but distributes poorly into body fat.
- The apparent volume of distribution of theophylline is approximately 0.45 L/kg (range 0.3-0.7 L/kg) based on ideal body weight.
- Theophylline passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF).
- Saliva theophylline concentrations approximate unbound serum concentrations, but are not reliable for routine or therapeutic monitoring unless special techniques are used. An increase in the volume of distribution of theophylline, primarily due to reduction in plasma protein binding, occurs in premature neonates, patients with hepatic cirrhosis, uncorrected acidemia, the elderly and in women during the third trimester of pregnancy.
- In such cases, the patient may show signs of toxicity at total (bound +unbound) serum concentrations of theophylline in the therapeutic range (10-20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug.
- Similarly, a patient with decreased theophylline binding may have a subtherapeutic total drug concentration while the pharmacologically active unbound concentration is in the therapeutic range.
- If only total serum theophylline concentration is measured, this may lead to an unnecessary and potentially dangerous dose increase. In patients with reduced protein binding, measurement of unbound serum theophylline concentration provides a more reliable means of dosage adjustment than measurement of total serum theophylline concentration.
- Generally, concentrations of unbound theophylline should be maintained in the range of 6-12 mcg/mL.
- Following oral dosing, theophylline does not undergo any measurable first-pass elimination. In adults and children beyond one year of age, approximately 90% of the dose is metabolized in the liver.
- Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. 1-methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a theophylline dose is N-methylated to caffeine.
- Theophylline demethylation to 3-methylxanthine is catalyzed by cytochrome P-450 1A2, while cytochromes P-450 2E1 and P-450 3A3 catalyze the hydroxylation to 1,3-dimethyluric acid. Demethylation to 1-methylxanthine appears to be catalyzed either by cytochrome P-450 1A2 or a closely related cytochrome.
- In neonates, the N-demethylation pathway is absent while the function of the hydroxylation pathway is markedly deficient. The activity of these pathways slowly increases to maximal levels by one year of age.
- Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of theophylline and serum concentrations in adults with normal renal function are <1 mcg/mL.
- In patients with end-stage renal disease, 3-methylxanthine may accumulate to concentrations that approximate the unmetabolized theophylline concentration.
- Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized theophylline concentration and thus, exert a pharmacologic effect.
- Both the N-demethylation and hydroxylation pathways of theophylline biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of theophylline metabolism, non-linearity of elimination may begin in some patients at serum theophylline concentrations <10 mcg/mL.
- Since this non-linearity results in more than proportional changes in serum theophylline concentrations with changes in dose, it is advisable to make increases or decreases in dose in small increments in order to achieve desired changes in serum theophylline concentrations.
- Accurate prediction of dose-dependency of theophylline metabolism in patients a priori is not possible, but patients with very high initial clearance rates (i.e., low steady state serum theophylline concentrations at above average doses) have the greatest likelihood of experiencing large changes in serum theophylline concentration in response to dosage changes.
- In neonates, approximately 50% of the theophylline dose is excreted unchanged in the urine.
- Beyond the first three months of life, approximately 10% of the theophylline dose is excreted unchanged in the urine.
- The remainder is excreted in the urine mainly as 1,3-dimethyluric acid (35-40%), 1-methyluric acid (20-25%) and 3-methylxanthine (15-20%). Since little theophylline is excreted unchanged in the urine and since active metabolites of theophylline (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children >3 months of age.
- In contrast, the large fraction of the theophylline dose excreted in the urine as unchanged theophylline and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum theophylline concentrations in neonates with reduced renal function.
- After multiple doses of theophylline, steady state is reached in 30-65 hours (average 40 hours) in adults.
- At steady state, on a dosage regimen with 6-hour intervals, the expected mean trough concentration is approximately 60% of the mean peak concentration, assuming a mean theophylline half-life of 8 hours.
- The difference between peak and trough concentrations is larger in patients with more rapid theophylline clearance.
- In patients with high theophylline clearance and half-lives of about 4-5 hours, such as children age 1 to 9 years, the trough serum theophylline concentration may be only 30% of peak with a 6-hour dosing interval.
- In these patients a slow release formulation would allow a longer dosing interval (8-12 hours) with a smaller peak/trough difference.
- The clearance of theophylline is decreased by an average of 30% in healthy elderly adults (> 60 yrs) compared to healthy young adults. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in elderly patients.
- The clearance of theophylline is very low in neonates. Theophylline clearance reaches maximal values by one year of age, remains relatively constant until about 9 years of age and then slowly decreases by approximately 50% to adult values at about age 16.
- Renal excretion of unchanged theophylline in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults.
- Careful attention to dosage selection and monitoring of serum theophylline concentrations are required in pediatric patients.
- Gender differences in theophylline clearance are relatively small and unlikely to be of clinical significance. Significant reduction in theophylline clearance, however, has been reported in women on the 20th day of the menstrual cycle and during the third trimester of pregnancy.
- Pharmacokinetic differences in theophylline clearance due to race have not been studied.
- Only a small fraction, e.g., about 10%, of the administered theophylline dose is excreted unchanged in the urine of children greater than three months of age and adults. Since little theophylline is excreted unchanged in the urine and since active metabolites of theophylline (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children >3 months of age.
- In contrast, approximately 50% of the administered theophylline dose is excreted unchanged in the urine in neonates.
- Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in neonates with decreased renal function.
- Theophylline clearance is decreased by 50% or more in patients with hepatic insufficiency (e.g., cirrhosis, acute hepatitis, cholestasis).
- Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with reduced hepatic function.
- Theophylline clearance is decreased by 50% or more in patients with CHF. The extent of reduction in theophylline clearance in patients with CHF appears to be directly correlated to the severity of the cardiac disease.
- Since theophylline clearance is independent of liver blood flow, the reduction in clearance appears to be due to impaired hepatocyte function rather than reduced perfusion.
- Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with CHF.
- Tobacco and marijuana smoking appears to increase the clearance of theophylline by induction of metabolic pathways.
- Theophylline clearance has been shown to increase by approximately 50% in young adult tobacco smokers and by approximately 80% in elderly tobacco smokers compared to non-smoking subjects.
- Passive smoke exposure has also been shown to increase theophylline clearance by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in theophylline clearance.
- Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients who stop smoking. Use of nicotine gum has been shown to have no effect on theophylline clearance.
- Fever, regardless of its underlying cause, can decrease the clearance of theophylline. The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of theophylline clearance. Precise data are lacking, but a temperature of 39oC (102oF) for at least 24 hours is probably required to produce a clinically significant increase in serum theophylline concentrations.
- Children with rapid rates of theophylline clearance (i.e., those who require a dose that is substantially larger than average to achieve a therapeutic peak serum theophylline concentration when afebrile) may be at greater risk of toxic effects from decreased clearance during sustained fever.
- Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with sustained fever.
- Other factors associated with decreased theophylline clearance include the third trimester of pregnancy, sepsis with multiple organ failure, and hypothyroidism.
- Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with any of these conditions.
- Other factors associated with increased theophylline clearance include hyperthyroidism and cystic fibrosis.
- In patients with chronic asthma, including patients with severe asthma requiring inhaled corticosteroids or alternate-day oral corticosteroids, many clinical studies have shown that theophylline decreases the frequency and severity of symptoms, including nocturnal exacerbations, and decreases the “as needed” use of inhaled beta-2 agonists.
- Theophylline has also been shown to reduce the need for short courses of daily oral prednisone to relieve exacerbations of airway obstruction that are unresponsive to bronchodilators in asthmatics.
- In patients with chronic obstructive pulmonary disease (COPD), clinical studies have shown that theophylline decreases dyspnea, air trapping, the work of breathing, and improves contractility of diaphragmatic muscles with little or no improvement in pulmonary function measurements.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Theophylline in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Theophylline in the drug label.
# How Supplied
- ELIXOPHYLLIN Elixir is a clear red solution with a mixed fruit flavor. Each tablespoonful (15 mL) contains 80 mg theophylline anhydrous.
- ELIXOPHYLLIN Elixir is available in bottles of
- 473 mL NDC 49708-644-90
## Storage
- Store at 25oC (77oF); excursions permitted to 15o - 30oC (59o - 86oF) .
- Dispense in tight container.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Theophylline in the drug label.
# Precautions with Alcohol
- Alcohol-Theophylline interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- THEOPHYLLINE ®
# Look-Alike Drug Names
There is limited information regarding Theophylline Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price
|
Theophylline
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
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# Overview
Theophylline is an anti-asthmatic that is FDA approved for the treatment of is indicated for the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.. Common adverse reactions include vomiting, diarrhea, abdominal pain, hematemesis, acid-base disturbances, rhabdomyolysis, supraventricular tachycardia, shock, nervousness, tremors, disorientation and seziures.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The steady-state peak serum theophylline concentration is a function of the dose, the dosing interval, and the rate of theophylline absorption and clearance in the individual patient.
- Because of marked individual differences in the rate of theophylline clearance, the dose required to achieve a peak serum theophylline concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter theophylline clearance (e.g., 400-1600 mg/day in adults <60 years old and 10-36 mg/kg/day in children 1-9 years old).
- For a given population there is no single theophylline dose that will provide both safe and effective serum concentrations for all patients.
- Administration of the median theophylline dose required to achieve a therapeutic serum theophylline concentration in a given population may result in either sub-therapeutic or potentially toxic serum theophylline concentrations in individual patients.
- For example, at a dose of 900 mg/d in adults <60 years or 22 mg/kg/d in children 1-9 years, the steady state peak serum theophylline concentration will be <10 mcg/mL in about 30% of patients, 10-20 mcg/mL in about 50% and 20-30 mcg/mL in about 20% of patients.
- The dose of theophylline must be individualized on the basis of peak serum theophylline concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk to adverse effects.
- Transient caffeine-like adverse effects and excessive serum concentrations in slow metabolizers can be avoided in most patients by starting with a sufficiently low dose and slowly increasing the dose, if judged to be clinically indicated, in small increments (See Table V).
- Dose increases should only be made if the previous dosage is well tolerated and at intervals of no less than 3 days to allow serum theophylline concentrations to reach the new steady state. Dosage adjustment should be guided by serum theophylline concentration measurement.
- Health care providers should instruct patients and care givers to discontinue any dosage that causes adverse effects, to withhold the medication until these symptoms are gone and to then resume therapy at a lower, previously tolerated dosage.
- If the patient’s symptoms are well controlled, there are no apparent adverse effects, and no intervening factors that might alter dosage requirements , serum theophylline concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others.
- In acutely ill patients, serum theophylline concentrations should be monitored at frequent intervals, e.g., every 24 hours.
- Theophylline distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight.
- Table V contains theophylline dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for theophylline dosage adjustment based upon serum theophylline concentrations.
- Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient.
- In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum theophylline concentration.
- Premature Neonates
- < 24 days postnatal age; 1.0 mg/kg every 12 hr
- >24 days postnatal age; 1.5 mg/kg every 12 hr
- Full term infants and infants up to 52 weeks of age:
- Total daily dose (mg) = [(0.2 x age in weeks)+5.0] x (Kg body Wt).
- Up to age 26 weeks; divide dose into 3 equal amounts administered at 8 hour intervals.
- >26 weeks of age; divide dose into 4 equal amounts administered at 6 hour intervals.
- Final Dosage.
- Adjusted to maintain a peak steady state serum theophylline concentration of 5-10 mcg/ml in neonates and 10-15 mcg/mL in older infants (see Table VI). :* Since the time required to reach steady-state is a function of theophylline half-life, up to 5 days may be required to achieve steady state in a premature neonate while only 2-3 days may be required in a 6 month old infant without other risk factors for impaired clearance in the absence of a loading dose.
- If a serum theophylline concentration is obtained before steady state is achieved, the maintenance dose should not be increased, even if the serum theophylline concentration is <10 mcg/mL.
- In children 1-15 years of age, the final theophylline dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS) or if it is not feasible to monitor serum theophylline concentrations.
- In adolescents ≥16 years and adults, including the elderly, the final theophylline dose should not exceed 400 mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS) or if it is not feasible to monitor serum theophylline concentrations.
- An inhaled beta-2 selective agonist, alone or in combination with a systemically administered corticosteroid, is the most effective treatment for acute exacerbations of reversible airways obstruction.
- Theophylline is a relatively weak bronchodilator, is less effective than an inhaled beta-2 selective agonist and provides no added benefit in the treatment of acute bronchospasm.
- If an inhaled or parenteral beta agonist is not available, a loading dose of an oral immediate release theophylline can be used as a temporary measure. * A single 5 mg/kg dose of theophylline, in a patient who has not received any theophylline in the previous 24 hours, will produce an average peak serum theophylline concentration of 10 mcg/mL (range 5-15 mcg/mL).
- If dosing with theophylline is to be continued beyond the loading dose, the guidelines in Sections A.1.b., B.3, or C., above, should be utilized and serum theophylline concentration monitored at 24 hour intervals to adjust final dosage.
- Patients with more rapid metabolism, clinically identified by higher than average dose requirements, should receive a smaller dose more frequently to prevent breakthrough symptoms resulting from low trough concentrations before the next dose.
- A reliably absorbed slow-release formulation will decrease fluctuations and permit longer dosing intervals.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Theophylline in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Theophylline in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Theophylline in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Theophylline in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Theophylline in pediatric patients.
# Contraindications
- ELIXOPHYLLIN Elixir is contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.
# Warnings
- Theophylline should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition:
- Active peptic ulcer disease
- Seizure disorders
- Cardiac arrhythmias (not including bradyarrhythmias)
- Conditions That Reduce Theophylline Clearance:
- Age
- Neonates (term and premature)
- Children <1 year
- Elderly (>60 years)
- Concurrent Diseases
- Acute pulmonary edema
- Congestive heart failure
- Cor pulmonale
- Fever; ≥102oF for 24 hours or more; or lesser temperature elevations for longer periods
- Hypothyroidism
- Liver disease; cirrhosis, acute hepatitis
- Reduced renal function in infants <3 months of age
- Sepsis with multi-organ failure
- Shock
- Cessation of Smoking
- Drug Interactions Adding a drug that inhibits theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin).
- Whenever a patient receiving theophylline develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with theophylline toxicity (even if another cause may be suspected), additional doses of theophylline should be withheld and a serum theophylline concentration measured immediately.
- Patients should be instructed not to continue any dosage that causes adverse effects and to withhold subsequent doses until the symptoms have resolved, at which time the clinician may instruct the patient to resume the drug at a lower dosage
- Increases in the dose of theophylline should not be made in response to an acute exacerbation of symptoms of chronic lung disease since theophylline provides little added benefit to inhaled beta2-selective agonists and systemically administered corticosteroids in this circumstance and increases the risk of adverse effects.
- A peak steady state serum theophylline concentration should be measured before increasing the dose in response to persistent chronic symptoms to ascertain whether an increase in dose is safe.
- Before increasing the theophylline dose on the basis of a low serum concentration, the clinician should consider whether the blood sample was obtained at an appropriate time in relationship to the dose and whether the patient has adhered to the prescribed regimen.
- As the rate of theophylline clearance may be dose-dependent (i.e., steady-state serum concentrations may increase disproportionately to the increase in dose), an increase in dose based upon a sub-therapeutic serum concentration measurement should be conservative.
- In general, limiting dose increases to about 25% of the previous total daily dose will reduce the risk of unintended excessive increases in serum theophylline concentration.
# Adverse Reactions
## Clinical Trials Experience
- Adverse reactions associated with theophylline are generally mild when peak serum theophylline concentrations are <20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia.
- When peak serum theophylline concentrations exceed 20 mcg/mL, however, theophylline produces a wide range of adverse reactions including persistent vomiting, cardiac arrhythmias, and intractable seizures which can be lethal. * The transient caffeine-like adverse reactions occur in about 50% of patients when theophylline therapy is initiated at doses higher than recommended initial doses (e.g., >300 mg/day in adults and >12 mg/kg/day in children beyond >1 year of age).
- During the initiation of theophylline therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists.
- Initiation of theophylline therapy at a low dose with subsequent slow titration to a predetermined age-related maximum dose will significantly reduce the frequency of these transient adverse effects (see DOSAGE AND ADMINISTRATION , TABLE V).
- In a small percentage of patients (<3% of children and <10% of adults) the caffeine-like adverse effects persist during maintenance therapy, even at peak serum theophylline concentrations within the therapeutic range (i.e., 10-20 mcg/mL).
- Dosage reduction may alleviate the caffeine-like adverse effects in these patients, however, persistent adverse effects should result in a reevaluation of the need for continued theophylline therapy and the potential therapeutic benefit of alternative treatment.
- Other adverse reactions that have been reported at serum theophylline concentrations <20 mcg/mL include diarrhea, irritability, restlessness, fine skeletal muscle tremors, and transient diuresis.
- In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum theophylline concentrations ≥15 mcg/mL.
- There have been a few isolated reports of seizures at serum theophylline concentrations <20 mcg/mL in patients with an underlying neurological disease or in elderly patients.
- The occurrence of seizures in elderly patients with serum theophylline concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form.
- The clinical characteristics of the seizures reported in patients with serum theophylline concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum theophylline concentrations resulting from an overdose (i.e., they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua).
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Theophylline in the drug label.
# Drug Interactions
There is limited information regarding Theophylline Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Theophylline in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Theophylline during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Theophylline with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Theophylline with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Theophylline with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Theophylline with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Theophylline with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Theophylline in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Theophylline in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Theophylline in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Theophylline in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Theophylline in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Theophylline in the drug label.
# Overdosage
- The chronicity and pattern of theophylline overdosage significantly influences clinical manifestations of toxicity, management and outcome.
- There are two common presentations: (1) acute overdose, i.e., ingestion of a single large excessive dose (>10 mg/kg) as occurs in the context of an attempted suicide or isolated medication error, and (2) chronic overdosage, i.e., ingestion of repeated doses that are excessive for the patient’s rate of theophylline clearance. The most common causes of chronic theophylline overdosage include patient or care giver error in dosing, clinician prescribing of an excessive dose or a normal dose in the presence of factors known to decrease the rate of theophylline clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum theophylline concentration to determine whether a dose increase is safe.
- Severe toxicity from theophylline overdose is a relatively rare event. In one health maintenance organization, the frequency of hospital admissions for chronic overdosage of theophylline was about 1 per 1000 person-years exposure.
- In another study, among 6000 blood samples obtained for measurement of serum theophylline concentration, for any reason, from patients treated in an emergency department, 7% were in the 20-30 mcg/mL range and 3% were >30 mcg/mL.
- Approximately two-thirds of the patients with serum theophylline concentrations in the 20-30 mcg/mL range had one or more manifestations of toxicity while >90% of patients with serum theophylline concentrations >30mcg/mL were clinically intoxicated.
- Similarly, in other reports, serious toxicity from theophylline is seen principally at serum concentrations >30 mcg/mL.
- Several studies have described the clinical manifestations of theophylline overdose and attempted to determine the factors that predict life-threatening toxicity.
- In general, patients who experience an acute overdose are less likely to experience seizures than patients who have experienced a chronic overdosage, unless the peak serum theophylline concentration is >100 mcg/mL.
- After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum theophylline concentrations >30 mcg/mL.
- The severity of toxicity after chronic overdosage is more strongly correlated with the patient’s age than the peak serum theophylline concentration; patients >60 years are at the greatest risk for severe toxicity and mortality after a chronic overdosage.
- Pre-existing or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e.g., patients with neurologic disorders have an increased risk of seizures and patients with cardiac disease have an increased risk of cardiac arrhythmias for a given serum theophylline concentration compared to patients without the underlying disease.
- The frequency of various reported manifestations of theophylline overdose according to the mode of overdose are listed in Table IV.
- Other manifestations of theophylline toxicity include increases in serum calcium, creatine kinase, myoglobin and leukocyte count, decreases in serum phosphate and magnesium, acute myocardial infarction, and urinary retention in men with obstructive uropathy.
- Seizures associated with serum theophylline concentrations >30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled.
- Death from theophylline toxicity is most often secondary to cardiorespiratory arrest and/or hypoxic encephalopathy following prolonged generalized seizures or intractable cardiac arrhythmias causing hemodynamic compromise.
- General Recommendations for Patients with Symptoms of Theophylline Overdose or Serum Theophylline Concentrations >30 mcg/mL (Note: Serum theophylline concentrations may continue to increase after presentation of the patient for medical care.)
- While simultaneously instituting treatment, contact a regional poison center to obtain updated information and advice on individualizing the recommendations that follow.
- Institute supportive care, including establishment of intravenous access, maintenance of the airway, and electrocardiographic monitoring.
- Treatment of seizures Because of the high morbidity and mortality associated with theophylline-induced seizures, treatment should be rapid and aggressive.
- Anticonvulsant therapy should be initiated with an intravenous benzodiazepine, e.g., diazepam, in increments of 0.1-0.2 mg/kg every 1-3 minutes until seizures are terminated. Repetitive seizures should be treated with a loading dose of phenobarbital (20 mg/kg infused over 30- 60 minutes). * Case reports of theophylline overdose in humans and animal studies suggest that phenytoin is ineffective in terminating theophylline-induced seizures.
- The doses of benzodiazepines and phenobarbital required to terminate theophylline-induced seizures are close to the doses that may cause severe respiratory depression or respiratory arrest; the clinician should therefore be prepared to provide assisted ventilation.
- Elderly patients and patients with COPD may be more susceptible to the respiratory depressant effects of anticonvulsants.
- Barbiturate-induced coma or administration of general anesthesia may be required to terminate repetitive seizures or status epilepticus. General anesthesia should be used with caution in patients with theophylline overdose because fluorinated volatile anesthetics may sensitize the myocardium to endogenous catecholamines released by theophylline.
- Enflurane appears to less likely to be associated with this effect than halothane and may, therefore, be safer.
- Neuromuscular blocking agents alone should not be used to terminate seizures since they abolish the musculoskeletal manifestations without terminating seizure activity in the brain.
- Anticipate Need for Anticonvulsants In patients with theophylline overdose who are at high risk for theophylline induced seizures, e.g., patients with acute overdoses and serum theophylline concentrations >100 mcg/mL chronic overdosage in patients >60 years of age with serum theophylline concentrations >30 mcg/mL, the need for anticonvulsant therapy should be anticipated.
- A benzodiazepine such as diazepam should be drawn into a syringe and kept at the patient’s bedside and medical personnel qualified to treat seizures should be immediately available.
- In selected patients at high risk for theophylline-induced seizures, consideration should be given to the administration of prophylactic anticonvulsant therapy.
- Situations where prophylactic anticonvulsant therapy should be considered in high risk patients include anticipated delays in instituting methods for extracorporeal removal of theophylline (e.g., transfer of a high risk patient from one health care facility to another for extracorporeal removal) and clinical circumstances that significantly interfere with efforts to enhance theophylline clearance (e.g., a neonate where dialysis may not be technically feasible or a patient with vomiting unresponsive to antiemetics who is unable to tolerate multiple-dose oral activated charcoal).
- In animal studies, prophylactic administration of phenobarbital, but not phenytoin, has been shown to delay the onset of theophylline induced generalized seizures and to increase the dose of theophylline required to induce seizures (i.e., markedly increases the LD50).
- Although there are no controlled studies in humans, a loading dose of intravenous phenobarbital (20 mg/kg infused over 60 minutes) may delay or prevent life-threatening seizures in high risk patients while efforts to enhance theophylline clearance are continued.
- Phenobarbital may cause respiratory depression, particularly in elderly patients and patients with COPD.
- Treatment of cardiac arrhythmias Sinus tachycardia and simple ventricular premature beats are not harbingers of life-threatening arrhythmias, they do not require treatment in the absence of hemodynamic compromise, and they resolve with declining serum theophylline concentrations.
- Other arrhythmias, especially those associated with hemodynamic compromise, should be treated with antiarrhythmic therapy appropriate for the type of arrhythmia.
- Gastrointestinal decontamination Oral activated charcoal (0.5 g/kg up to 20 g and repeat at least once 1-2 hours after the first dose) is extremely effective in blocking the absorption of theophylline throughout the gastrointestinal tract, even when administered several hours after ingestion. * If the patient is vomiting, the charcoal should be administered through a nasogastric tube or after administration of an antiemetic. Phenothiazine antiemetics such as prochlorperazine or perphenazine should be avoided since they can lower the seizure threshold and frequently cause dystonic reactions. * A single dose of sorbitol may be used to promote stooling to facilitate removal of theophylline bound to charcoal from the gastrointestinal tract.
- Sorbitol, however, should be dosed with caution since it is a potent purgative which can cause profound fluid and electrolyte abnormalities, particularly after multiple doses.
- Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing.
- Ipecac syrup should be avoided in theophylline overdoses. Although ipecac induces emesis, it does not reduce the absorption of theophylline unless administered within 5 minutes of ingestion and even then is less effective than oral activated charcoal.
- Moreover, ipecac induced emesis may persist for several hours after a single dose and significantly decrease the retention and the effectiveness of oral activated charcoal.
- Serum Theophylline Concentration Monitoring The serum theophylline concentration should be measured immediately upon presentation, 2-4 hours later, and then at sufficient intervals, e.g., every 4 hours, to guide treatment decisions and to assess the effectiveness of therapy.
- Serum theophylline concentrations may continue to increase after presentation of the patient for medical care as a result of continued absorption of theophylline from the gastrointestinal tract.
- Serial monitoring of serum theophylline serum concentrations should be continued until it is clear that the concentration is no longer rising and has returned to non-toxic levels.
- General Monitoring Procedures Electrocardiographic monitoring should be initiated on presentation and continued until the serum theophylline level has returned to a non-toxic level.
- Serum electrolytes and glucose should be measured on presentation and at appropriate intervals indicated by clinical circumstances. Fluid and electrolyte abnormalities should be promptly corrected. Monitoring and treatment should be continued until the serum concentration decreases below 20 mcg/mL.
- Enhance clearance of theophylline Multiple-dose oral activated charcoal (e.g., 0.5 mg/kg up to 20 g, every two hours) increases the clearance of theophylline at least twofold by adsorption of theophylline secreted into gastrointestinal fluids.
- Charcoal must be retained in, and pass through, the gastrointestinal tract to be effective; emesis should therefore be controlled by administration of appropriate antiemetics.
- Alternatively, the charcoal can be administered continuously through a nasogastric tube in conjunction with appropriate antiemetics.
- A single dose of sorbitol may be administered with the activated charcoal to promote stooling to facilitate clearance of the adsorbed theophylline from the gastrointestinal tract.
- Sorbitol alone does not enhance clearance of theophylline and should be dosed with caution to prevent excessive stooling which can result in severe fluid and electrolyte imbalances.
- Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing.
- In patients with intractable vomiting, extracorporeal methods of theophylline removal should be instituted.
- Serum Concentration >20<30 mcg/mL
- Administer a single dose of oral activated charcoal.
- Monitor the patient and obtain a serum theophylline concentration in 2-4 hours to insure that the concentration is not increasing.
- Serum Concentration >30<100 mcg/mL
- Administer multiple dose oral activated charcoal and measures to control emesis.
- Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
- Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled.
- Serum Concentration >100 mcg/mL
- Consider prophylactic anticonvulsant therapy.
- Administer multiple-dose oral activated charcoal and measures to control emesis.
- Consider extracorporeal removal, even if the patient has not experienced a seizure (see OVERDOSAGE, EXTRACORPOREAL REMOVAL).
- Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
- Serum Concentration >20<30 mcg/mL (with manifestations of theophylline toxicity)
- Administer a single dose of oral activated charcoal.
- Monitor the patient and obtain a serum theophylline concentration in 2-4 hours to insure that the concentration is not increasing.
- Serum Concentration >30 mcg/mL in patients <60 years of age
- Administer multiple-dose oral activated charcoal and measures to control emesis.
- Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
- Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled.
- Serum Concentration >30 mcg/mL in patients ≥60 years of age.
- Consider prophylactic anticonvulsant therapy.
- Administer multiple-dose oral activated charcoal and measures to control emesis.
- Consider extracorporeal removal even if the patient has not experienced a seizure (see OVERDOSAGE, EXTRACORPOREAL REMOVAL).
- Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
- Increasing the rate of theophylline clearance by extracorporeal methods may rapidly decrease serum concentrations, but the risks of the procedure must be weighed against the potential benefit. Charcoal hemoperfusion is the most effective method of extracorporeal removal, increasing theophylline clearance up to six fold, but serious complications, including hypotension, hypocalcemia, platelet consumption and bleeding diatheses may occur.
- Hemodialysis is about as efficient as multiple-dose oral activated charcoal and has a lower risk of serious complications than charcoal hemoperfusion.
- Hemodialysis should be considered as an alternative when charcoal hemoperfusion is not feasible and multiple-dose oral charcoal is ineffective because of intractable emesis.
- Serum theophylline concentrations may rebound 5-10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of theophylline from the tissue compartment. Peritoneal dialysis is ineffective for theophylline removal; exchange transfusions in neonates have been minimally effective.
# Pharmacology
## Mechanism of Action
- Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects).
- While the mechanisms of action of theophylline are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE III or antagonism of adenosine receptors.
- Some of the adverse effects associated with theophylline appear to be mediated by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow).
- Theophylline increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel.
## Structure
## Pharmacodynamics
There is limited information regarding Theophylline Pharmacodynamics in the drug label.
## Pharmacokinetics
- Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Theophylline does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver.
- The pharmacokinetics of theophylline vary widely among similar patients and cannot be predicted by age, sex, body weight or other demographic characteristics.
- In addition, certain concurrent illnesses and alterations in normal physiology and co-administration of other drugs (see Table II) can significantly alter the pharmacokinetic characteristics of theophylline. Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients.
- It is, therefore, recommended that serum theophylline concentrations be measured frequently in acutely ill patients (e.g., at 24-hour intervals) and periodically in patients receiving long-term therapy, e.g., at 6-12 month intervals. More frequent measurements should be made in the presence of any condition that may significantly alter theophylline clearance
- Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. After a single dose of 5 mg/kg in adults, a mean peak serum concentration of about 10 mcg/mL (range 5-15 mcg/mL) can be expected 1-2 hr after the dose.
- Co-administration of theophylline with food or antacids does not cause clinically significant changes in the absorption of theophylline from immediate-release dosage forms.
- Once theophylline enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound theophylline distributes throughout body water, but distributes poorly into body fat.
- The apparent volume of distribution of theophylline is approximately 0.45 L/kg (range 0.3-0.7 L/kg) based on ideal body weight.
- Theophylline passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF).
- Saliva theophylline concentrations approximate unbound serum concentrations, but are not reliable for routine or therapeutic monitoring unless special techniques are used. An increase in the volume of distribution of theophylline, primarily due to reduction in plasma protein binding, occurs in premature neonates, patients with hepatic cirrhosis, uncorrected acidemia, the elderly and in women during the third trimester of pregnancy.
- In such cases, the patient may show signs of toxicity at total (bound +unbound) serum concentrations of theophylline in the therapeutic range (10-20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug.
- Similarly, a patient with decreased theophylline binding may have a subtherapeutic total drug concentration while the pharmacologically active unbound concentration is in the therapeutic range.
- If only total serum theophylline concentration is measured, this may lead to an unnecessary and potentially dangerous dose increase. In patients with reduced protein binding, measurement of unbound serum theophylline concentration provides a more reliable means of dosage adjustment than measurement of total serum theophylline concentration.
- Generally, concentrations of unbound theophylline should be maintained in the range of 6-12 mcg/mL.
- Following oral dosing, theophylline does not undergo any measurable first-pass elimination. In adults and children beyond one year of age, approximately 90% of the dose is metabolized in the liver.
- Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. 1-methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a theophylline dose is N-methylated to caffeine.
- Theophylline demethylation to 3-methylxanthine is catalyzed by cytochrome P-450 1A2, while cytochromes P-450 2E1 and P-450 3A3 catalyze the hydroxylation to 1,3-dimethyluric acid. Demethylation to 1-methylxanthine appears to be catalyzed either by cytochrome P-450 1A2 or a closely related cytochrome.
- In neonates, the N-demethylation pathway is absent while the function of the hydroxylation pathway is markedly deficient. The activity of these pathways slowly increases to maximal levels by one year of age.
- Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of theophylline and serum concentrations in adults with normal renal function are <1 mcg/mL.
- In patients with end-stage renal disease, 3-methylxanthine may accumulate to concentrations that approximate the unmetabolized theophylline concentration.
- Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized theophylline concentration and thus, exert a pharmacologic effect.
- Both the N-demethylation and hydroxylation pathways of theophylline biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of theophylline metabolism, non-linearity of elimination may begin in some patients at serum theophylline concentrations <10 mcg/mL.
- Since this non-linearity results in more than proportional changes in serum theophylline concentrations with changes in dose, it is advisable to make increases or decreases in dose in small increments in order to achieve desired changes in serum theophylline concentrations.
- Accurate prediction of dose-dependency of theophylline metabolism in patients a priori is not possible, but patients with very high initial clearance rates (i.e., low steady state serum theophylline concentrations at above average doses) have the greatest likelihood of experiencing large changes in serum theophylline concentration in response to dosage changes.
- In neonates, approximately 50% of the theophylline dose is excreted unchanged in the urine.
- Beyond the first three months of life, approximately 10% of the theophylline dose is excreted unchanged in the urine.
- The remainder is excreted in the urine mainly as 1,3-dimethyluric acid (35-40%), 1-methyluric acid (20-25%) and 3-methylxanthine (15-20%). Since little theophylline is excreted unchanged in the urine and since active metabolites of theophylline (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children >3 months of age.
- In contrast, the large fraction of the theophylline dose excreted in the urine as unchanged theophylline and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum theophylline concentrations in neonates with reduced renal function.
- After multiple doses of theophylline, steady state is reached in 30-65 hours (average 40 hours) in adults.
- At steady state, on a dosage regimen with 6-hour intervals, the expected mean trough concentration is approximately 60% of the mean peak concentration, assuming a mean theophylline half-life of 8 hours.
- The difference between peak and trough concentrations is larger in patients with more rapid theophylline clearance.
- In patients with high theophylline clearance and half-lives of about 4-5 hours, such as children age 1 to 9 years, the trough serum theophylline concentration may be only 30% of peak with a 6-hour dosing interval.
- In these patients a slow release formulation would allow a longer dosing interval (8-12 hours) with a smaller peak/trough difference.
- The clearance of theophylline is decreased by an average of 30% in healthy elderly adults (> 60 yrs) compared to healthy young adults. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in elderly patients.
- The clearance of theophylline is very low in neonates. Theophylline clearance reaches maximal values by one year of age, remains relatively constant until about 9 years of age and then slowly decreases by approximately 50% to adult values at about age 16.
- Renal excretion of unchanged theophylline in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults.
- Careful attention to dosage selection and monitoring of serum theophylline concentrations are required in pediatric patients.
- Gender differences in theophylline clearance are relatively small and unlikely to be of clinical significance. Significant reduction in theophylline clearance, however, has been reported in women on the 20th day of the menstrual cycle and during the third trimester of pregnancy.
- Pharmacokinetic differences in theophylline clearance due to race have not been studied.
- Only a small fraction, e.g., about 10%, of the administered theophylline dose is excreted unchanged in the urine of children greater than three months of age and adults. Since little theophylline is excreted unchanged in the urine and since active metabolites of theophylline (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children >3 months of age.
- In contrast, approximately 50% of the administered theophylline dose is excreted unchanged in the urine in neonates.
- Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in neonates with decreased renal function.
- Theophylline clearance is decreased by 50% or more in patients with hepatic insufficiency (e.g., cirrhosis, acute hepatitis, cholestasis).
- Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with reduced hepatic function.
- Theophylline clearance is decreased by 50% or more in patients with CHF. The extent of reduction in theophylline clearance in patients with CHF appears to be directly correlated to the severity of the cardiac disease.
- Since theophylline clearance is independent of liver blood flow, the reduction in clearance appears to be due to impaired hepatocyte function rather than reduced perfusion.
- Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with CHF.
- Tobacco and marijuana smoking appears to increase the clearance of theophylline by induction of metabolic pathways.
- Theophylline clearance has been shown to increase by approximately 50% in young adult tobacco smokers and by approximately 80% in elderly tobacco smokers compared to non-smoking subjects.
- Passive smoke exposure has also been shown to increase theophylline clearance by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in theophylline clearance.
- Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients who stop smoking. Use of nicotine gum has been shown to have no effect on theophylline clearance.
- Fever, regardless of its underlying cause, can decrease the clearance of theophylline. The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of theophylline clearance. Precise data are lacking, but a temperature of 39oC (102oF) for at least 24 hours is probably required to produce a clinically significant increase in serum theophylline concentrations.
- Children with rapid rates of theophylline clearance (i.e., those who require a dose that is substantially larger than average [e.g., >22 mg/kg/day] to achieve a therapeutic peak serum theophylline concentration when afebrile) may be at greater risk of toxic effects from decreased clearance during sustained fever.
- Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with sustained fever.
- Other factors associated with decreased theophylline clearance include the third trimester of pregnancy, sepsis with multiple organ failure, and hypothyroidism.
- Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with any of these conditions.
- Other factors associated with increased theophylline clearance include hyperthyroidism and cystic fibrosis.
- In patients with chronic asthma, including patients with severe asthma requiring inhaled corticosteroids or alternate-day oral corticosteroids, many clinical studies have shown that theophylline decreases the frequency and severity of symptoms, including nocturnal exacerbations, and decreases the “as needed” use of inhaled beta-2 agonists.
- Theophylline has also been shown to reduce the need for short courses of daily oral prednisone to relieve exacerbations of airway obstruction that are unresponsive to bronchodilators in asthmatics.
- In patients with chronic obstructive pulmonary disease (COPD), clinical studies have shown that theophylline decreases dyspnea, air trapping, the work of breathing, and improves contractility of diaphragmatic muscles with little or no improvement in pulmonary function measurements.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Theophylline in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Theophylline in the drug label.
# How Supplied
- ELIXOPHYLLIN Elixir is a clear red solution with a mixed fruit flavor. Each tablespoonful (15 mL) contains 80 mg theophylline anhydrous.
- ELIXOPHYLLIN Elixir is available in bottles of
- 473 mL NDC 49708-644-90
## Storage
- Store at 25oC (77oF); excursions permitted to 15o - 30oC (59o - 86oF) [see USP Controlled Room Temperature].
- Dispense in tight container.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Theophylline in the drug label.
# Precautions with Alcohol
- Alcohol-Theophylline interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- THEOPHYLLINE ®[1]
# Look-Alike Drug Names
There is limited information regarding Theophylline Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price
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https://www.wikidoc.org/index.php/Aerolate_III
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7adfbf36556a4ff2e9e2ba02c117da1cc5f3b13d
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wikidoc
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Afrosoricida
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Afrosoricida
The order Afrosoricida (a Latin-Greek compound name which means "looking like African shrews") contains the golden moles of southern Africa and the tenrecs of Madagascar and Africa, two families of small mammals that are traditionally considered to be a part of the order Insectivora.
Some biologists use Tenrecomorpha as the name for the tenrec-golden mole clade, but prevailing evidence suggests Afrosoricida is more appropriate and Tenrecomorpha is used here as the name of the tenrec suborder.
Traditionally, these two families were grouped with the hedgehogs, shrews and moles in the Lipotyphla. However, there have always been minority opinions suggesting that Tenrecomorpha, or at least the golden moles, are not true lipotyphlans. These opinions are now supported by many genetic studies suggesting an association between Tenrecomorpha and various other African mammals in a proposed superorder known as Afrotheria; however there is no strong morphological evidence to link the Afrosoricida together with other Afrotherians. The Afrosoricida are sometimes considered part of the Afroinsectiphilia, a clade within the Afrotheria.
- INFRACLASS EUTHERIA: placental mammals
Superorder Afrotheria (?)
Clade Afroinsectiphilia
Order Afrosoricida
Suborder Tenrecomorpha
Family Tenrecidae: tenrecs and otter shrews; 30 species in 10 genera
Suborder Chrysochloridea
Family Chrysochloridae: golden moles; about 21 species in 9 genera
Order Macroscelidea: elephant shrews
Order Tubulidentata: Aardvark
Clade Paenungulata
Order Hyracoidea: hyraxes
Order Proboscidea: elephants
Order Sirenia: manatees and dugongs
(Other superorders, not listed here)
- Superorder Afrotheria (?)
Clade Afroinsectiphilia
Order Afrosoricida
Suborder Tenrecomorpha
Family Tenrecidae: tenrecs and otter shrews; 30 species in 10 genera
Suborder Chrysochloridea
Family Chrysochloridae: golden moles; about 21 species in 9 genera
Order Macroscelidea: elephant shrews
Order Tubulidentata: Aardvark
Clade Paenungulata
Order Hyracoidea: hyraxes
Order Proboscidea: elephants
Order Sirenia: manatees and dugongs
- Clade Afroinsectiphilia
Order Afrosoricida
Suborder Tenrecomorpha
Family Tenrecidae: tenrecs and otter shrews; 30 species in 10 genera
Suborder Chrysochloridea
Family Chrysochloridae: golden moles; about 21 species in 9 genera
Order Macroscelidea: elephant shrews
Order Tubulidentata: Aardvark
- Order Afrosoricida
Suborder Tenrecomorpha
Family Tenrecidae: tenrecs and otter shrews; 30 species in 10 genera
Suborder Chrysochloridea
Family Chrysochloridae: golden moles; about 21 species in 9 genera
- Suborder Tenrecomorpha
Family Tenrecidae: tenrecs and otter shrews; 30 species in 10 genera
- Family Tenrecidae: tenrecs and otter shrews; 30 species in 10 genera
- Suborder Chrysochloridea
Family Chrysochloridae: golden moles; about 21 species in 9 genera
- Family Chrysochloridae: golden moles; about 21 species in 9 genera
- Order Macroscelidea: elephant shrews
- Order Tubulidentata: Aardvark
- Clade Paenungulata
Order Hyracoidea: hyraxes
Order Proboscidea: elephants
Order Sirenia: manatees and dugongs
- Order Hyracoidea: hyraxes
- Order Proboscidea: elephants
- Order Sirenia: manatees and dugongs
- (Other superorders, not listed here)
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Afrosoricida
The order Afrosoricida (a Latin-Greek compound name which means "looking like African shrews") contains the golden moles of southern Africa and the tenrecs of Madagascar and Africa, two families of small mammals that are traditionally considered to be a part of the order Insectivora.
Some biologists use Tenrecomorpha as the name for the tenrec-golden mole clade, but prevailing evidence suggests Afrosoricida is more appropriate and Tenrecomorpha is used here as the name of the tenrec suborder.[1]
Traditionally, these two families were grouped with the hedgehogs, shrews and moles in the Lipotyphla. However, there have always been minority opinions suggesting that Tenrecomorpha, or at least the golden moles, are not true lipotyphlans. These opinions are now supported by many genetic studies suggesting an association between Tenrecomorpha and various other African mammals in a proposed superorder known as Afrotheria; however there is no strong morphological evidence to link the Afrosoricida together with other Afrotherians. The Afrosoricida are sometimes considered part of the Afroinsectiphilia, a clade within the Afrotheria.
- INFRACLASS EUTHERIA: placental mammals
Superorder Afrotheria (?)
Clade Afroinsectiphilia
Order Afrosoricida
Suborder Tenrecomorpha
Family Tenrecidae: tenrecs and otter shrews; 30 species in 10 genera
Suborder Chrysochloridea
Family Chrysochloridae: golden moles; about 21 species in 9 genera
Order Macroscelidea: elephant shrews
Order Tubulidentata: Aardvark
Clade Paenungulata
Order Hyracoidea: hyraxes
Order Proboscidea: elephants
Order Sirenia: manatees and dugongs
(Other superorders, not listed here)
- Superorder Afrotheria (?)
Clade Afroinsectiphilia
Order Afrosoricida
Suborder Tenrecomorpha
Family Tenrecidae: tenrecs and otter shrews; 30 species in 10 genera
Suborder Chrysochloridea
Family Chrysochloridae: golden moles; about 21 species in 9 genera
Order Macroscelidea: elephant shrews
Order Tubulidentata: Aardvark
Clade Paenungulata
Order Hyracoidea: hyraxes
Order Proboscidea: elephants
Order Sirenia: manatees and dugongs
- Clade Afroinsectiphilia
Order Afrosoricida
Suborder Tenrecomorpha
Family Tenrecidae: tenrecs and otter shrews; 30 species in 10 genera
Suborder Chrysochloridea
Family Chrysochloridae: golden moles; about 21 species in 9 genera
Order Macroscelidea: elephant shrews
Order Tubulidentata: Aardvark
- Order Afrosoricida
Suborder Tenrecomorpha
Family Tenrecidae: tenrecs and otter shrews; 30 species in 10 genera
Suborder Chrysochloridea
Family Chrysochloridae: golden moles; about 21 species in 9 genera
- Suborder Tenrecomorpha
Family Tenrecidae: tenrecs and otter shrews; 30 species in 10 genera
- Family Tenrecidae: tenrecs and otter shrews; 30 species in 10 genera
- Suborder Chrysochloridea
Family Chrysochloridae: golden moles; about 21 species in 9 genera
- Family Chrysochloridae: golden moles; about 21 species in 9 genera
- Order Macroscelidea: elephant shrews
- Order Tubulidentata: Aardvark
- Clade Paenungulata
Order Hyracoidea: hyraxes
Order Proboscidea: elephants
Order Sirenia: manatees and dugongs
- Order Hyracoidea: hyraxes
- Order Proboscidea: elephants
- Order Sirenia: manatees and dugongs
- (Other superorders, not listed here)
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https://www.wikidoc.org/index.php/Afrosoricida
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f523002e49222cf1dfdd5cb74de587c1ea7b94da
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wikidoc
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Agent Orange
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Agent Orange
Agent Orange and "Super Orange" were the nicknames given to a herbicide and defoliant used by the United States Armed Forces in its Herbicidal Warfare program during the Vietnam War.
Agent Orange was used from 1961 to 1971 and was by far the most used of the so-called "Rainbow Herbicides" utilized during the program. Degradation of Agent Orange (as well as Agents Purple, Pink, and Green) released dioxins, which have caused health problems for those exposed during the Vietnam War. Agents Blue and White were part of the same program but did not contain dioxins.
Studies of populations highly exposed to dioxin, though not necessarily Agent Orange, indicate increased risk of various types of cancer and genetic defects; the effect of long-term low-level exposure has not been established.
Since the 1980s, several lawsuits have been filed against the companies who produced Agent Orange, among them Dow Chemical, Monsanto and Diamond Shamrock (which produced 5%). U.S. veterans obtained a $180 million settlement in 1984, with most affected veterans receiving a one-time lump sum payment of $1,200. American veterans of the Vietnam War were seeking recognition of Agent Orange, compensation and treatment for maladies that they and their children suffered from; many exposed to Agent Orange have not been able to receive promised medical care through the Veterans Administration medical system, and only with rare exception have their affected children received healthcare assistance from the government. Vietnam veterans and their families who brought the original Agent Orange lawsuit stated 25 years ago that the government "is just waiting for us all to die". They alleged that most of those still alive will succumb to the effects of toxic exposure over the next several years, before age 65. Elsewhere, Australian, Canadian and New Zealand veterans obtained compensation in settlements that same year. In 1999, South Korean veterans filed a lawsuit in Korea; in January 2006, the Korean Appeal Court ordered Monsanto and Dow to pay US$62 million in compensation. However, no Vietnamese have received compensation, and on March 10, 2005 Judge Jack Weinstein of Brooklyn Federal Court dismissed the lawsuit filed by the Vietnamese victims of Agent Orange against the chemical companies that produced the defoliants/herbicides.
# Description
Agent Orange, given its name from the 55 U.S. gallon orange-striped barrels it was shipped in, is a roughly 1:1 mixture of two phenoxy herbicides in ester form, 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). These herbicides were developed during the 1940s by independent teams in England and the United States for use in controlling broad-leaf plants. Phenoxy agents work by mimicking a plant growth hormone, indoleacetic acid (IAA). When sprayed on broad-leaf plants they induce rapid, uncontrolled growth, eventually defoliating them. When sprayed on crops such as wheat or corn, it selectively kills just the broad-leaf plants in the field - the weeds - leaving the crop relatively unaffected. First introduced in 1946, these herbicides were in widespread use in agriculture by the middle of the 1950s and were first introduced in the agricultural farms of Aguadilla, Puerto Rico.
At the time Agent Orange was sold to the U.S. government for use in Vietnam, internal memos of its manufacturers reveal it was known that a dioxin, 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD), is produced as a byproduct of the manufacture of 2,4,5-T, and was thus present in any of the herbicides that used it. The National Toxicology Program has classified TCDD to be a human carcinogen, frequently associated with soft-tissue sarcoma, Non-Hodgkin's lymphoma, Hodgkin's disease and chronic lymphocytic leukemia (CLL). A link to dioxin exposure has been found to diabetes, in a study by the Institute of Medicine. Diseases with limited evidence of an association with Agent Orange are respiratory cancers, prostate cancer, multiple myeloma, Porphyria cutanea tarda (a type of skin disease), acute and subacute transient peripheral neuropathy, spina bifida, Type 2 diabetes, and acute myelogenous leukemia found only in the second or third generation. 2,4,5-T has since been banned for use in the U.S. and many other countries.
Although the herbicide 2,4-D does not contain dioxin, its impact on health and environment has not been thoroughly studied, and it remains one of the most-used herbicides in the world today.
# Use outside of Vietnam
In September 2000, the Veteran Administration (VA) recognized that Agent Orange was used in Korea in the late 1960s. Republic of Korea troops are reported to have done the spraying, which occurred along the demilitarized zone with North Korea. The VA has also acknowledged that Agent Orange was used domestically by U.S. forces .
## Canadian Forces Base Gagetown, New Brunswick, Canada
The U.S. military, with the permission of the Canadian government, secretly tested many unregistered U.S. military herbicides, including Agent Orange, in the forests near the Canadian Forces Base Gagetown in New Brunswick in 1966 and 1967. On September 12, 2007, Greg Thompson, Minister of Veterans Affairs, announced that the government of Canada is offering a one-time ex gratia payment of $20,000 as the compensation package for Agent Orange exposure at CFB Gagetown.
## Globe, Arizona
Billee Shoecraft died in 1977 of cancer. She began suffering from cancer after a helicopter sprayed her with the defoliant Kuron. Before her death, Shoecraft wrote a book about her experience in which she said that after she was sprayed her eyes were nearly swollen shut, her arms and legs were swollen twice normal size and her hair was coming out in patches. Kuron, an herbicide related to Agent Orange, was sprayed by the U.S. Forest Service to thin foliage and increase water runoff in the Pinal Mountains of the Tonto National Forest near Globe, Arizona, in 1968 and 1969. Dow Chemical Company and the U.S.Forest Service paid an undisclosed sum to five families. Shoecraft wrote a book entitled, Sue the Bastards!, about her incident in 1971.
# Effects of the program
## New Jersey Agent Orange Commission
In 1980, New Jersey created the New Jersey Agent Orange Commission, the first state commission created to study its effects. The commission's research project in association with Rutgers University was called "The Pointman Project". It was disbanded by Governor Christine Todd Whitman in 1996.
During Pointman I, commission researchers devised ways to determine small dioxin levels in blood. Prior to this, such levels could only be found in the adipose (fat) tissue. The project compared dioxin levels in a small group of Vietnam veterans who had been exposed to Agent Orange with a group of matched veterans who had not served in Vietnam. The results of this project were published in the Journal of the American Medical Association in 1988.
The second phase of the project continued to examine and compare dioxin levels in various groups of Vietnam veterans including Army, Marines and brown water riverboat Navy personnel.
# Lawsuits
In 1984, Agent Orange manufacturers paid Australian, Canadian and New Zealand veterans in an out-of-court settlement.
## U.S. Vietnamese victims class action lawsuit
On January 31, 2004, a victim's rights group, the Vietnam Association for Victims of Agent Orange/Dioxin (VAVA), filed a lawsuit in a US Federal District Court in Brooklyn, New York, against several U.S. companies for liability in causing personal injury, by developing and producing the chemical. Dow Chemical and Monsanto were the two largest producers of Agent Orange for the U.S. military and were named in the suit along with the dozens of other companies (Diamond Shamrock, Uniroyal, Thompson Chemicals, Hercules, etc.). A number of lawsuits by American GIs were settled out of court - without admission of liability by the chemical companies - in the years since the Vietnam War. In 1984, some chemical companies that manufactured Agent Orange paid $180 million into a fund for United States veterans following a lawsuit.
On March 10, 2005, District Court Judge Jack Weinstein - who had defended the U.S. veterans victims of Agent Orange - dismissed the suit, ruling that there was no legal basis for the plaintiffs' claims. The judge concluded that Agent Orange was not considered a poison under international law at the time of its use by the U.S.; that the U.S. was not prohibited from using it as a herbicide; and that the companies which produced the substance were not liable for the method of its use by the government. The U.S. government is not a party in the lawsuit, claiming sovereign immunity.
In order to assist those who have been impacted by Agent Orange/Dioxin, the Vietnamese have established "Peace villages", which each host between 50 to 100 victims, giving them medical and psychological help. As of 2006, there were 11 such villages, thus granting some social protection to fewer than a thousand victims. U.S. veterans of the war in Vietnam and individuals who are aware and sympathetic to the impacts of Agent Orange have also supported these programs in Vietnam. An international group of Veterans from the U.S. and its allies during the Vietnam war working together with their former enemy - veterans from the Vietnam Veterans Association - established the Vietnam Friendship Village located outside of Hanoi. The center provides medical care, rehabilitation and vocational training for children and veterans from Vietnam who have been impacted by Agent Orange.
The U.S. Department of Veterans Affairs has listed prostate cancer, respiratory cancers, multiple myeloma, type II diabetes, Hodgkin’s disease, non-Hodgkin’s lymphoma, soft tissue sarcoma, chloracne, porphyria cutanea tarda, peripheral neuropathy, and spina bifida in children of veterans exposed to Agent Orange as side effects of the herbicide.
## South Korean lawsuit
In 1999, about 20,000 South Koreans filed two separated lawsuits against U.S. companies, seeking more than $5 billion in damages. After losing a decision in 2002, they filed an appeal.
In January 2006, the South Korean Appeals Court ordered Dow Chemical and Monsanto to pay $62 million in compensation to about 6,800 people. The ruling acknowledged that "the defendants failed to ensure safety as the defoliants manufactured by the defendants had higher levels of dioxins than standard", and, quoting the U. S. National Academy of Science report, declared that there was a "causal relationship" between Agent Orange and 11 diseases, including cancers of the lung, larynx and prostate. However, the judges failed to acknowledge "the relationship between the chemical and peripheral neuropathy, the disease most widespread among Agent Orange victims" according to the Mercury News.
## Canada lawsuit
In July 12, 2005, Merchant Law Group LLP on behalf of over 1,100 Canada veterans and civilians who were living in and around the CFB Gagetown filled a lawsuit to pursue Class Action Litigation concerning Agent Orange and Agent Purple to the Court of Queen's Bench of Manitoba. Until September 30, 2007, the case is still going.
# Miscellaneous
- The Union Carbide company produced the constituents of Agent Orange at Homebush Bay in Sydney, Australia, where the 2000 Summer Olympics were staged.
- The Uniroyal plant in Elmira, Ontario was one of seven suppliers producing Agent Orange for the U. S. military's use in Vietnam.
- An international committee in support of Vietnamese victims of Agent Orange, has published a report on the impact of Agent Orange in Vietnam.
- A Canadian company that researched Agent Orange contamination on behalf of the Vietnamese government has expressed 'shock' that in some areas of Vietnam, dioxin contamination is 300 to 400 times higher than the standard accepted levels.
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Agent Orange
Agent Orange and "Super Orange" were the nicknames given to a herbicide and defoliant used by the United States Armed Forces in its Herbicidal Warfare program during the Vietnam War.
Agent Orange was used from 1961 to 1971 and was by far the most used of the so-called "Rainbow Herbicides" utilized during the program. Degradation of Agent Orange (as well as Agents Purple, Pink, and Green) released dioxins, which have caused health problems for those exposed during the Vietnam War. Agents Blue and White were part of the same program but did not contain dioxins.
Studies of populations highly exposed to dioxin, though not necessarily Agent Orange, indicate increased risk of various types of cancer and genetic defects; the effect of long-term low-level exposure has not been established.
Since the 1980s, several lawsuits have been filed against the companies who produced Agent Orange, among them Dow Chemical, Monsanto and Diamond Shamrock (which produced 5%[1]). U.S. veterans obtained a $180 million settlement in 1984, with most affected veterans receiving a one-time lump sum payment of $1,200. American veterans of the Vietnam War were seeking recognition of Agent Orange, compensation and treatment for maladies that they and their children suffered from; many exposed to Agent Orange have not been able to receive promised medical care through the Veterans Administration medical system, and only with rare exception have their affected children received healthcare assistance from the government. Vietnam veterans and their families who brought the original Agent Orange lawsuit stated 25 years ago that the government "is just waiting for us all to die". They alleged that most of those still alive will succumb to the effects of toxic exposure over the next several years, before age 65. Elsewhere, Australian, Canadian and New Zealand veterans obtained compensation in settlements that same year. In 1999, South Korean veterans filed a lawsuit in Korea; in January 2006, the Korean Appeal Court ordered Monsanto and Dow to pay US$62 million in compensation. However, no Vietnamese have received compensation, and on March 10, 2005 Judge Jack Weinstein of Brooklyn Federal Court dismissed the lawsuit filed by the Vietnamese victims of Agent Orange against the chemical companies that produced the defoliants/herbicides.
# Description
Agent Orange, given its name from the 55 U.S. gallon orange-striped barrels it was shipped in, is a roughly 1:1 mixture of two phenoxy herbicides in ester form, 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). These herbicides were developed during the 1940s by independent teams in England and the United States for use in controlling broad-leaf plants. Phenoxy agents work by mimicking a plant growth hormone, indoleacetic acid (IAA). When sprayed on broad-leaf plants they induce rapid, uncontrolled growth, eventually defoliating them. When sprayed on crops such as wheat or corn, it selectively kills just the broad-leaf plants in the field - the weeds - leaving the crop relatively unaffected. First introduced in 1946, these herbicides were in widespread use in agriculture by the middle of the 1950s and were first introduced in the agricultural farms of Aguadilla, Puerto Rico.
At the time Agent Orange was sold to the U.S. government for use in Vietnam, internal memos of its manufacturers reveal it was known that a dioxin, 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD), is produced as a byproduct of the manufacture of 2,4,5-T, and was thus present in any of the herbicides that used it. The National Toxicology Program has classified TCDD to be a human carcinogen, frequently associated with soft-tissue sarcoma, Non-Hodgkin's lymphoma, Hodgkin's disease and chronic lymphocytic leukemia (CLL). A link to dioxin exposure has been found to diabetes, in a study by the Institute of Medicine.[2] Diseases with limited evidence of an association with Agent Orange are respiratory cancers, prostate cancer, multiple myeloma, Porphyria cutanea tarda (a type of skin disease), acute and subacute transient peripheral neuropathy, spina bifida, Type 2 diabetes, and acute myelogenous leukemia found only in the second or third generation.[citation needed] 2,4,5-T has since been banned for use in the U.S. and many other countries.
Although the herbicide 2,4-D does not contain dioxin, its impact on health and environment has not been thoroughly studied, and it remains one of the most-used herbicides in the world today.
# Use outside of Vietnam
In September 2000, the Veteran Administration (VA) recognized that Agent Orange was used in Korea in the late 1960s. [1] Republic of Korea troops are reported to have done the spraying, which occurred along the demilitarized zone with North Korea. The VA has also acknowledged that Agent Orange was used domestically by U.S. forces [2].
## Canadian Forces Base Gagetown, New Brunswick, Canada
The U.S. military, with the permission of the Canadian government, secretly tested many unregistered U.S. military herbicides, including Agent Orange, in the forests near the Canadian Forces Base Gagetown in New Brunswick in 1966 and 1967. On September 12, 2007, Greg Thompson, Minister of Veterans Affairs, announced that the government of Canada is offering a one-time ex gratia payment of $20,000 as the compensation package for Agent Orange exposure at CFB Gagetown.[3]
## Globe, Arizona
Billee Shoecraft died in 1977 of cancer. She began suffering from cancer after a helicopter sprayed her with the defoliant Kuron. Before her death, Shoecraft wrote a book about her experience in which she said that after she was sprayed her eyes were nearly swollen shut, her arms and legs were swollen twice normal size and her hair was coming out in patches. Kuron, an herbicide related to Agent Orange, was sprayed by the U.S. Forest Service to thin foliage and increase water runoff in the Pinal Mountains of the Tonto National Forest near Globe, Arizona, in 1968 and 1969. Dow Chemical Company and the U.S.Forest Service paid an undisclosed sum to five families. Shoecraft wrote a book entitled, Sue the Bastards!, about her incident in 1971.
# Effects of the program
## New Jersey Agent Orange Commission
In 1980, New Jersey created the New Jersey Agent Orange Commission, the first state commission created to study its effects. The commission's research project in association with Rutgers University was called "The Pointman Project". It was disbanded by Governor Christine Todd Whitman in 1996.[4]
During Pointman I, commission researchers devised ways to determine small dioxin levels in blood. Prior to this, such levels could only be found in the adipose (fat) tissue. The project compared dioxin levels in a small group of Vietnam veterans who had been exposed to Agent Orange with a group of matched veterans who had not served in Vietnam. The results of this project were published in the Journal of the American Medical Association in 1988.[5]
The second phase of the project continued to examine and compare dioxin levels in various groups of Vietnam veterans including Army, Marines and brown water riverboat Navy personnel.
# Lawsuits
In 1984, Agent Orange manufacturers paid Australian, Canadian and New Zealand veterans in an out-of-court settlement.[6]
## U.S. Vietnamese victims class action lawsuit
On January 31, 2004, a victim's rights group, the Vietnam Association for Victims of Agent Orange/Dioxin (VAVA), filed a lawsuit in a US Federal District Court in Brooklyn, New York, against several U.S. companies for liability in causing personal injury, by developing and producing the chemical. Dow Chemical and Monsanto were the two largest producers of Agent Orange for the U.S. military and were named in the suit along with the dozens of other companies (Diamond Shamrock, Uniroyal, Thompson Chemicals, Hercules, etc.). A number of lawsuits by American GIs were settled out of court - without admission of liability by the chemical companies - in the years since the Vietnam War. In 1984, some chemical companies that manufactured Agent Orange paid $180 million into a fund for United States veterans following a lawsuit.
On March 10, 2005, District Court Judge Jack Weinstein - who had defended the U.S. veterans victims of Agent Orange - dismissed the suit, ruling that there was no legal basis for the plaintiffs' claims. The judge concluded that Agent Orange was not considered a poison under international law at the time of its use by the U.S.; that the U.S. was not prohibited from using it as a herbicide; and that the companies which produced the substance were not liable for the method of its use by the government. The U.S. government is not a party in the lawsuit, claiming sovereign immunity.
In order to assist those who have been impacted by Agent Orange/Dioxin, the Vietnamese have established "Peace villages", which each host between 50 to 100 victims, giving them medical and psychological help. As of 2006, there were 11 such villages, thus granting some social protection to fewer than a thousand victims. U.S. veterans of the war in Vietnam and individuals who are aware and sympathetic to the impacts of Agent Orange have also supported these programs in Vietnam. An international group of Veterans from the U.S. and its allies during the Vietnam war working together with their former enemy - veterans from the Vietnam Veterans Association - established the Vietnam Friendship Village[3] located outside of Hanoi. The center provides medical care, rehabilitation and vocational training for children and veterans from Vietnam who have been impacted by Agent Orange.
The U.S. Department of Veterans Affairs has listed prostate cancer, respiratory cancers, multiple myeloma, type II diabetes, Hodgkin’s disease, non-Hodgkin’s lymphoma, soft tissue sarcoma, chloracne, porphyria cutanea tarda, peripheral neuropathy, and spina bifida in children of veterans exposed to Agent Orange as side effects of the herbicide.
## South Korean lawsuit
In 1999, about 20,000 South Koreans filed two separated lawsuits against U.S. companies, seeking more than $5 billion in damages. After losing a decision in 2002, they filed an appeal.
In January 2006, the South Korean Appeals Court ordered Dow Chemical and Monsanto to pay $62 million in compensation to about 6,800 people. The ruling acknowledged that "the defendants failed to ensure safety as the defoliants manufactured by the defendants had higher levels of dioxins than standard", and, quoting the U. S. National Academy of Science report, declared that there was a "causal relationship" between Agent Orange and 11 diseases, including cancers of the lung, larynx and prostate. However, the judges failed to acknowledge "the relationship between the chemical and peripheral neuropathy, the disease most widespread among Agent Orange victims" according to the Mercury News.
## Canada lawsuit
In July 12, 2005, Merchant Law Group LLP on behalf of over 1,100 Canada veterans and civilians who were living in and around the CFB Gagetown filled a lawsuit to pursue Class Action Litigation concerning Agent Orange and Agent Purple to the Court of Queen's Bench of Manitoba. Until September 30, 2007, the case is still going.[7]
# Miscellaneous
- The Union Carbide company produced the constituents of Agent Orange at Homebush Bay in Sydney, Australia, where the 2000 Summer Olympics were staged.[4]
- The Uniroyal plant in Elmira, Ontario was one of seven suppliers producing Agent Orange for the U. S. military's use in Vietnam.
- An international committee[8] in support of Vietnamese victims of Agent Orange, has published a report on the impact of Agent Orange in Vietnam.[9][10]
- A Canadian company that researched Agent Orange contamination on behalf of the Vietnamese government has expressed 'shock' that in some areas of Vietnam, dioxin contamination is 300 to 400 times higher than the standard accepted levels.[11]
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https://www.wikidoc.org/index.php/Agent_Orange
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c63b6bdf04eaca23ab088572a4fca9264e62c68a
|
wikidoc
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Agranulocyte
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Agranulocyte
Agranulocytes are a category of white blood cells characterised by the absence of granules in their cytoplasm.
There are two types of agranulocytes:
- Lymphocytes
- Monocytes.
Lymphocytes are much more common in the lymphatic system, and include the so-called "natural killer T-cells". The blood has three types of lymphocytes: B cells, T cells and natural killer cells. B cells make antibodies that bind to pathogens to enable their destruction. CD4+ (helper) T cells co-ordinate the immune response (they are what becomes defective in an HIV infection). CD8+ (cytotoxic) T cells and natural killer cells are able to kill cells of the body that are infected by a virus. T cells are crucial to the immune response because they possess a unique 'memory' system which allows them to remember past invaders and prevent disease when a similar invader is encountered again.
Monocytes share the "vacuum cleaner" (phagocytosis) function of neutrophils, but are much longer lived as they have an additional role: they present pieces of pathogens to T cells so that the pathogens may be recognized again and killed, or so that an antibody response may be mounted. Monocytes are also known as macrophages after they migrate from the bloodstream and enter tissue.
Other white blood cells which are not agranulocytes are mainly the granulocytes neutrophils, eosinophils and basophils.
# Additional images
- Blood cell lineage
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Agranulocyte
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Agranulocytes are a category of white blood cells characterised by the absence of granules in their cytoplasm.
There are two types of agranulocytes:
- Lymphocytes
- Monocytes.
Lymphocytes are much more common in the lymphatic system, and include the so-called "natural killer T-cells". The blood has three types of lymphocytes: B cells, T cells and natural killer cells. B cells make antibodies that bind to pathogens to enable their destruction. CD4+ (helper) T cells co-ordinate the immune response (they are what becomes defective in an HIV infection). CD8+ (cytotoxic) T cells and natural killer cells are able to kill cells of the body that are infected by a virus. T cells are crucial to the immune response because they possess a unique 'memory' system which allows them to remember past invaders and prevent disease when a similar invader is encountered again.
Monocytes share the "vacuum cleaner" (phagocytosis) function of neutrophils, but are much longer lived as they have an additional role: they present pieces of pathogens to T cells so that the pathogens may be recognized again and killed, or so that an antibody response may be mounted. Monocytes are also known as macrophages after they migrate from the bloodstream and enter tissue.
Other white blood cells which are not agranulocytes are mainly the granulocytes neutrophils, eosinophils and basophils.
# Additional images
- Blood cell lineage
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https://www.wikidoc.org/index.php/Agranulocyte
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37f9be3b0afbb42126a9ec1c4b9c715134db2531
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wikidoc
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Air trapping
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Air trapping
# Overview
Air trapping (or gas trapping) is an abnormal retention of air in the lungs after expiration. It is observed in obstructive lung diseases such as asthma, and chronic obstructive pulmonary disease. The cause is obstruction such that the patient is unable to expel air completely.
Air trapping is a cause of obstructive pattern spirometry results, leading to an elevated residual volume. Air trapping is often incidentally diagnosed on computed tomography (CT) scanning. The only way to absolutely differentiate air trapping from emphysema is by taking expiratory images. On expiratory films, retained hyperlucent gas will be visualised in cases of air trapping.
Air trapping represents poorly aerated lung, but on its own is clinically benign. It is is a common problem for smokers who dive. On diving the lung volume collapses and pushes air into the poorly aerated regions. On arising from a deep depth, these air-trapped areas of lung expand. This places great pressure on the lung tissue which can rupture.
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Air trapping
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Air trapping (or gas trapping) is an abnormal retention of air in the lungs after expiration. It is observed in obstructive lung diseases such as asthma, and chronic obstructive pulmonary disease. The cause is obstruction such that the patient is unable to expel air completely.
Air trapping is a cause of obstructive pattern spirometry results, leading to an elevated residual volume. Air trapping is often incidentally diagnosed on computed tomography (CT) scanning. The only way to absolutely differentiate air trapping from emphysema is by taking expiratory images. On expiratory films, retained hyperlucent gas will be visualised in cases of air trapping.
Air trapping represents poorly aerated lung, but on its own is clinically benign. It is is a common problem for smokers who dive. On diving the lung volume collapses and pushes air into the poorly aerated regions. On arising from a deep depth, these air-trapped areas of lung expand. This places great pressure on the lung tissue which can rupture.
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https://www.wikidoc.org/index.php/Air_trapping
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1749e94e7261af51500925e464b61de078a34dd6
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wikidoc
|
Akira Makino
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Akira Makino
# Early life
Makino was born in 1922, in a small town in Osaka Prefecture. At the start of World War II, he was assigned to the navy's No. 33 patrol. In August of 1944, at the age of 22, he was transferred to an air base in Zamboanga on Mindanao Island, in the Philippines.
# Human Experiments
According to Makino, experimentation on about 30 prisoners was carried out between December 1944 and February 1945. The prisoners included women and children, as well as two Filipino men suspected of spying for the United States. On these prisoners, Makino performed operations including amputations, abdominal dissections and other experiments. In his interview with the Kyodo News Agency, he described, in particular, his experience with the two Filipino men suspected of spying. He said he had sedated the men by placing ether-soaked cloth over their mouths, and then was instructed to study their livers after making an incision with a surgical knife. Makino stated that, at the time, he thought it was a "horrible" thing that he was doing, but that he was too scared to refuse orders because he would have been killed for disobeying.
# Revelation
After remaining silent for decades, Makino decided to reveal everything to the public in 2006. It is believed that Makino's account is the first of its kind from a Japanese veteran concerning human experimentation in Southeast Asia during World War II. Initially he faced severe opposition from his wartime friends, but he decided to come forward with anyway. In his controversial revelation, Makino said, "We should not repeat such miseries again. I want to tell the truth about the war, even if it is to only one person or two."
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Akira Makino
Template:Nihongo was a former medic in the Imperial Japanese Navy who, in 2006, became the first Japanese ex-soldier to admit to the experiments conducted on human beings in the Philippines during World War II.
# Early life
Makino was born in 1922, in a small town in Osaka Prefecture. At the start of World War II, he was assigned to the navy's No. 33 patrol. In August of 1944, at the age of 22, he was transferred to an air base in Zamboanga on Mindanao Island, in the Philippines.
# Human Experiments
According to Makino, experimentation on about 30 prisoners was carried out between December 1944 and February 1945. The prisoners included women and children, as well as two Filipino men suspected of spying for the United States.[1] On these prisoners, Makino performed operations including amputations, abdominal dissections and other experiments. In his interview with the Kyodo News Agency, he described, in particular, his experience with the two Filipino men suspected of spying. He said he had sedated the men by placing ether-soaked cloth over their mouths, and then was instructed to study their livers after making an incision with a surgical knife.[2] Makino stated that, at the time, he thought it was a "horrible" thing that he was doing, but that he was too scared to refuse orders because he would have been killed for disobeying.[2]
# Revelation
After remaining silent for decades, Makino decided to reveal everything to the public in 2006. It is believed that Makino's account is the first of its kind from a Japanese veteran concerning human experimentation in Southeast Asia during World War II.[1] Initially he faced severe opposition from his wartime friends, but he decided to come forward with anyway. In his controversial revelation, Makino said, "We should not repeat such miseries again. I want to tell the truth about the war, even if it is to only one person or two."[1]
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https://www.wikidoc.org/index.php/Akira_Makino
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